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Mappings

ICD-10-CM

ICD10CM:M85.1 Skeletal fluorosis

MONDO records `ICD10CM:M85.1` as a `skos:exactMatch` of MONDO:0400003, and the two carry the same label.

ICD-11 Foundation

icd11f:1269698463 Skeletal fluorosis

MONDO records `icd11f:1269698463` as a `skos:exactMatch` of MONDO:0400003, and the two carry the same label.

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Discussions and Knowledge Gaps

5

Does defective collagen synthesis drive the accelerated bone turnover of skeletal fluorosis, or do the two simply co-occur under fluoride?

KNOWLEDGE GAP sf_collagen_turnover_link

Attached to

pathophysiology#Impaired Collagen Synthesis and Matrix Mineralization pathophysiology#Accelerated and Disordered Bone Turnover

The edge from `Impaired Collagen Synthesis and Matrix Mineralization` to `Accelerated and Disordered Bone Turnover` is curated `causal_link_type: DIRECT`, and nothing in this entry's reference set supports that grade. The only sentence naming both quantities is PMID:3295994's - "Increased metabolic turnover of the bone, impaired bone collagen synthesis and increased avidity for calcium are features in fluoride toxicity" - which lists them as features of the toxicity rather than deriving one from the other. Both are separately well evidenced as consequences of fluoride, so a shared upstream cause explains the co-occurrence without the edge. Two resolutions: find a source asserting the step, or weaken the link to INDIRECT_UNKNOWN_INTERMEDIATES, which is what the three edges out of `Fluorapatite Substitution in Bone Mineral` already carry for the same reason. Not changed here because it is a curation call rather than a defect in the evidence.

Does fluoride stimulate or suppress osteoblasts in skeletal fluorosis?

INTERPRETATION sf_osteoblast_dose_response

Attached to

pathophysiology#Osteoblast Proliferation and Activation pathophysiology#Impaired Collagen Synthesis and Matrix Mineralization

Both, in the curated evidence, and this entry does not choose. Stated in one unit so the comparison is visible: at 0.2 mM fluoride - about 3.8 mg/L of fluoride ion - proliferation of osteoblast-like human Saos-2 cells rose dose-dependently, with osteocalcin and bone alkaline phosphatase raised through BMP/Smad. At 2.26 mg/L, proliferation of mouse osteoblasts *fell* dose-dependently, with TGF-beta1 and autophagy markers rising. So the stimulatory result is at the *higher* dose, not the lower one, which is the opposite of the low-stimulates/high-suppresses pattern "biphasic" would imply - the word is therefore not used here. What separates the two results in the curated evidence is the cell system, human osteosarcoma line against mouse primary osteoblasts, and nothing curated here tests either dose in the other system. The `Osteoblast Proliferation and Activation` node is named for the stimulatory reading because that is what the field's reviews describe as driving progression, and the suppressive result is curated on the same node as a REFUTE rather than omitted.

Show evidence (2 references)

PMID:23918166 SUPPORT In Vitro

"We found that fluoride enhanced the proliferation of Saos-2 cells in a dose-dependent manner and 0.2 mM of fluoride resulted in a higher expression of osteoblast marker genes."

The stimulatory reading, with its dose.

PMID:29505816 REFUTE In Vitro

"Our results demonstrated that sodium fluoride (NaF) (2.26 mg/L F-) exposure lead to a significant decrease in proliferation rate of mouse osteoblast cells in a dose-dependent manner with a concomitant increase in the expression levels of TGF-β1 and autophagic markers."

The suppressive reading, with its dose. Graded REFUTE against the stimulatory claim.

Is oxidative stress part of the pathogenesis of skeletal fluorosis, or not?

CONTROVERSY sf_oxidative_stress

Attached to

pathophysiology#Osteoblast Proliferation and Activation pathophysiology#Accelerated and Disordered Bone Turnover

Two published positions, stated at their strongest on both sides. For: the 2021 mechanism review calls oxidative stress "an essential mechanism in the pathogenesis of fluorosis" - not a hedge, and not merely a listing among pathways under study - and reports raised malondialdehyde in the fluoride-exposed group, with oxidative stress correlating positively with calcineurin activity. Against: a study measuring the antioxidant defence system directly, in patients from a 5 ppm endemic area and in rabbits given 150 ppm for six months, found no difference from controls in lipid peroxidation, glutathione, vitamin C, catalase, superoxide dismutase, glutathione peroxidase or glutathione S-transferase, and concluded against the theory. The two are less opposed than they look, and the reason matters: the negative study measured *blood*, and the review's positive finding is in *bone tissue*. A null result in erythrocytes does not settle what is happening in the osteocyte, so this entry does not read the negative as a refutation of the mechanism. What it does do is leave the mechanism unlocated: no source curated here measures oxidative stress in human fluorotic bone. That is why there is still no oxidative-stress node - the mechanism has no curated human tissue-level measurement to hang one on - rather than because the negative won. Both positions are curated so the next curator can see which measurement would settle it.

Show evidence (5 references)

PMID:34769367 SUPPORT Other

"Oxidative stress is considered to be an essential mechanism in the pathogenesis of fluorosis."

The strongest statement of the positive position in any source curated here, and the review's own assessment rather than a listing of what is studied.

PMID:34769367 SUPPORT Other

"However, malondialdehyde (MDA) levels of the fluoride-infected group were significantly higher than the control group, and oxidative stress levels were also positively correlated with CaN activity"

A measurement behind that assessment rather than the assessment itself - raised malondialdehyde, correlating with calcineurin activity. Graded OTHER because the review reports it secondhand from the primary studies it cites.

PMID:32207100 SUPPORT INDIRECT Other

"The review focuses on recent findings related to skeletal fluorosis and role of oxidative stress in its development."

Graded INDIRECT: a second review's framing of its own scope, which reports the field's attention rather than a finding.

+ 2 more references

Is TGF-beta signalling up or down in fluoride-exposed bone?

INTERPRETATION sf_tgf_beta_direction

Attached to

pathophysiology#Osteoblast Proliferation and Activation pathophysiology#Histone-Mediated Repression of TGF-beta Receptor Signalling

The curated evidence points both ways and the entry models both. On one side, TGF-beta1 is raised in a fluoride-exposed human population and NaF activates a TGF-beta1/Smad2/3/CyclinD1 axis driving osteoblast proliferation. On the other, fluoride raises H3K9 trimethylation at the TGFBR2 and SMAD3 promoters and expression of both, and of COL1A1, falls. These are compatible if the ligand and the receptor arm move independently, or if the two cell systems and doses differ enough - but nothing curated here demonstrates either reconciliation, so the entry carries the proliferative arm and the repressive arm as separate nodes reaching different consequences, and says so rather than picking one.

Show evidence (2 references)

PMID:34080770 SUPPORT Human Clinical

"in the fluoride-challenged population, we observed that miR-486-3p expression decreased while CyclinD1 and transforming growth factor (TGF)-β1 increased"

TGF-beta1 raised in the exposed population, alongside CyclinD1.

PMID:29275289 REFUTE In Vitro

"Expression of two other vital genes COL1A1 and MMP13 involved in TGFBR2-SMAD signaling pathway was also found to be down-regulated with a decrease in expression of TGFBR2 and SMAD3."

Graded REFUTE against a uniformly up-regulated reading: the receptor and SMAD3 are epigenetically repressed, and COL1A1 falls with them.

Are the neurological complications of skeletal fluorosis compressive, or is fluoride directly neurotoxic?

INTERPRETATION sf_neuro_mechanism

Attached to

pathophysiology#Spinal Canal and Foraminal Narrowing pathophysiology#Compressive Myelopathy and Radiculopathy

Compressive, on the evidence curated here, and the distinction is not academic - it is why decompression is offered at all and why the neurological chain in this entry runs through bone rather than through nerve. The Ethiopian surveys traced the deficits to sclerosis and osteophytosis narrowing the canal and foramina, and the Indian review states that the complications are mechanical and that evidence for direct fluoride neurotoxicity is lacking. Recorded as an INTERPRETATION rather than settled because "evidence is lacking" is a statement about a literature at a date, not a demonstration of absence, and fluoride neurotoxicity is actively studied in other organs. A muscle-biopsy series adds a third line from the periphery - the wasting in established disease is neurogenic, with no primary myopathy - which rules out a different alternative than the one this discussion turns on, but points the same way.

Show evidence (4 references)

PMID:19305069 SUPPORT Other

"Neurological complications of endemic skeletal fluorosis, namely radiculopathy, myelopathy or both are mechanical in nature and till date the evidence for direct neurotoxicity of fluoride is lacking."

The statement this discussion turns on.

PMID:2172892 SUPPORT Human Clinical

"These deficits were clearly found to be a consequence of fluoride deposition in bones, resulting in generalised sclerosis and osteophytosis, with reduction in the diameter of the intervertebral foramina and of the spinal conal."

The anatomical route, traced in a decade of field surveys.

PMID:10878791 SUPPORT Human Clinical

"It may be concluded that the primary changes are related to the nerve, with muscle being affected secondarily."

An independent line to the same conclusion, from the other end: muscle biopsies in established disease show the muscle is affected through the nerve, not directly.

+ 1 more reference

⚙

Pathophysiology

16

Chronic Excess Fluoride Intake

The initiating exposure: fluoride taken in above the skeleton's tolerance for years to decades, by ingestion of groundwater, brick tea or coal-contaminated food, or by inhalation. The total quantity ingested, rather than the route, is what the older clinical literature identifies as the single determinant of how the disease runs.

Downstream

Skeletal Fluoride Accumulation

Gut Microbial Tryptophan Metabolism Disruption The one arm of this chain that does not run through the skeleton: the cited work reports fluoride disrupting gut microbial tryptophan metabolism in both model rats and human patients, without locating that step relative to absorption.

Show evidence (2 references)

PMID:3295994 SUPPORT Other

"The total quantity of ingested fluoride is the single most important factor which determines the clinical course of the disease which is characterized by immobilization of joints of the axial skeleton and of the major joints of the extremities."

Names dose as the determinant of clinical course, and names the outcome the chain below ends at. Graded OTHER: a review's synthesis rather than one study's measurement.

PMID:34769367 SUPPORT Other

"High concentrations of fluoride in the environment and drinking water are major causes"

The dominant exposure route, from the current mechanistic review.

Skeletal Fluoride Accumulation

Fluoride leaving the circulation is fixed in calcified tissue, so the skeleton is both the store and the target. This is what makes the disease cumulative rather than dose-rate dependent, and it is why the neurological complications downstream are a consequence of bone rather than of nerve.

bone tissue UBERON:0002481

Animal models

NaF-exposed Swiss albino mouse Mouse recapitulates Produces skeletal fluorosis with measurable fluoride deposition and an altered bone metal profile at a dose ten times the human permissible limit.

Inbred mouse strain panel for fluoride bone susceptibility Mouse recapitulates Bone fluoride rose with dose in femora and vertebral bodies in every strain, which is this node with a dose-response attached.

Downstream

Fluorapatite Substitution in Bone Mineral

Histone-Mediated Repression of TGF-beta Receptor Signalling Recorded INDIRECT_UNKNOWN_INTERMEDIATES: the chromatin changes were produced by exposing cells to fluoride, and nothing curated here connects skeletal fluoride burden to the histone mark as cause to effect.

Show evidence (2 references)

PMID:31501957 SUPPORT Other

"Skeletal fluorosis is a rare toxic osteopathy characterized by massive bone fixation of fluoride."

"Massive bone fixation of fluoride" is this node in the source's own words. Graded OTHER as a review's characterisation of the disease.

PMID:3295994 SUPPORT Other

"Fluoride is a cumulative toxin which can alter accretion and resorption of bone tissue."

States the cumulative-toxin property this node records, and that it acts on both accretion and resorption.

Fluorapatite Substitution in Bone Mineral

Fluoride entering bone mineral changes the mineral phase and the tissue's handling of calcium. The 1986 clinical review records increased avidity for calcium alongside increased turnover and impaired collagen synthesis as the three features of fluoride toxicity in bone; this entry curates them as three nodes because they have different downstream consequences.

biomineral tissue development GO:0031214 ⚠ ABNORMAL

Animal models

NaF-exposed Swiss albino mouse Mouse rescues The supplementation arm: calcium and vitamin D reduced fluoride deposition and restored the bone's elemental homeostasis.

Downstream

Osteoblast Proliferation and Activation Recorded INDIRECT_UNKNOWN_INTERMEDIATES: that fluoride in mineral is followed by osteoblast activation is not in dispute, but nothing curated here connects the altered mineral phase to the signalling changes below as cause to effect.

Impaired Collagen Synthesis and Matrix Mineralization

Secondary Hyperparathyroidism Recorded INDIRECT_KNOWN_INTERMEDIATES because the intermediates are named in the cited sources rather than inferred: the skeleton's increased avidity for calcium, and fluoride's inhibition of vitamin D hydroxylation, which impairs calcium absorption.

Show evidence (3 references)

PMID:42336527 SUPPORT Other

"Chronic fluoride exposure alters bone mineral crystals due to its high affinity for calcium, reducing mechanical strength and disturbing phosphorus balance."

The mineral-phase claim this node is named for, and the mechanism behind it - fluoride's affinity for calcium alters the bone mineral crystal, at the cost of mechanical strength. Graded OTHER as a review's synthesis.

PMID:38135514 SUPPORT INDIRECT Other

"Once ingested, fluoride is incorporated into calcium-rich areas, including the dental and skeletal systems."

Graded INDIRECT: states that ingested fluoride is incorporated into the calcium-rich skeletal and dental tissues, which is the deposition step this node's substitution claim rests on rather than the substitution itself.

PMID:3295994 SUPPORT Other

"Increased metabolic turnover of the bone, impaired bone collagen synthesis and increased avidity for calcium are features in fluoride toxicity."

Names all three features this node branches into - turnover, collagen, and calcium avidity. Graded OTHER as a review synthesis.

Osteoblast Proliferation and Activation

Osteoblasts proliferate and switch on osteogenic markers under fluoride, through BMP/Smad and TGF-beta1/Smad2/3/CyclinD1 signalling and with Wnt/beta-catenin hyperactivated from the gut arm below. This is the node the field means by "active osteogenesis", and it is the reason skeletal fluorosis makes more bone rather than less.

osteoblast CL:0000062

BMP signaling pathway GO:0030509 ↑ INCREASED

Downstream

Accelerated and Disordered Bone Turnover

Show evidence (6 references)

PMID:34769367 SUPPORT Other

"Currently, active osteogenesis and accelerated bone turnover are considered critical processes in the progression of skeletal fluorosis."

The field's summary of what drives progression. Graded OTHER: a review's statement of consensus rather than its own result.

PMID:23918166 SUPPORT In Vitro

"We found that fluoride enhanced the proliferation of Saos-2 cells in a dose-dependent manner and 0.2 mM of fluoride resulted in a higher expression of osteoblast marker genes."

The dose-dependent proliferative response in osteoblast-like cells.

PMID:23918166 SUPPORT In Vitro

"immunofluorescence analysis showed that the promotion effects of 0.2 mM of fluoride on Saos-2 cells differentiation were associated with the activation of the BMP/Smad pathway."

The pathway it runs through, with Smad4 knockdown as the test.

+ 3 more references

Gut Microbial Tryptophan Metabolism Disruption

Fluoride disrupts tryptophan metabolism in the gut microbiota, lowering serum indole-3-acetic acid. Recorded as its own initiating arm because it is upstream of bone and is pharmacologically separable: restoring the metabolite, or the dietary tryptophan behind it, protects the skeleton.

Animal models

Skeletal fluorosis model rat for the gut-bone axis Rat recapitulates The metabolite deficit was found in the model and in human patients in the same study, which is the strongest fidelity claim available for any model here.

Downstream

Aryl Hydrocarbon Receptor Underactivation with Wnt Hyperactivation

Show evidence (1 reference)

PMID:41380608 SUPPORT Other

"we found that fluoride disrupted gut microbial tryptophan metabolism, resulting in decreased serum levels of indole-3-acetic acid (3-IAA) in both SF model rats and human SF patients."

The finding this node records. Graded OTHER because the sentence reports the result in the rat model and in human patients together, and no single evidence source describes both halves.

Aryl Hydrocarbon Receptor Underactivation with Wnt Hyperactivation

Loss of the microbial metabolite leaves the aryl hydrocarbon receptor under-activated, and Wnt/beta-catenin signalling hyperactivates in consequence, driving excessive osteoblast differentiation and pathological bone formation.

canonical Wnt signaling pathway GO:0060070 ↑ INCREASED

Animal models

Skeletal fluorosis model rat for the gut-bone axis Rat rescues Restoring 3-IAA reactivated AHR, suppressed Wnt signalling and reduced bone damage in vivo - the result the tryptophan treatment record rests on.

Downstream

Osteoblast Proliferation and Activation

Show evidence (3 references)

PMID:41380608 SUPPORT Model Organism

"This deficiency in 3-IAA impaired the activation of aryl hydrocarbon receptor (AHR), leading to Wnt/β-Catenin pathway hyperactivation, excessive osteoblast differentiation/mineralization, and pathological bone formation."

The signalling chain this node records, end to end.

PMID:41380608 SUPPORT Model Organism

"Restoring 3-IAA levels, either through direct supplementation or an intermittent high-tryptophan diet-reactivated AHR, suppressed Wnt/β-Catenin signaling, and alleviated bone damage in vivo."

The rescue arm, which is what makes this causal rather than correlated - restoring the metabolite suppressed Wnt signalling and reduced bone damage.

PMID:34769367 SUPPORT INDIRECT Other

"researchers have conducted extensive studies in fields of signaling pathways (Wnt/β-catenin, Notch, PI3K/Akt/mTOR, Hedgehog, parathyroid hormone, and insulin signaling pathways), stress pathways (oxidative stress and endoplasmic reticulum stress pathways), epigenetics (DNA methylation and..."

Graded INDIRECT: the review names Wnt/beta-catenin among the pathways under study in this disease, which situates the node but does not establish the AHR route above it.

Impaired Collagen Synthesis and Matrix Mineralization

While osteoblast number and activity rise, the matrix they lay down is defective: type I collagen expression falls, and mineralization with it. This is the paradox at the centre of the disease - more bone, worse bone - and the reason the skeleton becomes both denser and more fragile.

osteoblast CL:0000062

collagen fibril organization GO:0030199 ↓ DECREASED

Animal models

Fluoride-intoxicated Wistar rat on manipulated dietary calcium Rat recapitulates Osteocalcin, osteonectin and osteopontin were downregulated under fluoride and recovered in the reversal arm - matrix protein expression tracking the node.

Downstream

Accelerated and Disordered Bone Turnover Curated without evidence: no source in this entry's reference set asserts that the collagen defect drives the turnover change, only that the two co-occur in fluoride toxicity. See discussion sf_collagen_turnover_link.

Show evidence (5 references)

PMID:37558119 SUPPORT Model Organism

"Expression of collagen Col1a1, Col1a2, COL1A1 was significantly reduced in treated mice."

The collagen loss measured in mice given fluoride at an environmentally relevant dose.

PMID:24300170 REFUTE In Vitro

"we demonstrated that fluoride significantly promoted osteoblasts proliferation and alkaline phosphate (ALP) expression as well as the mRNA expression levels of bone differentiation markers, including type I collagen (COL1A1), ALP and osteonectin"

The opposite collagen direction, in primary rat osteoblasts: COL1A1 mRNA rises rather than falls. Graded REFUTE against this node's claim that type I collagen expression falls. The node keeps that claim because it rests on the in-vivo result at an environmentally relevant dose, while this is primary culture at a culture dose; the same paper is cited on the upstream Wnt edge for its DKK-1 blockade, which is a separate finding and not a collagen direction.

PMID:37558119 SUPPORT Model Organism

"To unravel the pathogenesis of skeletal fluorosis, we established fluorosis mice by treating environmentally relevant concentration of F (15 ppm NaF) through drinking water for 4 months."

The exposure that produced it - 15 ppm in drinking water for four months, which is within the range endemic populations drink.

+ 2 more references

Histone-Mediated Repression of TGF-beta Receptor Signalling

A second epigenetic route to the same defective matrix: fluoride raises H3K9 trimethylation at the TGFBR2 and SMAD3 promoters, and expression of those genes and of COL1A1 falls with it. Curated separately from the methylation route because it points the opposite way on TGF-beta from the proliferation arm, which is a tension this entry records rather than resolves.

Downstream

Impaired Collagen Synthesis and Matrix Mineralization

Show evidence (2 references)

PMID:29275289 SUPPORT In Vitro

"H3K9 ChIP PCR array analysis identified hyper H3K9 trimethylation in promoter regions of TGFBR2 and SMAD3."

The chromatin mark and the promoters it lands on, in a human osteosarcoma cell line.

PMID:29275289 SUPPORT In Vitro

"Expression of two other vital genes COL1A1 and MMP13 involved in TGFBR2-SMAD signaling pathway was also found to be down-regulated with a decrease in expression of TGFBR2 and SMAD3."

The expression consequence, including COL1A1, which is what connects this node to the matrix node below it.

Secondary Hyperparathyroidism

The fluoridated skeleton takes up calcium avidly, and in a proportion of patients parathyroid drive rises in response, adding its own bone changes to the picture. Curated as a node rather than a comorbidity because it feeds back onto bone resorption.

Downstream

Osteocyte-Driven Osteoclastogenesis Recorded INDIRECT_KNOWN_INTERMEDIATES because the intermediate is named: the osteocyte. The cited coculture work compares PTH with fluoride on osteocyte-driven osteoclast differentiation and finds fluoride's effect the larger, so this edge is an addition to the fluoride effect rather than the route for it.

Show evidence (1 reference)

PMID:3295994 SUPPORT Other

"In a proportion of cases secondary hyperparathyroidism is observed with associated characteristic bone changes."

States both the finding and its partial penetrance - "in a proportion of cases" - which is why this node is not on the main chain.

Osteocyte-Driven Osteoclastogenesis

Osteocytes exposed to fluoride drive osteoclast precursors toward differentiation, raising TRAP, RANK, JNK and NFATc1. This is the resorptive half of the accelerated turnover, and it is what stops the disease being a pure bone-forming disorder.

osteocyte CL:0000137 osteoclast CL:0000092

osteoclast differentiation GO:0030316 ↑ INCREASED

Downstream

Accelerated and Disordered Bone Turnover

Show evidence (2 references)

PMID:32156525 SUPPORT In Vitro

"Gene expression levels of TRAP, RANK, JNK and NFAtc1 significantly increased in fluoride affected osteoclast precursor cocultured with osteocyte-like cells."

The osteoclastogenic markers raised in the transwell coculture this node describes.

PMID:32156525 SUPPORT In Vitro

"The impact of fluoride on osteocyte-driven osteoclast differentiation was stronger than that of PTH."

The comparison that ranks the two drivers, and the reason the parathyroid edge above is recorded as additive rather than as the mechanism.

Accelerated and Disordered Bone Turnover

Formation and resorption both run fast, and the matrix produced is defective. The convergence point of every arm above, and the process the field identifies as critical to progression.

ossification GO:0001503 ↑ INCREASED bone resorption GO:0045453 ↑ INCREASED

bone tissue UBERON:0002481

Animal models

Fluoride-intoxicated Wistar rat on manipulated dietary calcium Rat recapitulates Reproduces the entry's central paradox directly: turnover up while bone mineral content and mechanical properties fall, with trabecular separation and porosity rising - denser activity, weaker bone.

Downstream

Mixed Osteosclerosis, Osteomalacia and Osteoporosis

Show evidence (2 references)

PMID:3295994 SUPPORT Other

"Increased metabolic turnover of the bone, impaired bone collagen synthesis and increased avidity for calcium are features in fluoride toxicity."

Names increased metabolic turnover as a defining feature of fluoride toxicity in bone.

PMID:34769367 SUPPORT Other

"Currently, active osteogenesis and accelerated bone turnover are considered critical processes in the progression of skeletal fluorosis."

The current review's placement of this process at the centre of progression.

Mixed Osteosclerosis, Osteomalacia and Osteoporosis

The skeletal lesion is not one thing. Osteosclerosis, osteomalacia and osteoporosis coexist in varying proportion, with exostosis formation on top. This entry does not force a single lesion, for the same reason it does not force a single mode of bone cell response.

bone element UBERON:0001474

Animal models

Inbred mouse strain panel for fluoride bone susceptibility Mouse fails to recapitulate The model does not reproduce the finding the human disease is diagnosed on. Fluoride accumulated in bone and degraded bone quality, but bone mineral density barely moved - and increased bone mineral density is the radiographic sign this entry binds `HP:0005789` to and calls the diagnosis.

Downstream

Ligament and Interosseous Membrane Ossification

Joint Immobilization and Skeletal Deformity

Show evidence (2 references)

PMID:3295994 SUPPORT Other

"A combination of osteosclerosis, osteomalacia and osteoporosis of varying degrees as well as exostosis formation characterizes the bone lesions."

The mixed lesion this node is named for, stated as such.

PMID:34769367 SUPPORT Other

"patients with skeletal fluorosis mainly present with symptoms of osteosclerosis, osteochondrosis, osteoporosis, and degenerative changes in joint cartilage."

The modern review lists the same mixture, adding osteochondrosis and degenerative joint cartilage change.

Ligament and Interosseous Membrane Ossification

Ossification spreads beyond bone into the ligaments and interosseous membranes, which is the radiographic signature of the disease and the step that converts a metabolic bone disorder into a mechanical one.

ossification GO:0001503 ↑ INCREASED

ligament UBERON:0000211

Downstream

Spinal Canal and Foraminal Narrowing

Joint Immobilization and Skeletal Deformity

Show evidence (2 references)

PMID:31501957 SUPPORT Other

"Radiographic presentation is mainly characterized by bone changes with osteocondensation and later ossification of many ligaments and interosseous membranes."

The sequence this node records - osteocondensation first, then ossification of ligaments and interosseous membranes.

PMID:2661032 SUPPORT Other

"A 20-30 years' occupational and/or environmental exposure to fluorine may cause osteosclerosis, especially of the spine and pelvic bones, and calcification of spinal ligaments."

The same finding from the occupational literature, with the exposure duration it takes and the sites it favours.

Spinal Canal and Foraminal Narrowing

Generalised sclerosis and osteophytosis reduce the diameter of the spinal canal and of the intervertebral foramina. This is the node that makes the neurological disease mechanical, and it is why the chain runs through bone rather than through nerve.

vertebral canal UBERON:0006692

Downstream

Compressive Myelopathy and Radiculopathy

Show evidence (1 reference)

PMID:2172892 SUPPORT Human Clinical

"These deficits were clearly found to be a consequence of fluoride deposition in bones, resulting in generalised sclerosis and osteophytosis, with reduction in the diameter of the intervertebral foramina and of the spinal conal."

Traces the deficits back through the narrowing to the bone deposition, in a decade of surveys in the Ethiopian Rift Valley.

Compressive Myelopathy and Radiculopathy

Cord and root compression from the narrowed canal and foramina, producing spastic paresis, spasms and sphincter disturbance in advanced disease. The mechanism is compression, not neurotoxicity - this entry curates that distinction explicitly, because it is the point on which the management of the neurological disease turns.

spinal cord UBERON:0002240

Show evidence (3 references)

PMID:2172892 SUPPORT Human Clinical

"The neurological manifestations in the forms of myelopathy with and without radiculopathy (respectively 72% and 28%) occurred after exposure to high fluoride (greater than 4 ppm) for longer than 10 years."

The split between myelopathy with and without radiculopathy, and the exposure it takes to get there - above 4 ppm for more than ten years.

PMID:2172892 SUPPORT Human Clinical

"Advanced osteosclerosis commonly causes severe spastic quadriparesis in flexion, accompanied by distressing spasms and urinary incontinence."

The advanced presentation, and what it costs the patient.

PMID:19305069 SUPPORT Other

"Neurological complications of endemic skeletal fluorosis, namely radiculopathy, myelopathy or both are mechanical in nature and till date the evidence for direct neurotoxicity of fluoride is lacking."

The load-bearing statement for this node's causal_link_type and for the `sf_neuro_mechanism` discussion: the complications are mechanical, and direct fluoride neurotoxicity is not evidenced. Graded OTHER as a review's assessment of a literature rather than its own measurement.

Joint Immobilization and Skeletal Deformity

The clinical endpoint: the joints of the axial skeleton and the major limb joints stiffen and immobilise, with crippling deformity. This is what "crippling fluorosis" names.

Show evidence (3 references)

PMID:3295994 SUPPORT Other

"The total quantity of ingested fluoride is the single most important factor which determines the clinical course of the disease which is characterized by immobilization of joints of the axial skeleton and of the major joints of the extremities."

The distribution of the immobilization, axial first and then the large limb joints.

PMID:12660366 SUPPORT Other

"The main manifestations of skeletal fluorosis are crippling bone deformities, spinal compressions, and restricted movements of joints."

The three manifestations named together - deformity, spinal compression and restricted joint movement - which are the three endpoints this chain reaches.

PMID:3295994 SUPPORT Other

"Contrary to earlier thinking, severe crippling forms of skeletal fluorosis are seen in paediatric age group too."

That the crippling form occurs in children too. Curated because the older assumption was that it did not, and the coal-burning surveys below confirm it.

⬡

Pathograph

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Phenotypes

9

Musculoskeletal 6

Restricted Joint Mobility Limitation of joint mobility HP:0001376

Show evidence (1 reference)

PMID:3295994 SUPPORT Other

"The total quantity of ingested fluoride is the single most important factor which determines the clinical course of the disease which is characterized by immobilization of joints of the axial skeleton and of the major joints of the extremities."

The distribution and course of the immobilization this phenotype records.

Osteosclerosis Generalized osteosclerosis HP:0005789

Bound to `HP:0005789` (Generalized osteosclerosis). The Ethiopian field surveys describe "generalised sclerosis" and the occupational review "osteosclerosis, especially of the spine and pelvic bones", so the generalized term is what the cited evidence carries; the broader `HP:0011001` (Increased bone mineral density) would have lost that. Note the deep-research report offered `HP:0100774` for "Osteosclerosis"; HPO calls that term *Hyperostosis*, and it is not bound here.

Show evidence (3 references)

PMID:2661032 SUPPORT Other

"A 20-30 years' occupational and/or environmental exposure to fluorine may cause osteosclerosis, especially of the spine and pelvic bones, and calcification of spinal ligaments."

Names the finding and the sites it favours.

PMID:37883215 SUPPORT Human Clinical

"Radiologic imaging performed for suspected fractures revealed periosteal reaction, cortical thickening with increased bone density, and ligament and tendon ossification, which were not present on imaging obtained 3 years before presentation."

The radiographic picture in an individual patient, and unusually with a three-year-earlier normal comparison that dates its development.

PMID:2172892 SUPPORT Human Clinical

"These deficits were clearly found to be a consequence of fluoride deposition in bones, resulting in generalised sclerosis and osteophytosis, with reduction in the diameter of the intervertebral foramina and of the spinal conal."

Names the sclerosis as generalised, which is the binding this record makes.

Neurogenic Muscle Atrophy Skeletal muscle atrophy HP:0003202

Filed under Musculoskeletal because the lesion is in muscle, but it is a neurological readout and `reports_on` points at the myelopathy node accordingly. A frequency is not recorded: 16 of 22 had neurogenic EMG changes, but the denominator is a biopsy series of patients with established disease, not a prevalence sample.

Show evidence (2 references)

PMID:10878791 SUPPORT Human Clinical

"Histochemistry and histopathology of muscle biopsies showed features of muscle atrophy, evidenced by 'type I' atrophy and 'type I' grouping. No myopathic changes were observed."

The histological finding, and the absence of the myopathic alternative in the same biopsies.

PMID:10878791 SUPPORT INDIRECT Human Clinical

"This study included 22 patients with established osteofluorosis. 16 of them showed only EMG changes of neurogenic muscle disease."

Graded INDIRECT: the cohort and the electrophysiology behind the biopsy finding rather than the finding itself.

Skeletal Deformity Kyphosis HP:0002808

Show evidence (2 references)

PMID:36426635 SUPPORT INDIRECT Human Clinical

"Radiographs demonstrated diffuse periosteal new bone formation and sclerosis consistent with skeletal fluorosis."

Graded INDIRECT: the radiographic description is of periosteal new bone and sclerosis rather than of kyphosis specifically. The same case presented with hand swelling and long bone deformities.

PMID:3295994 SUPPORT Other

"Contrary to earlier thinking, severe crippling forms of skeletal fluorosis are seen in paediatric age group too."

That the crippling deformity occurs in children as well as adults.

Exostoses HP:0100777

Show evidence (1 reference)

PMID:3295994 SUPPORT Other

"A combination of osteosclerosis, osteomalacia and osteoporosis of varying degrees as well as exostosis formation characterizes the bone lesions."

Names exostosis formation alongside the three mineral lesions as what characterises the bone in this disease.

Spastic Paresis Spastic tetraparesis HP:0001285

Bound to `HP:0001285` (Spastic tetraparesis), defined by HPO as "Spastic weakness affecting all four limbs" and carrying "Spastic quadriparesis" as an exact synonym - a word-for-word match to the cited survey's "severe spastic quadriparesis in flexion". Two nearby terms were considered and rejected. `HP:0002313` (Spastic paraparesis) was bound in an earlier draft and is wrong on distribution: it is a lower-limb deficit, and both the quote and the entry's own mechanism - compression at the cervical canal - point to four limbs. `HP:0002510` (Spastic tetraplegia) has the right distribution but is defined as "Spastic *paralysis* affecting all four limbs", so it over-claims severity against a source that says paresis. Nothing curated here describes the deficit at an earlier stage, so this record binds the presentation the evidence actually reports rather than a generalization the evidence does not.

Show evidence (1 reference)

PMID:2172892 SUPPORT Human Clinical

"Advanced osteosclerosis commonly causes severe spastic quadriparesis in flexion, accompanied by distressing spasms and urinary incontinence."

The advanced neurological presentation, and the binding is taken from it directly: the source says spastic *quadri*paresis, and `HP:0001285` carries "Spastic quadriparesis" as an exact synonym.

Constitutional 3

Joint Pain and Stiffness Arthralgia HP:0002829

Show evidence (1 reference)

PMID:12660366 SUPPORT Other

"The main manifestations of skeletal fluorosis are crippling bone deformities, spinal compressions, and restricted movements of joints."

Names restricted joint movement among the main manifestations.

Urinary Incontinence HP:0000020

Show evidence (1 reference)

PMID:2172892 SUPPORT Human Clinical

"Advanced osteosclerosis commonly causes severe spastic quadriparesis in flexion, accompanied by distressing spasms and urinary incontinence."

Names urinary incontinence, with the spasms, as accompanying the advanced spastic presentation that advanced osteosclerosis causes.

Bone Pain HP:0002653

Show evidence (1 reference)

PMID:12660366 SUPPORT INDIRECT Other

"The main manifestations of skeletal fluorosis are crippling bone deformities, spinal compressions, and restricted movements of joints."

Graded INDIRECT: the sentence names crippling bone deformities and restricted movement rather than pain as such, and pain is the symptom that accompanies them in the clinical descriptions cited elsewhere in this entry.

🧬

Genetic Associations

5

ATP2B1 susceptibility variants

Gene: ATP2B1 hgnc:814 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (3 references)

PMID:37211801 SUPPORT Human Clinical

"The results suggested that rs17249754 and rs7136259 were associated with skeletal fluorosis."

The two associated loci.

PMID:37211801 SUPPORT Human Clinical

"In China, 962 individuals were recruited, including 342 cases of skeletal fluorosis."

The study size behind them.

PMID:37211801 SUPPORT Human Clinical

"After controlling confounders, the protective effect of GG genotype in rs17249754 was apparent in individuals over 45 years old, female, with urine fluoride concentration below 1.6 mg/L, serum calcium above 2.25 mmol/L or serum phosphorus between 1.1 and 1.3."

The strata the effects are reported within, which is what this record's notes turn on.

ALOX15 variants

Gene: ALOX15 hgnc:433 relationship_type: DISPUTED variant_origin: GERMLINE

Show evidence (2 references)

PMID:31565963 REFUTE Human Clinical

"The genotypes of ALOX15 rs7220870, rs2664593 and rs1107852 were not associated with the risk of SF."

Graded REFUTE against a single-SNP association: none of the three genotypes was associated with risk across the 1,023-subject study.

PMID:31565963 SUPPORT Human Clinical

"After reconstructing the haplotype of rs7220870 and rs11078528, the risk effect of haplotype CA was found in Han participants aged ≤45 years or with moderate fluoride intake."

The positive half, and its limits - one ethnic group, and only in defined age and fluoride-intake strata.

ESR1 rs9340799

Gene: ESR1 hgnc:3467 relationship_type: PROTECTIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:39824337 SUPPORT Human Clinical

"Binary logistic regression found that carried the ESR1 Rs9340799 G allele played a protective role in brick-tea-type fluorosis"

The protective association, and the population it was found in.

PMID:39824337 SUPPORT Human Clinical

"The X-ray of the participants were diagnosed according to the diagnostic criteria of Chinese endemic skeletal fluorosis (WS192-2008)."

The case definition the association rests on.

PMID:39824337 SUPPORT INDIRECT Human Clinical

"Our data suggested that there may be a genetic component to the risk of skeletal fluorosis in participants of different ethnicities and that this difference could modified by tea fluoride intake, sex or age."

Graded INDIRECT: the authors' own summary of what the study establishes, which qualifies the individual association rather than asserting it.

COL1A1 rs1800012

Gene: COL1A1 hgnc:2197 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (2 references)

PMID:39824337 SUPPORT Human Clinical

"Russians carried the COL1A1 Rs1800012 T allele had a significantly higher risk of developing skeletal fluorosis"

The association, and the single ethnic group it was found in.

PMID:39824337 SUPPORT Human Clinical

"When stratified by sex, carriage of the T allele in COL1A1 Rs1800012 significantly increased the risk of developing skeletal fluorosis in Russian men."

The sex-stratified result, which narrows it further.

BMP2 variants tested and not associated

Gene: BMP2 hgnc:1069 relationship_type: DISPUTED variant_origin: GERMLINE

Show evidence (2 references)

PMID:33660557 REFUTE Human Clinical

"Logistic regressions 2 analysis did not find the association between SNPs (Rs235764, Rs235739 and Rs996544) and skeletal fluorosis."

Graded REFUTE against this record's own claim. Three SNPs tested, none associated, and the genetic-model, linkage-disequilibrium and haplotype analyses negative as well.

PMID:33660557 SUPPORT Human Clinical

"Using the standard WS/192-2008 (China), 221 skeletal fluorosis cases were diagnosed, including 123 Tibetans and 98 Kazakhs."

The cohort and the diagnostic standard the negative rests on.

💊

Medical Actions

5

Water Improvement and Defluoridation

Action: defluoridation of the drinking water supply Ontology label: Preventive Intervention NCIT:C15843

Platform: Other

Replacing or treating high-fluoride drinking water. The only intervention in this entry with pooled evidence that it reduces disease prevalence, and the one the public-health literature is built around.

Mechanism Target:

INHIBITS Chronic Excess Fluoride Intake — Removes the exposure the initiating node describes.

Show evidence (1 reference)

PMID:33333408 SUPPORT Human Clinical

"With water improvement, water fluoride levels decreased from 2.72 mg/L to 0.54 mg/L (95% confidence intervals: -2.75, -1.58), which was below the standard for drinking water (1.5 mg/L)."

Evidence for the link rather than the outcome: water fluoride fell from 2.72 to 0.54 mg/L, below the 1.5 mg/L standard, which is the exposure node being acted on.

Show evidence (1 reference)

PMID:33333408 SUPPORT Human Clinical

"after water improvement, the prevalence of dental fluorosis decreased from 54.5% to 36.2% (95% confidence intervals: 0.12, 0.31) in children, and the prevalence of skeletal fluorosis decreased from 13.7% to 4.2% (95% confidence intervals: 0.16, 0.40) in adults."

Adult skeletal fluorosis prevalence fell from 13.7% to 4.2% over an average of nearly sixteen years of water improvement.

Symptomatic and Supportive Management

Action: symptomatic management Ontology label: Supportive Care NCIT:C15747

Platform: Other

Once established, the skeletal disease is not reversed by any treatment curated here, and management is directed at symptoms.

Mechanism Target:

MODULATES Joint Immobilization and Skeletal Deformity — Directed at the clinical endpoint. No treatment in this entry acts on a node upstream of it once exposure has stopped.

Show evidence (2 references)

PMID:31501957 SUPPORT Other

"Management of fluorosis generally focuses on symptom treatment."

States the management position this record records.

PMID:37558119 SUPPORT Other

"Globally, 200 million people are suffering from toxic manifestations of Fluoride(F), dental and skeletal fluorosis; unfortunately, there is no treatment."

The blunter statement of the same thing, and the scale it applies at - 200 million people, and no treatment. Graded OTHER as a paper's framing of its field rather than its own result.

Surgical Decompression for Compressive Myelopathy

Action: spinal cord decompression Ontology label: Spinal Cord Decompression NCIT:C124141

Platform: Surgery

Decompression for the neurological complications. Its role is limited and it is selected on imaging rather than offered routinely, which follows from the neurological disease being mechanical.

Mechanism Target:

BYPASSES Compressive Myelopathy and Radiculopathy — Recorded BYPASSES: decompression relieves the compression without acting on the ossification producing it, which continues while exposure does.

Show evidence (1 reference)

PMID:19305069 SUPPORT Other

"Surgery has a limited role in alleviating the neurological disability and should be tailored to the individual based on the imaging findings."

States both the limited role and the imaging-led selection this record describes.

Show evidence (1 reference)

PMID:19305069 SUPPORT INDIRECT Other

"Neurological complications of endemic skeletal fluorosis, namely radiculopathy, myelopathy or both are mechanical in nature and till date the evidence for direct neurotoxicity of fluoride is lacking."

Graded INDIRECT: that the complications are mechanical is the rationale for offering decompression at all, but the sentence does not itself evaluate the operation.

Calcium and Vitamin D Supplementation

Action: calcium and vitamin D supplementation Ontology label: Nutritional Support NCIT:C15433

Agent: calcium CHEBI:29108 vitamin D CHEBI:27300

Platform: Small molecule

Calcium and vitamin D given alongside, or after, fluoride exposure. Two independent rodent studies report it alleviating established skeletal fluorosis: in mice it reduced fluoride deposition and restored the bone's elemental profile, and in rats low dietary calcium aggravated the disease while calcium plus fluoride-free water normalised bone turnover and restored osteocalcin, osteonectin and osteopontin expression. Rodent evidence only in this entry.

Mechanism Target:

INHIBITS Fluorapatite Substitution in Bone Mineral — Acts on the mineral node: supplementation reduced fluoride deposition in bone and retained its elemental homeostasis.

Show evidence (1 reference)

PMID:33057951 SUPPORT Model Organism

"supplementation of calcium and vitamin D effectively alleviated dental and skeletal fluorosis, reduced F deposition, and retained elemental homeostasis of the bone."

The deposition and elemental-profile result, in vivo.

MODULATES Accelerated and Disordered Bone Turnover — Acts on the turnover node: bone turnover was normalised and the matrix-protein genes recovered in the reversal arm.

Show evidence (2 references)

PMID:32770327 SUPPORT Model Organism

"Expressions of osteocalcin, osteonectin and osteopontin were upregulated after providing NCD and FFW."

The matrix-protein expression recovering in the calcium-plus-fluoride-free water arm.

PMID:32770327 SUPPORT Model Organism

"Bone turnover in group 4X was normalised."

The turnover result itself, in the same reversal arm.

Show evidence (2 references)

PMID:32770327 SUPPORT Model Organism

"In conclusion, low calcium aggravates skeletal fluorosis which could be mitigated on supplementation of Ca and FFW."

The authors' own conclusion, and the reason this record exists in both directions: low calcium aggravates the disease, and supplementing it mitigates.

PMID:42336527 SUPPORT INDIRECT Other

"It also inhibits vitamin D hydroxylation, decreasing active vitamin D bioavailability and impairing calcium and phosphorus absorption."

Graded INDIRECT: a rationale rather than an outcome - fluoride inhibits vitamin D hydroxylation and impairs calcium absorption, which is the deficit this supplementation would be replacing.

Tryptophan Supplementation to Restore Gut-Derived AHR Signalling

Action: dietary tryptophan supplementation Ontology label: Nutritional Support NCIT:C15433

Agent: L-tryptophan CHEBI:16828 indole-3-acetic acid CHEBI:16411

Platform: Small molecule

Restoring indole-3-acetic acid, by direct supplementation or an intermittent high-tryptophan diet, suppressed Wnt signalling and reduced bone damage in the rat model. Curated as an investigational lead, not a treatment - there is no human evidence here.

Mechanism Target:

INHIBITS Aryl Hydrocarbon Receptor Underactivation with Wnt Hyperactivation — Reactivates the receptor whose underactivation this node describes.

Show evidence (1 reference)

PMID:41380608 SUPPORT Model Organism

"Restoring 3-IAA levels, either through direct supplementation or an intermittent high-tryptophan diet-reactivated AHR, suppressed Wnt/β-Catenin signaling, and alleviated bone damage in vivo."

The rescue result, in vivo.

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Environmental Factors

5

Chronic ingestion of fluoride-rich groundwater

Hazard type: CHEMICAL

Route: ORAL

Duration: CHRONIC

Exposome domain: GENERAL EXTERNAL

The dominant exposure worldwide. Fluoride dissolved from bedrock into shallow groundwater, drunk for years. The dose-response is close to linear from relatively low concentrations, which is why this exposure is curated with a threshold rather than as a simple presence.

Show evidence (2 references)

PMID:34769367 SUPPORT Other

"High concentrations of fluoride in the environment and drinking water are major causes"

Names drinking water as a major cause.

PMID:37861949 SUPPORT Human Clinical

"When comparing the highest versus the lowest fluoride category, the summary risk ratio (RR) for SF prevalence was 2.05 (95% CI 1.60; 2.64), with a value of 2.73 (95% CI 1.92; 3.90) for drinking water and 1.40 (95% CI 0.90; 2.17) for urinary fluoride."

The pooled risk ratio across 23 studies, and the useful detail that the association is stronger for water fluoride than for urinary fluoride.

Mechanism Target:

TRIGGERS Chronic Excess Fluoride Intake — This is the intake the initiating node describes, by its commonest route.

Show evidence (1 reference)

PMID:37861949 SUPPORT Human Clinical

"The dose-response curve based on a one-stage cubic spline regression model showed an almost linear positive relation between exposure and SF occurrence starting from relatively low concentrations up to 5 mg/L and 2.5 mg/L, respectively, for water and urinary fluoride, with no substantial..."

The dose-response relation between water fluoride and disease occurrence, which is what makes this exposure causal rather than merely associated.

Habitual consumption of high-fluoride brick tea

Hazard type: CHEMICAL

Route: ORAL

Duration: CHRONIC

Exposome domain: SPECIFIC EXTERNAL

Brick tea is pressed from older stems and leaves of the tea plant and its fluoride content exceeds China's national standard; in Tibetan, Kazakh and Mongolian communities it is drunk in quantity. Curated separately from groundwater because the intervention is different - the tea has to change, not the well.

Show evidence (2 references)

PMID:36583212 SUPPORT Other

"The available evidence revealed that brick tea may be produced from older stems and leaves of the tea plant and that the fluoride content of brick tea exceeds the national standard."

Why brick tea and not tea generally: it is made from older stems and leaves, and its fluoride content exceeds the national standard. Graded OTHER as a review's synthesis across studies.

PMID:33660557 SUPPORT Human Clinical

"Using the standard WS/192-2008 (China), 221 skeletal fluorosis cases were diagnosed, including 123 Tibetans and 98 Kazakhs."

221 diagnosed cases among Tibetan and Kazakh brick-tea drinkers, against China's national diagnostic standard - the scale of this exposure's effect.

Mechanism Target:

TRIGGERS Chronic Excess Fluoride Intake — A second oral route to the same initiating node.

Show evidence (1 reference)

PMID:26499132 SUPPORT Human Clinical

"The average daily fluoride intake from drinking brick tea in all seven districts in Tibet was much higher than the national standard."

The dose actually delivered by this route: measured daily fluoride intake from brick tea above the national standard across all seven Tibetan districts surveyed, which is the excess this edge asserts.

Indoor combustion of fluoride-rich coal for cooking and food drying

Hazard type: CHEMICAL

Route: INHALATION ORAL

Duration: CHRONIC

Exposome domain: SPECIFIC EXTERNAL

In parts of southwest China, high-fluoride coal is burned indoors on open stoves, and foodstuffs baked over the stove take up fluoride from the smoke. The route is both inhalational and dietary, and the cited survey found the disease in children exposed during growth.

Show evidence (1 reference)

PMID:20041010 SUPPORT Human Clinical

"Overall prevalence of child skeletal fluorosis due to indoor burning of coal was 7.5%."

The prevalence this exposure produced in children in Guizhou.

Mechanism Target:

TRIGGERS Chronic Excess Fluoride Intake — Recorded with both INHALATION and ORAL routes because the same practice contaminates the indoor air and the food dried in it.

Show evidence (1 reference)

PMID:20041010 SUPPORT Human Clinical

"Any student lived in a household that burned coal, used an open-burning stove, or baked foodstuffs over a coal stove was deemed high-risk for skeletal fluorosis."

The exposure definition the survey used, which names both the stove and the food.

Occupational and industrial inhalation of fluoride

Hazard type: CHEMICAL

Route: INHALATION

Duration: CHRONIC

Exposome domain: SPECIFIC EXTERNAL

Twenty to thirty years of industrial exposure produces the same osteosclerosis and spinal ligament calcification as the endemic dietary forms.

Show evidence (1 reference)

PMID:28840484 NO_EVIDENCE Other

"Although the systemic toxicity of fluoride has been extensively studied, still there is lacuna in the field of pulmonary fluoride toxicity."

Graded NO_EVIDENCE and curated deliberately. This review of pulmonary fluoride toxicity is the natural place to look for the inhalational arm's mechanism and it says the field has a lacuna there. It bears on the lung rather than on the skeleton, so it supports no claim in this entry - but recording that the inhalational mechanism is not characterised stops the next curator assuming it was simply not looked for.

Mechanism Target:

TRIGGERS Chronic Excess Fluoride Intake — The inhalational route to the same initiating node.

Show evidence (1 reference)

PMID:2661032 SUPPORT Other

"A 20-30 years' occupational and/or environmental exposure to fluorine may cause osteosclerosis, especially of the spine and pelvic bones, and calcification of spinal ligaments."

The exposure duration and the skeletal result, from the occupational literature.

Deliberate inhalation of fluorocarbon propellants

Hazard type: CHEMICAL

Route: INHALATION

Duration: CHRONIC

Exposome domain: SPECIFIC EXTERNAL

`exposure_term` binds the generic `ECTO:9000423` (exposure to fluoride). ECTO was searched and has no term for 1,1-difluoroethane or for propellant inhalation; the specific agent and route are carried in `preferred_term`.

Chronic huffing of difluoroethane-containing compressed gas dusters produces skeletal fluorosis outside any endemic area; two independent published cases are curated here. Recorded as a distinct route because it delivers the exposure with no endemic-area history to prompt the diagnosis - how commonly it does so is not established by this entry's evidence.

Show evidence (2 references)

PMID:36426635 SUPPORT Human Clinical

"We report a case of skeletal fluorosis from chronic inhalation of an electronic duster product containing 1,1-difluoroethane."

The exposure and the agent, in the index case.

PMID:37883215 SUPPORT Human Clinical

"Radiologic imaging performed for suspected fractures revealed periosteal reaction, cortical thickening with increased bone density, and ligament and tendon ossification, which were not present on imaging obtained 3 years before presentation."

A second, independent case with the same agent - and imaging from three years earlier showing none of it, which dates the disease to the exposure.

Mechanism Target:

TRIGGERS Chronic Excess Fluoride Intake — A non-endemic, non-dietary route to the same initiating node, at doses far above anything the environmental routes deliver.

Show evidence (1 reference)

PMID:36426635 SUPPORT Human Clinical

"Diagnostic testing demonstrated urine fluoride 64.5 mg/L (ref <3) and serum fluoride 1.8 mg/L (ref <0.13)."

The measured burden, against the laboratory reference intervals - urine fluoride more than twenty times the upper limit.

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Biochemical Markers

3

Urinary fluoride (Increased)

Pathograph Readouts

Readout Of Chronic Excess Fluoride Intake Positive Diagnostic

Reports current intake. It is a weaker predictor of disease than water fluoride, which is expected of a short-half-life exposure marker for a disease that accumulates over decades.

Show evidence (2 references)

PMID:37861949 SUPPORT Human Clinical

"When comparing the highest versus the lowest fluoride category, the summary risk ratio (RR) for SF prevalence was 2.05 (95% CI 1.60; 2.64), with a value of 2.73 (95% CI 1.92; 3.90) for drinking water and 1.40 (95% CI 0.90; 2.17) for urinary fluoride."

The pooled estimate for urinary fluoride, 1.40 with an interval crossing 1, against 2.73 for drinking water.

PMID:37861949 SUPPORT Human Clinical

"The RR for developing moderate-severe forms increases at 5.00 mg/L and 2.5 mg/L of water and urinary fluoride, respectively."

The urinary threshold above which moderate-severe disease risk rises.

Reference Ranges

–3.0 mg/L

`loinc_term` absent: no LOINC lookup was performed and the slot is `recommended`. This is a clinical laboratory's reference limit as quoted in a case report, not a population-derived interval.

Show evidence (1 reference)

PMID:36426635 SUPPORT Human Clinical

"Diagnostic testing demonstrated urine fluoride 64.5 mg/L (ref <3) and serum fluoride 1.8 mg/L (ref <0.13)."

The reference limit is quoted inline with the patient's value - urine fluoride 64.5 mg/L against a reference below 3.

Show evidence (1 reference)

PMID:2661032 SUPPORT Other

"early diagnosis is based on the history of occupational exposure, examination of urinary fluoride excretion (over 8 mg F-/litre in 24 hours) and radiological signs."

The occupational diagnostic threshold, expressed as 24-hour excretion rather than concentration.

Serum fluoride (Increased)

Pathograph Readouts

Readout Of Chronic Excess Fluoride Intake Positive Diagnostic

Reports circulating fluoride, the fraction en route to the skeleton.

Show evidence (1 reference)

PMID:36426635 SUPPORT Human Clinical

"Diagnostic testing demonstrated urine fluoride 64.5 mg/L (ref <3) and serum fluoride 1.8 mg/L (ref <0.13)."

Serum fluoride roughly fourteen times the upper reference limit in the index case.

Reference Ranges

–0.13 mg/L

As for urinary fluoride, this is a laboratory reference limit quoted in a case report rather than a population-derived interval, and `loinc_term` is absent for the same reason.

Show evidence (1 reference)

PMID:36426635 SUPPORT Human Clinical

"Diagnostic testing demonstrated urine fluoride 64.5 mg/L (ref <3) and serum fluoride 1.8 mg/L (ref <0.13)."

The serum reference limit, quoted inline with the patient's value.

Serum soluble Klotho (Increased)

Pathograph Readouts

Correlates With Mixed Osteosclerosis, Osteomalacia and Osteoporosis Positive Prognostic

Recorded CORRELATES_WITH, not READOUT_OF: the study relates sKlotho to disease severity, and this entry curates no account of what sKlotho measures in bone.

Show evidence (2 references)

PMID:32721666 SUPPORT Human Clinical

"Serum sKlotho levels were also positively associated with the severity of SF"

The association and its direction - positive, with severity.

PMID:32721666 SUPPORT Human Clinical

"The mediation analysis showed that serum sKlotho levels mediated 17.76% of the increase in the severity of SF caused by an increase of 1 mg/day of TFI."

The mediated fraction, which is what makes this a candidate mechanism marker rather than only a correlate.

Show evidence (2 references)

PMID:32721666 SUPPORT Model Organism

"Moreover, a significant increase of serum sKlotho levels in fluoride-exposed groups was also seen in the rat model."

The same direction in the rat model, which is the study's own verification of the human finding.

PMID:32721666 SUPPORT INDIRECT Human Clinical

"A cross sectional case control study was conducted in residents over 50 years old from brick-tea drinking areas in Qinghai and Xinjiang Provinces, China."

Graded INDIRECT: the population and design the association rests on, rather than the result.

🔬

Diagnosis

3

Radiographic Diagnosis

The diagnosis is radiographic: increased bone density in the axial skeleton first, then ossification of ligaments and interosseous membranes.

Show evidence (2 references)

PMID:31501957 SUPPORT Other

"Radiographic presentation is mainly characterized by bone changes with osteocondensation and later ossification of many ligaments and interosseous membranes."

The radiographic sequence the diagnosis rests on.

PMID:37883215 SUPPORT Human Clinical

"Radiologic imaging performed for suspected fractures revealed periosteal reaction, cortical thickening with increased bone density, and ligament and tendon ossification, which were not present on imaging obtained 3 years before presentation."

The same findings in an individual case, itemised.

Exposure History and Urinary Fluoride

Radiography alone does not distinguish this disease from several others, so the diagnosis rests on exposure history and fluoride measurement alongside it. The occupational literature sets a 24-hour urinary excretion threshold.

The threshold quoted is for occupational exposure and is expressed as 24-hour excretion, which is not interchangeable with the spot concentration reference limits recorded under `biochemical`. Both are curated; neither is converted into the other here.

Show evidence (1 reference)

PMID:2661032 SUPPORT Other

"early diagnosis is based on the history of occupational exposure, examination of urinary fluoride excretion (over 8 mg F-/litre in 24 hours) and radiological signs."

The three-part diagnostic basis, with the urinary threshold.

China National Diagnostic Standard WS/192-2008

Chinese field studies diagnose against a national standard rather than study-specific criteria, which is what makes their prevalence figures comparable.

The standard's own content is not curated here - its text was not obtained, and this record cites only the fact of its use.

Show evidence (1 reference)

PMID:33660557 SUPPORT Human Clinical

"Using the standard WS/192-2008 (China), 221 skeletal fluorosis cases were diagnosed, including 123 Tibetans and 98 Kazakhs."

Names the standard and shows it in use as the case definition.

📊

Prevalence

5

Children in a coal-burning endemic area, Zhijin County, Guizhou, China

Point Prevalence 7500.0 per 100,000 >1 in 1,000

7.5% of 1,616 schoolchildren aged 7-16, screened in 2004. Radiographic diagnosis was applied to the 23% assessed as high-risk by household coal use, so the denominator is the whole surveyed cohort and the figure is a screening prevalence rather than a whole-population one.

Show evidence (1 reference)

PMID:20041010 SUPPORT Human Clinical

"Overall prevalence of child skeletal fluorosis due to indoor burning of coal was 7.5%."

The reported prevalence.

Adults in fluorosis-endemic areas of China, before water improvement

Point Prevalence 13700.0 per 100,000 >1 in 1,000

13.7% pooled across 17 studies, and the figure the post-intervention comparison below is made against.

Show evidence (1 reference)

PMID:33333408 SUPPORT Human Clinical

"after water improvement, the prevalence of dental fluorosis decreased from 54.5% to 36.2% (95% confidence intervals: 0.12, 0.31) in children, and the prevalence of skeletal fluorosis decreased from 13.7% to 4.2% (95% confidence intervals: 0.16, 0.40) in adults."

The before figure, in the sentence that carries both.

Adults in fluorosis-endemic areas of China, after water improvement

Point Prevalence 4200.0 per 100,000 >1 in 1,000

4.2% after an average of 15.8 years of water improvement. Curated as its own record rather than as a note on the record above, because it is a different population state and the pair is the strongest evidence in this entry that the disease is preventable.

Show evidence (1 reference)

PMID:33333408 SUPPORT Human Clinical

"after water improvement, the prevalence of dental fluorosis decreased from 54.5% to 36.2% (95% confidence intervals: 0.12, 0.31) in children, and the prevalence of skeletal fluorosis decreased from 13.7% to 4.2% (95% confidence intervals: 0.16, 0.40) in adults."

The after figure, from the same pooled analysis.

Tindigani village, Northern Tanzania (East African Rift Valley)

Point Prevalence 3300.0 per 100,000 >1 in 1,000

3.3% (95% CI 2.4-4.3) of 1,532 residents screened door-to-door in a village of 1,944. Diagnosis was on pre-defined angles of lower-limb deformity rather than radiography, which is a different case definition from the Chinese records above and not directly comparable with them. Curated to record that this is not a China-only disease: drinking-water fluoride in the surveyed sources ran to 38.59 mg/L.

Show evidence (3 references)

PMID:38135514 SUPPORT Human Clinical

"Of the 1,532 individuals who were screened, 45 had skeletal fluorosis, giving a prevalence of 3.3% (95% CI=2.4, 4.3)."

The prevalence and its denominator.

PMID:38135514 SUPPORT Human Clinical

"Diagnosis of skeletal fluorosis was based on pre-defined angles of deformity of the lower limbs."

The case definition, which is what makes this figure not directly comparable with the radiographically diagnosed Chinese records above.

PMID:38135514 SUPPORT INDIRECT Human Clinical

"Fluoride concentrations ranged from 0.45-38.59 mg/L of fluoride."

Graded INDIRECT: the exposure range behind the prevalence rather than the prevalence itself.

Symptomatic volunteers, Vavuniya District, Sri Lanka

Cases In Literature Rare

Not a population prevalence and deliberately not given a rate: 6 skeletal and 10 pre-skeletal cases among 60 symptomatic volunteers selected for suspicious features, which is a case yield in a referred series rather than an occurrence in a population. Recorded because it is a second non-Chinese endemic setting and because of what it says about recognition - see the differential-diagnosis section.

Show evidence (1 reference)

PMID:30415519 SUPPORT Human Clinical

"In a cohort of 60 individuals in Vavuniya with symptoms suggestive of skeletal fluoride toxicity, 6 had skeletal fluorosis, 10 had pre-skeletal fluorosis, and groundwater sources had fluoride levels much higher than WHO recommended upper limit for drinking water."

The case counts, and the groundwater exposure behind them.

🌍

Epidemiology

1

Dose-Dependent Endemic Distribution with Co-Factors

Occurrence tracks fluoride dose close to linearly up to about 5 mg/L in water, and the endemic literature names climate, physical labour, nutritional status, other trace elements in the water and renal disease as modifiers of who among the exposed is affected.

Show evidence (3 references)

PMID:37861949 SUPPORT Human Clinical

"The dose-response curve based on a one-stage cubic spline regression model showed an almost linear positive relation between exposure and SF occurrence starting from relatively low concentrations up to 5 mg/L and 2.5 mg/L, respectively, for water and urinary fluoride, with no substantial..."

The dose-response shape, including the plateau above the threshold.

PMID:19305069 SUPPORT Other

"Epidemiological and experimental studies in the endemic areas suggest the role of temperate climate, hard physical labor, nutritional status, presence of abnormal concentrations of trace elements like strontium, uranium, silica in water supplies, high fluoride levels in foods and presence of..."

The co-factor list. Renal disease is the mechanistically clearest of them, since the kidney is the principal organ of fluoride excretion - though no source curated here quantifies the renal share, so this record does not treat it as the sole route.

PMID:20041010 SUPPORT Human Clinical

"Children aged 12-16 years were significantly more likely to be diagnosed with skeletal fluorosis than children aged 7-11 years (OR = 1.84, 95% CI: 1.17-2.90; P = .0082)."

The age gradient within a childhood cohort, which is what cumulative dose predicts.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Skeletal Fluorosis:

Ankylosing Spondylitis

Overlapping Features Spinal ligament calcification and axial stiffness overlap closely. The discriminators are the exposure history and the fluoride measurements, not the radiograph.

Show evidence (1 reference)

PMID:2661032 SUPPORT Other

"The radiological picture may mimic many other diseases, especially ankylosing spondylitis, diffuse idiopathic hyperostosis, and rare bone diseases, such as Albers-Schönberg disease."

Names this differential explicitly, alongside the others in this section.

Diffuse Idiopathic Skeletal Hyperostosis

Overlapping Features Flowing ossification along the spine is the shared feature; DISH does not produce the generalised osteosclerosis or the interosseous membrane ossification.

Show evidence (1 reference)

PMID:2661032 SUPPORT Other

"The radiological picture may mimic many other diseases, especially ankylosing spondylitis, diffuse idiopathic hyperostosis, and rare bone diseases, such as Albers-Schönberg disease."

Named in the same list of radiological mimics.

Osteopetrosis

Overlapping Features Albers-Schonberg disease shares the dense skeleton. It is congenital and lacks the ligamentous ossification and the exposure history.

Show evidence (1 reference)

PMID:2661032 SUPPORT Other

"The radiological picture may mimic many other diseases, especially ankylosing spondylitis, diffuse idiopathic hyperostosis, and rare bone diseases, such as Albers-Schönberg disease."

Named among the rare bone diseases the radiological picture mimics.

Rheumatological Disease Generally

Overlapping Features Before the radiograph is taken, the presentation is joint pain and stiffness, and the disease is not clinically obvious.

Show evidence (2 references)

PMID:31501957 SUPPORT Other

"Skeletal fluorosis is not clinically obvious and can be confused with other rheumatologic disorders."

States the general confusion this record names.

PMID:30415519 SUPPORT Human Clinical

"All 16 had been misdiagnosed as various types of arthritis."

The confusion measured rather than asserted: every one of the sixteen Sri Lankan patients with confirmed fluoride bone disease had been carrying an arthritis diagnosis.

📊

Related Datasets

3

Gene expression profiling of HOS (human osteosarcoma) cells exposed to fluoride geo:GSE70719

Human osteosarcoma cells exposed to a sub-lethal fluoride concentration for 30 days, framed by its authors as a model of fluorosis. A cell line, not patient material.

human MICROARRAY

Show evidence (1 reference)

GEO:GSE70719 SUPPORT Other

"To understand the molecular mechanism of fluoride induced toxicity gene expression profiling was performed on osteosarcoma cells (HOS). Cells were exposed to sub-lethal concentration of fluoride (8 ppm) for 30 days. Our result demonstrates that fluoride alters multiple biological pathways..."

The design and the framing, from GEO's own summary. Graded OTHER as a repository record rather than a study result.

miRNA expression profile in HOS cells exposed to sodium fluoride geo:GSE57550

Small non-coding RNA profiling in the same cell system, aimed at the epigenetic arm of fluorosis pathogenesis. The companion resource to the entry's microRNA and histone nodes.

human MICROARRAY

Show evidence (1 reference)

GEO:GSE57550 SUPPORT Other

"Aberrant change in RUNX2-mediated signaling cascade is one of the decisive steps during the pathogenesis of fluorosis."

The stated purpose - epigenetic alterations in fluorosis - and the RUNX2 framing. Graded OTHER as a repository record.

Global gene expression changes in osteoblasts from fluoride-tolerant mice geo:GSE203511

RNA-seq of MC3T3-E1 osteoblasts made fluoride-tolerant by gradient exposure. Note this profiles *resistance* rather than injury, so it bears on the disease by contrast; and it is a mouse cell line.

mouse BULK RNA SEQ

Show evidence (1 reference)

GEO:GSE203511 SUPPORT Other

"Fluoride-tolerant MC3T3-E1 cells were developed by gradient fluoride exposure."

The design, and the resistance framing that makes this a contrast resource rather than a model of the lesion. Graded OTHER as a repository record.

🐁

Animal Models

4

NaF-exposed Swiss albino mouse

15 ppm sodium fluoride in drinking water for four or eight months, with arms for exposure withdrawal and for calcium plus vitamin D supplementation. The model this entry's calcium and vitamin D treatment record rests on.

Species

Mouse

Genotype

Wild type (Swiss albino)

Publication

PMID:33057951

Pathograph links

Skeletal Fluoride Accumulation recapitulates fidelity: moderate observes: organism Produces skeletal fluorosis with measurable fluoride deposition and an altered bone metal profile at a dose ten times the human permissible limit.

Limitations: Four to eight months in a mouse against years to decades in a human, at 15 ppm against the 1.5 ppm permissible limit - the exposure is compressed in time and raised in dose to fit a rodent lifespan.

Show evidence (1 reference)

PMID:33057951 SUPPORT Model Organism

"NaF treatment caused dental fluorosis, skeletal fluorosis, and alteration of bone's metal profile."

The model produces the disease this entry curates, plus its dental sibling.

Fluorapatite Substitution in Bone Mineral rescues fidelity: moderate observes: organism The supplementation arm: calcium and vitamin D reduced fluoride deposition and restored the bone's elemental homeostasis.

Limitations: A rescue in a rodent at a fixed supraphysiological dose. No human trial of this intervention is curated anywhere in this entry.

Readouts

Bone fluoride deposition and elemental profile

Direction: RESTORED

Interpretation: The measured outcome behind the calcium and vitamin D treatment record.

Show evidence (1 reference)

PMID:33057951 SUPPORT Model Organism

"supplementation of calcium and vitamin D effectively alleviated dental and skeletal fluorosis, reduced F deposition, and retained elemental homeostasis of the bone."

Deposition reduced and elemental homeostasis retained.

Show evidence (1 reference)

PMID:33057951 SUPPORT Model Organism

"supplementation of calcium and vitamin D effectively alleviated dental and skeletal fluorosis, reduced F deposition, and retained elemental homeostasis of the bone."

The rescue this link records.

Fluoride-intoxicated Wistar rat on manipulated dietary calcium

100 ppm fluoride in water for six months against normal (0.5%) and low (0.25%) calcium diets, then a three-month reversal phase with fluoride-free water. The model that separates fluoride's effect from dietary calcium's.

Species

Rat

Genotype

Wild type (Wistar)

Publication

PMID:32770327

Pathograph links

Accelerated and Disordered Bone Turnover recapitulates fidelity: moderate observes: organism Reproduces the entry's central paradox directly: turnover up while bone mineral content and mechanical properties fall, with trabecular separation and porosity rising - denser activity, weaker bone.

Limitations: The effect is largest in the low-calcium arm, so the model as run confounds fluoride excess with dietary calcium deficiency; the normal-calcium arm is what isolates the fluoride effect.

Readouts

Bone turnover, mineral content and biomechanical properties

Direction: INCREASED

Interpretation: Turnover increased while mineral content and biomechanics decreased - the dissociation this node is about.

Show evidence (1 reference)

PMID:32770327 SUPPORT Model Organism

"The results revealed that in phase I, bone turnover was significantly increased whereas bone mineral content and biomechanical properties of group 4 were significantly decreased"

The measurement, in the low-calcium fluoride arm.

Trabecular separation and total porosity

Direction: INCREASED

Interpretation: The microarchitectural correlate of the disordered turnover.

Show evidence (1 reference)

PMID:32770327 SUPPORT Model Organism

"Trabecular separation and total porosity increased in groups 2 and 4."

Both rose in the calcium-deficient arms.

Show evidence (1 reference)

PMID:32770327 SUPPORT Model Organism

"The results revealed that in phase I, bone turnover was significantly increased whereas bone mineral content and biomechanical properties of group 4 were significantly decreased"

Establishes the model as informative for this node.

Impaired Collagen Synthesis and Matrix Mineralization recapitulates fidelity: moderate observes: organism Osteocalcin, osteonectin and osteopontin were downregulated under fluoride and recovered in the reversal arm - matrix protein expression tracking the node.

Limitations: Transcript-level, in rat bone. The human node is built on COL1A1 and TGF-beta receptor work in cell systems, and nothing curated connects the two directly.

Readouts

Osteocalcin, osteonectin and osteopontin expression

Direction: DECREASED

Interpretation: Matrix protein transcription falling under fluoride.

Show evidence (1 reference)

PMID:32770327 SUPPORT Model Organism

"Expression of osteocalcin, osteonectin and osteopontin genes was significantly downregulated in group 4."

The downregulation, in the low-calcium fluoride arm.

Show evidence (1 reference)

PMID:32770327 SUPPORT Model Organism

"Expression of osteocalcin, osteonectin and osteopontin genes was significantly downregulated in group 4."

The matrix-protein result this link rests on.

Inbred mouse strain panel for fluoride bone susceptibility

0, 25, 50 and 100 ppm fluoride across three inbred strains chosen for their different susceptibility to enamel fluorosis, with bone fluoride, DEXA and three-point bend, compression and femoral-neck fracture testing. The model that speaks to this entry's genetic susceptibility records.

Species

Mouse

Genotype

Wild type, three inbred backgrounds

Background

A/J (susceptible), SWR/J (intermediate), 129P3/J (resistant)

Publication

PMID:16920415

Pathograph links

Skeletal Fluoride Accumulation recapitulates fidelity: high observes: organism Bone fluoride rose with dose in femora and vertebral bodies in every strain, which is this node with a dose-response attached.

Show evidence (1 reference)

PMID:16920415 SUPPORT Model Organism

"Concordant with increasing fluoride dose were significant increases of fluoride concentration in femora and vertebral bodies from all 3 strains."

Accumulation, dose-dependent, in all three backgrounds.

Mixed Osteosclerosis, Osteomalacia and Osteoporosis fails to recapitulate fidelity: low observes: organism The model does not reproduce the finding the human disease is diagnosed on. Fluoride accumulated in bone and degraded bone quality, but bone mineral density barely moved - and increased bone mineral density is the radiographic sign this entry binds `HP:0005789` to and calls the diagnosis.

Limitations: A model that reproduces the exposure and the mechanical consequence while missing the density change cannot be used to argue about the sclerotic lesion. It remains informative about susceptibility and about bone quality, and it is the one curated source showing those two can come apart.

Divergences from the human mechanism

species mismatch invalidating

The mouse accumulates skeletal fluoride at these doses without the density increase that defines the human radiographic lesion, so the defining feature of the human disease is absent from the model.

temporal scope qualifying

The exposure runs for a fraction of a mouse lifespan; human osteosclerosis is the product of years to decades of accumulation, and the study cannot say whether density would move later.

Readouts

Bone mineral density by DEXA

Direction: UNCHANGED

Interpretation: A real negative, not a missing measurement: DEXA was performed in all three strains at all four doses and barely moved.

Show evidence (1 reference)

PMID:16920415 SUPPORT Model Organism

"Fluoride treatment had little effect on the bone mineral densities (BMD) in the 3 strains."

The density measurement that did not change.

Bone quality by mechanical testing

Direction: DECREASED

Interpretation: Bone quality degraded in the susceptible strain and not at all in the resistant one, which is the susceptibility gradient this model exists to show.

Show evidence (1 reference)

PMID:16920415 SUPPORT Model Organism

"Mechanical testing showed significant alterations in "bone quality" in the A/J strain, whereas moderate alterations in "bone quality" in the SWR/J strain and no effects in the 129P3/J strain were observed."

The strain-dependent mechanical result.

Show evidence (2 references)

PMID:16920415 REFUTE Model Organism

"Fluoride treatment had little effect on the bone mineral densities (BMD) in the 3 strains."

Graded REFUTE against reading this model as reproducing the human sclerotic lesion. It is the substantive negative claim the `FAILS_TO_RECAPITULATE` relationship makes.

+ 1 more reference

Notes

The pairing with `genetic:` is the point of curating this model. Three of the five genetic records here report human susceptibility variants and two report nulls; this is the animal counterpart, and it locates the susceptibility in bone quality rather than in bone density. The strains were originally selected for *enamel* fluorosis susceptibility, so the bone result is a transfer of that gradient rather than a bone-derived one, which is worth knowing before leaning on it.

Skeletal fluorosis model rat for the gut-bone axis

The model behind this entry's gut arm. Serum 3-IAA was measured in model rats and in human patients together, and the rescue arms - direct supplementation and an intermittent high-tryptophan diet - were run in vivo.

Species

Rat

Genotype

Wild type

Publication

PMID:41380608

Pathograph links

Gut Microbial Tryptophan Metabolism Disruption recapitulates fidelity: moderate observes: organism The metabolite deficit was found in the model and in human patients in the same study, which is the strongest fidelity claim available for any model here.

Limitations: The mechanism downstream of the metabolite - AHR, then Wnt - is established in the rodent arm only, and the human arm of the study is the serum measurement.

Show evidence (1 reference)

PMID:41380608 SUPPORT Other

"we found that fluoride disrupted gut microbial tryptophan metabolism, resulting in decreased serum levels of indole-3-acetic acid (3-IAA) in both SF model rats and human SF patients."

Graded OTHER because the sentence reports the model rats and the human patients together and no single `evidence_source` value describes both.

Aryl Hydrocarbon Receptor Underactivation with Wnt Hyperactivation rescues fidelity: moderate observes: organism Restoring 3-IAA reactivated AHR, suppressed Wnt signalling and reduced bone damage in vivo - the result the tryptophan treatment record rests on.

Limitations: Rodent only, and this entry curates no human tryptophan or 3-IAA intervention.

Readouts

Wnt/beta-catenin signalling and bone damage after 3-IAA restoration

Direction: RESTORED

Interpretation: The rescue, measured in vivo.

Show evidence (1 reference)

PMID:41380608 SUPPORT Model Organism

"Restoring 3-IAA levels, either through direct supplementation or an intermittent high-tryptophan diet-reactivated AHR, suppressed Wnt/β-Catenin signaling, and alleviated bone damage in vivo."

Signalling suppressed and bone damage alleviated.

Show evidence (1 reference)

PMID:41380608 SUPPORT Model Organism

"Restoring 3-IAA levels, either through direct supplementation or an intermittent high-tryptophan diet-reactivated AHR, suppressed Wnt/β-Catenin signaling, and alleviated bone damage in vivo."

The rescue this link records.

{ }

Source YAML

click to show

name: Skeletal Fluorosis
creation_date: "2026-09-07T17:10:22Z"
category: Environmental Osteopathy
parents:
- Metabolic Bone Disease
- Environmental Disease
disease_term:
  preferred_term: skeletal fluorosis
  term:
    id: MONDO:0400003
    label: skeletal fluorosis
synonyms:
- Fluorosis of the skeleton
- Endemic skeletal fluorosis
- Osteofluorosis
- Crippling fluorosis

description: >-
  Skeletal fluorosis is a crippling metabolic bone and joint disease caused by
  chronic ingestion or inhalation of excess fluoride. Fluoride is a cumulative
  toxin that fixes in calcified tissue, and the skeleton is where the dose
  accumulates: bone turnover accelerates, the matrix laid down is defective, and
  the result is a mixture of osteosclerosis, osteomalacia and osteoporosis with
  exostosis formation. Ligaments and interosseous membranes ossify. The joints of
  the axial skeleton and the large limb joints stiffen and finally immobilise,
  and where the spinal canal and intervertebral foramina narrow enough, the
  patient develops a compressive myelopathy or radiculopathy. Unlike its sibling
  dental fluorosis, which is fixed at the time the enamel forms, skeletal
  fluorosis accrues for as long as the exposure continues. The exposure is
  usually environmental - fluoride-rich groundwater above all, and in specific
  regions high-fluoride brick tea or food dried over indoor coal fires - but the
  same disease is produced by industrial inhalation and by deliberate inhalation
  of fluorocarbon propellants.

mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:M85.1
      label: Skeletal fluorosis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO:0400003
    mapping_justification: >-
      MONDO records `ICD10CM:M85.1` as a `skos:exactMatch` of MONDO:0400003, and the
      two carry the same label.
  icd11f_mappings:
  - term:
      id: icd11f:1269698463
      label: Skeletal fluorosis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO:0400003
    mapping_justification: >-
      MONDO records `icd11f:1269698463` as a `skos:exactMatch` of MONDO:0400003, and
      the two carry the same label.

pathophysiology:
- name: Chronic Excess Fluoride Intake
  description: >-
    The initiating exposure: fluoride taken in above the skeleton's tolerance for
    years to decades, by ingestion of groundwater, brick tea or coal-contaminated
    food, or by inhalation. The total quantity ingested, rather than the route, is
    what the older clinical literature identifies as the single determinant of how
    the disease runs.
  biological_scale: ORGANISM
  downstream:
  - target: Skeletal Fluoride Accumulation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:3295994
      reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        Elevated urinary fluoride and increased bone fluoride content are indicators of
        fluoride toxicity.
      explanation: >-
        Ties the ingested load to a raised bone fluoride content, which is the
        accumulation this edge asserts. Indirect because the review reports the two as
        markers of toxicity rather than measuring deposition as a consequence of intake.
  - target: Gut Microbial Tryptophan Metabolism Disruption
    causal_link_type: DIRECT
    description: >-
      The one arm of this chain that does not run through the skeleton: the cited
      work reports fluoride disrupting gut microbial tryptophan metabolism in both
      model rats and human patients, without locating that step relative to
      absorption.
    evidence:
    - reference: PMID:41380608
      reference_title: "Gut microbiota-derived indole-3-Acetic Acid attenuates skeletal fluorosis via AHR-mediated suppression of Wnt/β-Catenin signaling."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: >-
        we found that fluoride disrupted gut microbial tryptophan metabolism, resulting
        in decreased serum levels of indole-3-acetic acid (3-IAA) in both SF model rats
        and human SF patients
      explanation: >-
        States the edge itself: fluoride exposure disrupts gut microbial tryptophan
        metabolism. Graded OTHER to match this entry's existing grading of the same
        sentence, which reports the finding in model rats and human patients together
        and so fits no single evidence_source cleanly.
  evidence:
  - reference: PMID:3295994
    reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The total quantity of ingested fluoride is the single most important factor which determines the clinical course of the disease which is characterized by immobilization of joints of the axial skeleton and of the major joints of the extremities."
    explanation: >-
      Names dose as the determinant of clinical course, and names the outcome the
      chain below ends at. Graded OTHER: a review's synthesis rather than one study's
      measurement.
  - reference: PMID:34769367
    reference_title: "Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "High concentrations of fluoride in the environment and drinking water are major causes"
    explanation: The dominant exposure route, from the current mechanistic review.

- name: Skeletal Fluoride Accumulation
  description: >-
    Fluoride leaving the circulation is fixed in calcified tissue, so the skeleton
    is both the store and the target. This is what makes the disease cumulative
    rather than dose-rate dependent, and it is why the neurological complications
    downstream are a consequence of bone rather than of nerve.
  biological_scale: TISSUE
  locations:
  - preferred_term: bone tissue
    term:
      id: UBERON:0002481
      label: bone tissue
  downstream:
  - target: Fluorapatite Substitution in Bone Mineral
    causal_link_type: DIRECT
  - target: Histone-Mediated Repression of TGF-beta Receptor Signalling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recorded INDIRECT_UNKNOWN_INTERMEDIATES: the chromatin changes were produced by
      exposing cells to fluoride, and nothing curated here connects skeletal fluoride
      burden to the histone mark as cause to effect.
    evidence:
    - reference: PMID:29275289
      reference_title: "Role of fluoride induced histone trimethylation in development of skeletal fluorosis."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        The expression of histone methyltransferases (EHMT1 and EHZ2) and level of
        global histone trimethylation (H3K9 and H3K27) have been assessed and observed
        to be increased significantly after fluoride exposure (8 mg/L).
      explanation: >-
        Establishes that fluoride raises H3K9 trimethylation, which is the chromatin
        change this edge ends at. Indirect for the reason the edge description already
        gives: the mark was produced by exposing cells to fluoride in medium, not by a
        skeletal fluoride burden.
  evidence:
  - reference: PMID:31501957
    reference_title: "Skeletal fluorosis: don't miss the diagnosis!"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Skeletal fluorosis is a rare toxic osteopathy characterized by massive bone fixation of fluoride."
    explanation: >-
      "Massive bone fixation of fluoride" is this node in the source's own words.
      Graded OTHER as a review's characterisation of the disease.
  - reference: PMID:3295994
    reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Fluoride is a cumulative toxin which can alter accretion and resorption of bone tissue."
    explanation: >-
      States the cumulative-toxin property this node records, and that it acts on
      both accretion and resorption.

- name: Fluorapatite Substitution in Bone Mineral
  description: >-
    Fluoride entering bone mineral changes the mineral phase and the tissue's
    handling of calcium. The 1986 clinical review records increased avidity for
    calcium alongside increased turnover and impaired collagen synthesis as the
    three features of fluoride toxicity in bone; this entry curates them as three
    nodes because they have different downstream consequences.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: biomineral tissue development
    modifier: ABNORMAL
    term:
      id: GO:0031214
      label: biomineral tissue development
  downstream:
  - target: Osteoblast Proliferation and Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recorded INDIRECT_UNKNOWN_INTERMEDIATES: that fluoride in mineral is followed
      by osteoblast activation is not in dispute, but nothing curated here connects
      the altered mineral phase to the signalling changes below as cause to effect.
  - target: Impaired Collagen Synthesis and Matrix Mineralization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Secondary Hyperparathyroidism
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Recorded INDIRECT_KNOWN_INTERMEDIATES because the intermediates are named in
      the cited sources rather than inferred: the skeleton's increased avidity for
      calcium, and fluoride's inhibition of vitamin D hydroxylation, which impairs
      calcium absorption.
    evidence:
    - reference: PMID:42336527
      reference_title: "Environmental fluoride exposure and bone metabolism: Molecular pathways and health implications."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "It also inhibits vitamin D hydroxylation, decreasing active vitamin D bioavailability and impairing calcium and phosphorus absorption."
      explanation: >-
        The named intermediate step. Graded OTHER as a review's synthesis of
        mechanism rather than a study's own measurement.
  evidence:
  - reference: PMID:42336527
    reference_title: "Environmental fluoride exposure and bone metabolism: Molecular pathways and health implications."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Chronic fluoride exposure alters bone mineral crystals due to its high affinity for calcium, reducing mechanical strength and disturbing phosphorus balance."
    explanation: >-
      The mineral-phase claim this node is named for, and the mechanism behind it -
      fluoride's affinity for calcium alters the bone mineral crystal, at the cost of
      mechanical strength. Graded OTHER as a review's synthesis.
  - reference: PMID:38135514
    reference_title: "Prevalence of Skeletal Fluorosis in Northern Tanzania: A Follow-Up Study."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Once ingested, fluoride is incorporated into calcium-rich areas, including the dental and skeletal systems."
    explanation: >-
      Graded INDIRECT: states that ingested fluoride is incorporated into the
      calcium-rich skeletal and dental tissues, which is the deposition step this
      node's substitution claim rests on rather than the substitution itself.
  - reference: PMID:3295994
    reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Increased metabolic turnover of the bone, impaired bone collagen synthesis and increased avidity for calcium are features in fluoride toxicity."
    explanation: >-
      Names all three features this node branches into - turnover, collagen, and
      calcium avidity. Graded OTHER as a review synthesis.

- name: Osteoblast Proliferation and Activation
  description: >-
    Osteoblasts proliferate and switch on osteogenic markers under fluoride,
    through BMP/Smad and TGF-beta1/Smad2/3/CyclinD1 signalling and with
    Wnt/beta-catenin hyperactivated from the gut arm below. This is the node the
    field means by "active osteogenesis", and it is the reason skeletal fluorosis
    makes more bone rather than less.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: BMP signaling pathway
    modifier: INCREASED
    term:
      id: GO:0030509
      label: BMP signaling pathway
  downstream:
  - target: Accelerated and Disordered Bone Turnover
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34769367
      reference_title: "Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: >-
        the PI3K/Akt signaling may cause excessive proliferation and differentiation of
        osteoblasts and accelerate bone turnover, resulting in osteosclerotic skeletal
        fluorosis
      explanation: >-
        Asserts the link in the direction this edge draws it: excessive osteoblast
        proliferation and differentiation accelerating bone turnover.
  evidence:
  - reference: PMID:34769367
    reference_title: "Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Currently, active osteogenesis and accelerated bone turnover are considered critical processes in the progression of skeletal fluorosis."
    explanation: >-
      The field's summary of what drives progression. Graded OTHER: a review's
      statement of consensus rather than its own result.
  - reference: PMID:23918166
    reference_title: "Fluoride promotes viability and differentiation of osteoblast-like Saos-2 cells via BMP/Smads signaling pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that fluoride enhanced the proliferation of Saos-2 cells in a dose-dependent manner and 0.2 mM of fluoride resulted in a higher expression of osteoblast marker genes."
    explanation: The dose-dependent proliferative response in osteoblast-like cells.
  - reference: PMID:23918166
    reference_title: "Fluoride promotes viability and differentiation of osteoblast-like Saos-2 cells via BMP/Smads signaling pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "immunofluorescence analysis showed that the promotion effects of 0.2 mM of fluoride on Saos-2 cells differentiation were associated with the activation of the BMP/Smad pathway."
    explanation: The pathway it runs through, with Smad4 knockdown as the test.
  - reference: PMID:34080770
    reference_title: "miR-486-3p regulates CyclinD1 and promotes fluoride-induced osteoblast proliferation and activation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in the fluoride-challenged population, we observed that miR-486-3p expression decreased while CyclinD1 and transforming growth factor (TGF)-β1 increased"
    explanation: >-
      The same axis measured in an exposed human population rather than in culture -
      miR-486-3p down, CyclinD1 and TGF-beta1 up.
  - reference: PMID:34080770
    reference_title: "miR-486-3p regulates CyclinD1 and promotes fluoride-induced osteoblast proliferation and activation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we observed that NaF activates the TGF-β1/Smad2/3/CyclinD1 axis"
    explanation: The mechanism behind that correlation, in human osteoblasts.
  - reference: PMID:29505816
    reference_title: "TGF-β1 acts as mediator in fluoride-induced autophagy in the mouse osteoblast cells."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Our results demonstrated that sodium fluoride (NaF) (2.26 mg/L F-) exposure lead to a significant decrease in proliferation rate of mouse osteoblast cells in a dose-dependent manner with a concomitant increase in the expression levels of TGF-β1 and autophagic markers."
    explanation: >-
      Graded REFUTE against this node as stated. At 2.26 mg/L fluoride *decreased*
      mouse osteoblast proliferation, dose-dependently, with TGF-beta1 and autophagy
      up. Curated next to the positive results rather than instead of them - see the
      `sf_osteoblast_dose_response` discussion, which is what this contradiction is
      about.

- name: Gut Microbial Tryptophan Metabolism Disruption
  description: >-
    Fluoride disrupts tryptophan metabolism in the gut microbiota, lowering serum
    indole-3-acetic acid. Recorded as its own initiating arm because it is upstream
    of bone and is pharmacologically separable: restoring the metabolite, or the
    dietary tryptophan behind it, protects the skeleton.
  biological_scale: ORGANISM
  downstream:
  - target: Aryl Hydrocarbon Receptor Underactivation with Wnt Hyperactivation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41380608
      reference_title: "Gut microbiota-derived indole-3-Acetic Acid attenuates skeletal fluorosis via AHR-mediated suppression of Wnt/β-Catenin signaling."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This deficiency in 3-IAA impaired the activation of aryl hydrocarbon receptor
        (AHR), leading to Wnt/β-Catenin pathway hyperactivation
      explanation: >-
        States both halves of this edge: loss of the microbial metabolite leaves AhR
        under-activated, and Wnt/beta-catenin hyperactivates in consequence.
  evidence:
  - reference: PMID:41380608
    reference_title: "Gut microbiota-derived indole-3-Acetic Acid attenuates skeletal fluorosis via AHR-mediated suppression of Wnt/β-Catenin signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "we found that fluoride disrupted gut microbial tryptophan metabolism, resulting in decreased serum levels of indole-3-acetic acid (3-IAA) in both SF model rats and human SF patients."
    explanation: >-
      The finding this node records. Graded OTHER because the sentence reports the
      result in the rat model and in human patients together, and no single
      evidence source describes both halves.

- name: Aryl Hydrocarbon Receptor Underactivation with Wnt Hyperactivation
  description: >-
    Loss of the microbial metabolite leaves the aryl hydrocarbon receptor
    under-activated, and Wnt/beta-catenin signalling hyperactivates in consequence,
    driving excessive osteoblast differentiation and pathological bone formation.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
  downstream:
  - target: Osteoblast Proliferation and Activation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24300170
      reference_title: "Fluoride promotes osteoblastic differentiation through canonical Wnt/β-catenin signaling pathway."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        the positive effect of fluoride on ALP activity and mRNA expressions of COL1A1,
        ALP, osteonection and Runx2 was abolished by DKK-1, a blocker of the
        Wnt/β-catenin receptor
      explanation: >-
        Blocking Wnt/beta-catenin abolishes the osteoblastic response, so the pathway is
        necessary for the activation this edge points at rather than merely co-occurring
        with it.
    - reference: PMID:41380608
      reference_title: "Gut microbiota-derived indole-3-Acetic Acid attenuates skeletal fluorosis via AHR-mediated suppression of Wnt/β-Catenin signaling."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        leading to Wnt/β-Catenin pathway hyperactivation, excessive osteoblast
        differentiation/mineralization, and pathological bone formation
      explanation: >-
        Places excessive osteoblast differentiation immediately downstream of
        Wnt/beta-catenin hyperactivation in the same causal statement.
  evidence:
  - reference: PMID:41380608
    reference_title: "Gut microbiota-derived indole-3-Acetic Acid attenuates skeletal fluorosis via AHR-mediated suppression of Wnt/β-Catenin signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This deficiency in 3-IAA impaired the activation of aryl hydrocarbon receptor (AHR), leading to Wnt/β-Catenin pathway hyperactivation, excessive osteoblast differentiation/mineralization, and pathological bone formation."
    explanation: The signalling chain this node records, end to end.
  - reference: PMID:41380608
    reference_title: "Gut microbiota-derived indole-3-Acetic Acid attenuates skeletal fluorosis via AHR-mediated suppression of Wnt/β-Catenin signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Restoring 3-IAA levels, either through direct supplementation or an intermittent high-tryptophan diet-reactivated AHR, suppressed Wnt/β-Catenin signaling, and alleviated bone damage in vivo."
    explanation: >-
      The rescue arm, which is what makes this causal rather than correlated -
      restoring the metabolite suppressed Wnt signalling and reduced bone damage.
  - reference: PMID:34769367
    reference_title: "Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "researchers have conducted extensive studies in fields of signaling pathways (Wnt/β-catenin, Notch, PI3K/Akt/mTOR, Hedgehog, parathyroid hormone, and insulin signaling pathways), stress pathways (oxidative stress and endoplasmic reticulum stress pathways), epigenetics (DNA methylation and non-coding RNAs), and their inter-regulation involved in the pathogenesis of skeletal fluorosis."
    explanation: >-
      Graded INDIRECT: the review names Wnt/beta-catenin among the pathways under
      study in this disease, which situates the node but does not establish the
      AHR route above it.

- name: Impaired Collagen Synthesis and Matrix Mineralization
  description: >-
    While osteoblast number and activity rise, the matrix they lay down is
    defective: type I collagen expression falls, and mineralization with it. This
    is the paradox at the centre of the disease - more bone, worse bone - and the
    reason the skeleton becomes both denser and more fragile.
  biological_scale: MOLECULAR
  notes: >-
    The COL1A1 direction conflict is curated on this node as a REFUTE item rather
    than described here, following the convention `sf_osteoblast_dose_response`
    states for the proliferation disagreement on the same node. What that item
    cannot carry: no study has compared the two systems directly, so nothing here
    resolves the discrepancy in favour of either.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: DECREASED
    term:
      id: GO:0030199
      label: collagen fibril organization
  downstream:
  - target: Accelerated and Disordered Bone Turnover
    causal_link_type: DIRECT
    description: >-
      Curated without evidence: no source in this entry's reference set asserts that
      the collagen defect drives the turnover change, only that the two co-occur in
      fluoride toxicity. See discussion sf_collagen_turnover_link.
  evidence:
  - reference: PMID:37558119
    reference_title: "Chronic exposure to environmentally relevant concentration of fluoride impairs osteoblast's collagen synthesis and matrix mineralization: Involvement of epigenetic regulation in skeletal fluorosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Expression of collagen Col1a1, Col1a2, COL1A1 was significantly reduced in treated mice."
    explanation: The collagen loss measured in mice given fluoride at an environmentally relevant dose.
  - reference: PMID:24300170
    reference_title: Fluoride promotes osteoblastic differentiation through canonical Wnt/β-catenin signaling pathway.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrated that fluoride significantly promoted osteoblasts proliferation and
      alkaline phosphate (ALP) expression as well as the mRNA expression levels of bone
      differentiation markers, including type I collagen (COL1A1), ALP and osteonectin
    explanation: >-
      The opposite collagen direction, in primary rat osteoblasts: COL1A1 mRNA rises
      rather than falls. Graded REFUTE against this node's claim that type I collagen
      expression falls. The node keeps that claim because it rests on the in-vivo
      result at an environmentally relevant dose, while this is primary culture at a
      culture dose; the same paper is cited on the upstream Wnt edge for its DKK-1
      blockade, which is a separate finding and not a collagen direction.
  - reference: PMID:37558119
    reference_title: "Chronic exposure to environmentally relevant concentration of fluoride impairs osteoblast's collagen synthesis and matrix mineralization: Involvement of epigenetic regulation in skeletal fluorosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "To unravel the pathogenesis of skeletal fluorosis, we established fluorosis mice by treating environmentally relevant concentration of F (15 ppm NaF) through drinking water for 4 months."
    explanation: >-
      The exposure that produced it - 15 ppm in drinking water for four months,
      which is within the range endemic populations drink.
  - reference: PMID:37558119
    reference_title: "Chronic exposure to environmentally relevant concentration of fluoride impairs osteoblast's collagen synthesis and matrix mineralization: Involvement of epigenetic regulation in skeletal fluorosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "a study revealed the involvement of epigenetic regulation by promoter hypermethylation of Col1a1"
    explanation: The epigenetic route to it, by promoter hypermethylation of Col1a1.
  - reference: PMID:3295994
    reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Increased metabolic turnover of the bone, impaired bone collagen synthesis and increased avidity for calcium are features in fluoride toxicity."
    explanation: >-
      Impaired collagen synthesis was already one of the three named features of
      fluoride bone toxicity in 1986, four decades before the epigenetic account.

- name: Histone-Mediated Repression of TGF-beta Receptor Signalling
  description: >-
    A second epigenetic route to the same defective matrix: fluoride raises H3K9
    trimethylation at the TGFBR2 and SMAD3 promoters, and expression of those genes
    and of COL1A1 falls with it. Curated separately from the methylation route
    because it points the opposite way on TGF-beta from the proliferation arm, which
    is a tension this entry records rather than resolves.
  biological_scale: MOLECULAR
  downstream:
  - target: Impaired Collagen Synthesis and Matrix Mineralization
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29275289
      reference_title: "Role of fluoride induced histone trimethylation in development of skeletal fluorosis."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Expression of two other vital genes COL1A1 and MMP13 involved in TGFBR2-SMAD
        signaling pathway was also found to be down-regulated with a decrease in
        expression of TGFBR2 and SMAD3
      explanation: >-
        Reports COL1A1 falling together with the repressed TGFBR2 and SMAD3, which is
        the collagen deficit this edge asserts follows the chromatin repression.
  evidence:
  - reference: PMID:29275289
    reference_title: "Role of fluoride induced histone trimethylation in development of skeletal fluorosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "H3K9 ChIP PCR array analysis identified hyper H3K9 trimethylation in promoter regions of TGFBR2 and SMAD3."
    explanation: The chromatin mark and the promoters it lands on, in a human osteosarcoma cell line.
  - reference: PMID:29275289
    reference_title: "Role of fluoride induced histone trimethylation in development of skeletal fluorosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression of two other vital genes COL1A1 and MMP13 involved in TGFBR2-SMAD signaling pathway was also found to be down-regulated with a decrease in expression of TGFBR2 and SMAD3."
    explanation: >-
      The expression consequence, including COL1A1, which is what connects this node
      to the matrix node below it.


- name: Secondary Hyperparathyroidism
  description: >-
    The fluoridated skeleton takes up calcium avidly, and in a proportion of
    patients parathyroid drive rises in response, adding its own bone changes to
    the picture. Curated as a node rather than a comorbidity because it feeds back
    onto bone resorption.
  biological_scale: ORGANISM
  downstream:
  - target: Osteocyte-Driven Osteoclastogenesis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Recorded INDIRECT_KNOWN_INTERMEDIATES because the intermediate is named: the
      osteocyte. The cited coculture work compares PTH with fluoride on
      osteocyte-driven osteoclast differentiation and finds fluoride's effect the
      larger, so this edge is an addition to the fluoride effect rather than the
      route for it.
    evidence:
    - reference: PMID:32156525
      reference_title: "Effect of fluoride on osteocyte-driven osteoclastic differentiation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The impact of fluoride on osteocyte-driven osteoclast differentiation was stronger than that of PTH."
      explanation: >-
        Places PTH on the osteocyte-driven arm this edge runs through, and sizes it
        against fluoride's own effect.
  evidence:
  - reference: PMID:3295994
    reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In a proportion of cases secondary hyperparathyroidism is observed with associated characteristic bone changes."
    explanation: >-
      States both the finding and its partial penetrance - "in a proportion of
      cases" - which is why this node is not on the main chain.

- name: Osteocyte-Driven Osteoclastogenesis
  description: >-
    Osteocytes exposed to fluoride drive osteoclast precursors toward
    differentiation, raising TRAP, RANK, JNK and NFATc1. This is the resorptive half
    of the accelerated turnover, and it is what stops the disease being a pure
    bone-forming disorder.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: osteoclast differentiation
    modifier: INCREASED
    term:
      id: GO:0030316
      label: osteoclast differentiation
  downstream:
  - target: Accelerated and Disordered Bone Turnover
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34769367
      reference_title: "Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        By up-regulating RANKL and inhibiting SOST, PTH enhances the effectiveness of
        low-dose of fluoride in bone turnover promotion
      explanation: >-
        Connects osteocyte RANKL output to bone turnover promotion. Indirect because the
        sentence is framed around PTH modulating fluoride's effect rather than around
        osteoclastogenesis driving turnover directly.
  evidence:
  - reference: PMID:32156525
    reference_title: "Effect of fluoride on osteocyte-driven osteoclastic differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Gene expression levels of TRAP, RANK, JNK and NFAtc1 significantly increased in fluoride affected osteoclast precursor cocultured with osteocyte-like cells."
    explanation: The osteoclastogenic markers raised in the transwell coculture this node describes.
  - reference: PMID:32156525
    reference_title: "Effect of fluoride on osteocyte-driven osteoclastic differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The impact of fluoride on osteocyte-driven osteoclast differentiation was stronger than that of PTH."
    explanation: >-
      The comparison that ranks the two drivers, and the reason the parathyroid edge
      above is recorded as additive rather than as the mechanism.

- name: Accelerated and Disordered Bone Turnover
  description: >-
    Formation and resorption both run fast, and the matrix produced is defective.
    The convergence point of every arm above, and the process the field identifies
    as critical to progression.
  biological_scale: TISSUE
  locations:
  - preferred_term: bone tissue
    term:
      id: UBERON:0002481
      label: bone tissue
  biological_processes:
  - preferred_term: ossification
    modifier: INCREASED
    term:
      id: GO:0001503
      label: ossification
  - preferred_term: bone resorption
    modifier: INCREASED
    term:
      id: GO:0045453
      label: bone resorption
  downstream:
  - target: Mixed Osteosclerosis, Osteomalacia and Osteoporosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34769367
      reference_title: "Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: >-
        it can not only cause osteosclerosis by enhancing osteogenic activity but also
        lead to osteoporosis by promoting bone resorption
      explanation: >-
        Derives both poles of the mixed lesion from the two halves of the turnover
        imbalance, which is what makes this node mixed rather than a single lesion.
  evidence:
  - reference: PMID:3295994
    reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Increased metabolic turnover of the bone, impaired bone collagen synthesis and increased avidity for calcium are features in fluoride toxicity."
    explanation: Names increased metabolic turnover as a defining feature of fluoride toxicity in bone.
  - reference: PMID:34769367
    reference_title: "Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Currently, active osteogenesis and accelerated bone turnover are considered critical processes in the progression of skeletal fluorosis."
    explanation: The current review's placement of this process at the centre of progression.

- name: Mixed Osteosclerosis, Osteomalacia and Osteoporosis
  description: >-
    The skeletal lesion is not one thing. Osteosclerosis, osteomalacia and
    osteoporosis coexist in varying proportion, with exostosis formation on top.
    This entry does not force a single lesion, for the same reason it does not force
    a single mode of bone cell response.
  biological_scale: TISSUE
  locations:
  - preferred_term: bone element
    term:
      id: UBERON:0001474
      label: bone element
  downstream:
  - target: Ligament and Interosseous Membrane Ossification
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30415519
      reference_title: "Skeletal fluorosis in Vavuniya District: an observational study."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The radiographic criteria of skeletal fluorosis were trabecular haziness,
        osteosclerosis, osteophytes, cortical thickening and ligamentous or muscle
        attachment ossification.
      explanation: >-
        Places osteosclerosis and ligamentous ossification in the same radiographic
        picture. Indirect: the criteria list establishes that the two occur together,
        not that the bone lesion produces the ligamentous one.
  - target: Joint Immobilization and Skeletal Deformity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:3295994
      reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        The total quantity of ingested fluoride is the single most important factor
        which determines the clinical course of the disease which is characterized by
        immobilization of joints of the axial skeleton and of the major joints of the
        extremities.
      explanation: >-
        Names joint immobilization as the clinical course of the disease whose bone
        lesion this node describes. Indirect because the sentence runs from ingested
        dose to clinical outcome without asserting the lesion-to-immobilization step.
  evidence:
  - reference: PMID:3295994
    reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A combination of osteosclerosis, osteomalacia and osteoporosis of varying degrees as well as exostosis formation characterizes the bone lesions."
    explanation: The mixed lesion this node is named for, stated as such.
  - reference: PMID:34769367
    reference_title: "Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "patients with skeletal fluorosis mainly present with symptoms of osteosclerosis, osteochondrosis, osteoporosis, and degenerative changes in joint cartilage."
    explanation: >-
      The modern review lists the same mixture, adding osteochondrosis and
      degenerative joint cartilage change.

- name: Ligament and Interosseous Membrane Ossification
  description: >-
    Ossification spreads beyond bone into the ligaments and interosseous membranes,
    which is the radiographic signature of the disease and the step that converts a
    metabolic bone disorder into a mechanical one.
  biological_scale: TISSUE
  locations:
  - preferred_term: ligament
    term:
      id: UBERON:0000211
      label: ligament
  biological_processes:
  - preferred_term: ossification
    modifier: INCREASED
    term:
      id: GO:0001503
      label: ossification
  downstream:
  - target: Spinal Canal and Foraminal Narrowing
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:2172892
      reference_title: "Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        resulting in generalised sclerosis and osteophytosis, with reduction in the
        diameter of the intervertebral foramina and of the spinal canal
      explanation: >-
        States the narrowing as the consequence of the sclerosis and osteophytosis this
        edge starts from, in a survey of the endemic population.
  - target: Joint Immobilization and Skeletal Deformity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36583212
      reference_title: "Brick tea consumption and its relationship with fluorosis in Tibetan areas."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        Radiographic examination of SF may show increased bone matrix density and
        fibrous ossification, tendon attachment calcification, joint degeneration,
        degenerative hyperplasia, and ossification changes in the fibrous tissues
      explanation: >-
        Reports fibrous and tendon-attachment ossification alongside joint degeneration.
        Indirect: the two are listed as coexisting radiographic findings rather than as
        cause and effect.
  evidence:
  - reference: PMID:31501957
    reference_title: "Skeletal fluorosis: don't miss the diagnosis!"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Radiographic presentation is mainly characterized by bone changes with osteocondensation and later ossification of many ligaments and interosseous membranes."
    explanation: >-
      The sequence this node records - osteocondensation first, then ossification of
      ligaments and interosseous membranes.
  - reference: PMID:2661032
    reference_title: "Occupational skeletal fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A 20-30 years' occupational and/or environmental exposure to fluorine may cause osteosclerosis, especially of the spine and pelvic bones, and calcification of spinal ligaments."
    explanation: >-
      The same finding from the occupational literature, with the exposure duration
      it takes and the sites it favours.

- name: Spinal Canal and Foraminal Narrowing
  description: >-
    Generalised sclerosis and osteophytosis reduce the diameter of the spinal canal
    and of the intervertebral foramina. This is the node that makes the neurological
    disease mechanical, and it is why the chain runs through bone rather than
    through nerve.
  biological_scale: TISSUE
  locations:
  - preferred_term: vertebral canal
    term:
      id: UBERON:0006692
      label: vertebral canal
  downstream:
  - target: Compressive Myelopathy and Radiculopathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:2172892
      reference_title: "Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These deficits were clearly found to be a consequence of fluoride deposition in
        bones, resulting in generalised sclerosis and osteophytosis, with reduction in
        the diameter of the intervertebral foramina and of the spinal conal.
      explanation: >-
        Names the reduction in canal and foraminal diameter, which is this edge's source
        node, and attributes the myelopathic and radiculopathic deficits to it.
    - reference: PMID:2172892
      reference_title: "Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Advanced osteosclerosis commonly causes severe spastic quadriparesis in flexion,
        accompanied by distressing spasms and urinary incontinence.
      explanation: >-
        Reports the neurological syndrome this edge ends at. Indirect because it
        attributes the syndrome to advanced osteosclerosis, which is upstream of this
        edge's source: reaching the narrowing takes an inference step.
  evidence:
  - reference: PMID:2172892
    reference_title: "Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These deficits were clearly found to be a consequence of fluoride deposition in bones, resulting in generalised sclerosis and osteophytosis, with reduction in the diameter of the intervertebral foramina and of the spinal conal."
    explanation: >-
      Traces the deficits back through the narrowing to the bone deposition, in a
      decade of surveys in the Ethiopian Rift Valley.

- name: Compressive Myelopathy and Radiculopathy
  description: >-
    Cord and root compression from the narrowed canal and foramina, producing
    spastic paresis, spasms and sphincter disturbance in advanced disease. The
    mechanism is compression, not neurotoxicity - this entry curates that
    distinction explicitly, because it is the point on which the management of the
    neurological disease turns.
  biological_scale: ORGANISM
  locations:
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  evidence:
  - reference: PMID:2172892
    reference_title: "Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neurological manifestations in the forms of myelopathy with and without radiculopathy (respectively 72% and 28%) occurred after exposure to high fluoride (greater than 4 ppm) for longer than 10 years."
    explanation: >-
      The split between myelopathy with and without radiculopathy, and the exposure
      it takes to get there - above 4 ppm for more than ten years.
  - reference: PMID:2172892
    reference_title: "Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Advanced osteosclerosis commonly causes severe spastic quadriparesis in flexion, accompanied by distressing spasms and urinary incontinence."
    explanation: The advanced presentation, and what it costs the patient.
  - reference: PMID:19305069
    reference_title: "Neurology of endemic skeletal fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Neurological complications of endemic skeletal fluorosis, namely radiculopathy, myelopathy or both are mechanical in nature and till date the evidence for direct neurotoxicity of fluoride is lacking."
    explanation: >-
      The load-bearing statement for this node's causal_link_type and for the
      `sf_neuro_mechanism` discussion: the complications are mechanical, and direct
      fluoride neurotoxicity is not evidenced. Graded OTHER as a review's assessment
      of a literature rather than its own measurement.

- name: Joint Immobilization and Skeletal Deformity
  description: >-
    The clinical endpoint: the joints of the axial skeleton and the major limb
    joints stiffen and immobilise, with crippling deformity. This is what "crippling
    fluorosis" names.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:3295994
    reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The total quantity of ingested fluoride is the single most important factor which determines the clinical course of the disease which is characterized by immobilization of joints of the axial skeleton and of the major joints of the extremities."
    explanation: The distribution of the immobilization, axial first and then the large limb joints.
  - reference: PMID:12660366
    reference_title: "Antioxidant defense system and lipid peroxidation in patients with skeletal fluorosis and in fluoride-intoxicated rabbits."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The main manifestations of skeletal fluorosis are crippling bone deformities, spinal compressions, and restricted movements of joints."
    explanation: >-
      The three manifestations named together - deformity, spinal compression and
      restricted joint movement - which are the three endpoints this chain reaches.
  - reference: PMID:3295994
    reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Contrary to earlier thinking, severe crippling forms of skeletal fluorosis are seen in paediatric age group too."
    explanation: >-
      That the crippling form occurs in children too. Curated because the older
      assumption was that it did not, and the coal-burning surveys below confirm it.


phenotypes:
- category: Musculoskeletal
  name: Joint Pain and Stiffness
  description: Pain and stiffness in the spine and large joints, and usually the presenting complaint.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  reports_on:
  - target: Joint Immobilization and Skeletal Deformity
    relationship: READOUT_OF
  evidence:
  - reference: PMID:12660366
    reference_title: "Antioxidant defense system and lipid peroxidation in patients with skeletal fluorosis and in fluoride-intoxicated rabbits."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The main manifestations of skeletal fluorosis are crippling bone deformities, spinal compressions, and restricted movements of joints."
    explanation: Names restricted joint movement among the main manifestations.

- category: Musculoskeletal
  name: Restricted Joint Mobility
  description: >-
    Progressive limitation of movement, beginning in the axial skeleton and
    extending to the major limb joints, ending in immobilization.
  phenotype_term:
    preferred_term: Limitation of joint mobility
    term:
      id: HP:0001376
      label: Limitation of joint mobility
  reports_on:
  - target: Joint Immobilization and Skeletal Deformity
    relationship: READOUT_OF
  evidence:
  - reference: PMID:3295994
    reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The total quantity of ingested fluoride is the single most important factor which determines the clinical course of the disease which is characterized by immobilization of joints of the axial skeleton and of the major joints of the extremities."
    explanation: The distribution and course of the immobilization this phenotype records.

- category: Skeletal
  name: Osteosclerosis
  description: >-
    Increased bone density, most marked in the spine and pelvis, and the
    radiographic finding the diagnosis is usually made on.
  phenotype_term:
    preferred_term: generalized osteosclerosis
    term:
      id: HP:0005789
      label: Generalized osteosclerosis
  diagnostic: true
  reports_on:
  - target: Mixed Osteosclerosis, Osteomalacia and Osteoporosis
    relationship: READOUT_OF
  evidence:
  - reference: PMID:2661032
    reference_title: "Occupational skeletal fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A 20-30 years' occupational and/or environmental exposure to fluorine may cause osteosclerosis, especially of the spine and pelvic bones, and calcification of spinal ligaments."
    explanation: Names the finding and the sites it favours.
  - reference: PMID:37883215
    reference_title: "Skeletal Fluorosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiologic imaging performed for suspected fractures revealed periosteal reaction, cortical thickening with increased bone density, and ligament and tendon ossification, which were not present on imaging obtained 3 years before presentation."
    explanation: >-
      The radiographic picture in an individual patient, and unusually with a
      three-year-earlier normal comparison that dates its development.
  - reference: PMID:2172892
    reference_title: "Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These deficits were clearly found to be a consequence of fluoride deposition in bones, resulting in generalised sclerosis and osteophytosis, with reduction in the diameter of the intervertebral foramina and of the spinal conal."
    explanation: >-
      Names the sclerosis as generalised, which is the binding this record makes.
  notes: >-
    Bound to `HP:0005789` (Generalized osteosclerosis). The Ethiopian field surveys
    describe "generalised sclerosis" and the occupational review "osteosclerosis,
    especially of the spine and pelvic bones", so the generalized term is what the
    cited evidence carries; the broader `HP:0011001` (Increased bone mineral
    density) would have lost that. Note the deep-research report offered `HP:0100774`
    for "Osteosclerosis"; HPO calls that term *Hyperostosis*, and it is not bound
    here.

- category: Musculoskeletal
  name: Neurogenic Muscle Atrophy
  description: >-
    Muscle wasting in established disease that is neurogenic in origin, not
    myopathic: biopsy shows type I atrophy and type I grouping with no myopathic
    change. Curated because the distinction is the same one the whole neurological
    arm of this entry turns on - the muscle is affected through the nerve.
  phenotype_term:
    preferred_term: Neurogenic skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  reports_on:
  - target: Compressive Myelopathy and Radiculopathy
    relationship: READOUT_OF
  evidence:
  - reference: PMID:10878791
    reference_title: "Studies on skeletal muscle biopsies in endemic skeletal fluorosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histochemistry and histopathology of muscle biopsies showed features of muscle atrophy, evidenced by 'type I' atrophy and 'type I' grouping. No myopathic changes were observed."
    explanation: >-
      The histological finding, and the absence of the myopathic alternative in the
      same biopsies.
  - reference: PMID:10878791
    reference_title: "Studies on skeletal muscle biopsies in endemic skeletal fluorosis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study included 22 patients with established osteofluorosis. 16 of them showed only EMG changes of neurogenic muscle disease."
    explanation: >-
      Graded INDIRECT: the cohort and the electrophysiology behind the biopsy
      finding rather than the finding itself.
  notes: >-
    Filed under Musculoskeletal because the lesion is in muscle, but it is a
    neurological readout and `reports_on` points at the myelopathy node accordingly.
    A frequency is not recorded: 16 of 22 had neurogenic EMG changes, but the
    denominator is a biopsy series of patients with established disease, not a
    prevalence sample.

- category: Genitourinary
  name: Urinary Incontinence
  description: >-
    Sphincter disturbance accompanying the advanced compressive myelopathy, not a
    renal or bladder effect of fluoride.
  phenotype_term:
    preferred_term: Urinary incontinence
    term:
      id: HP:0000020
      label: Urinary incontinence
  reports_on:
  - target: Compressive Myelopathy and Radiculopathy
    relationship: READOUT_OF
  evidence:
  - reference: PMID:2172892
    reference_title: "Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Advanced osteosclerosis commonly causes severe spastic quadriparesis in flexion, accompanied by distressing spasms and urinary incontinence."
    explanation: >-
      Names urinary incontinence, with the spasms, as accompanying the advanced
      spastic presentation that advanced osteosclerosis causes.

- category: Skeletal
  name: Bone Pain
  description: Deep skeletal pain in the fluorotic skeleton.
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
  reports_on:
  - target: Mixed Osteosclerosis, Osteomalacia and Osteoporosis
    relationship: READOUT_OF
  evidence:
  - reference: PMID:12660366
    reference_title: "Antioxidant defense system and lipid peroxidation in patients with skeletal fluorosis and in fluoride-intoxicated rabbits."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "The main manifestations of skeletal fluorosis are crippling bone deformities, spinal compressions, and restricted movements of joints."
    explanation: >-
      Graded INDIRECT: the sentence names crippling bone deformities and restricted
      movement rather than pain as such, and pain is the symptom that accompanies
      them in the clinical descriptions cited elsewhere in this entry.

- category: Skeletal
  name: Skeletal Deformity
  description: >-
    Kyphosis and limb deformity in advanced disease, including in children exposed
    during growth.
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  reports_on:
  - target: Joint Immobilization and Skeletal Deformity
    relationship: READOUT_OF
  evidence:
  - reference: PMID:36426635
    reference_title: "Skeletal fluorosis secondary to harmful inhalant use."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographs demonstrated diffuse periosteal new bone formation and sclerosis consistent with skeletal fluorosis."
    explanation: >-
      Graded INDIRECT: the radiographic description is of periosteal new bone and
      sclerosis rather than of kyphosis specifically. The same case presented with
      hand swelling and long bone deformities.
  - reference: PMID:3295994
    reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Contrary to earlier thinking, severe crippling forms of skeletal fluorosis are seen in paediatric age group too."
    explanation: That the crippling deformity occurs in children as well as adults.

- category: Skeletal
  name: Exostoses
  description: >-
    Bony outgrowths at ligament and tendon attachments, listed with the
    osteosclerosis, osteomalacia and osteoporosis as part of the characteristic
    lesion rather than as a separate complication.
  phenotype_term:
    preferred_term: Exostoses
    term:
      id: HP:0100777
      label: Exostoses
  reports_on:
  - target: Mixed Osteosclerosis, Osteomalacia and Osteoporosis
    relationship: READOUT_OF
  evidence:
  - reference: PMID:3295994
    reference_title: "Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A combination of osteosclerosis, osteomalacia and osteoporosis of varying degrees as well as exostosis formation characterizes the bone lesions."
    explanation: >-
      Names exostosis formation alongside the three mineral lesions as what
      characterises the bone in this disease.

- category: Neurologic
  name: Spastic Paresis
  description: >-
    Spastic paresis from cord compression, with spasms and sphincter disturbance in
    advanced disease. Mechanical in origin.
  phenotype_term:
    preferred_term: Spastic quadriparesis in flexion
    term:
      id: HP:0001285
      label: Spastic tetraparesis
  reports_on:
  - target: Compressive Myelopathy and Radiculopathy
    relationship: READOUT_OF
  evidence:
  - reference: PMID:2172892
    reference_title: "Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Advanced osteosclerosis commonly causes severe spastic quadriparesis in flexion, accompanied by distressing spasms and urinary incontinence."
    explanation: >-
      The advanced neurological presentation, and the binding is taken from it
      directly: the source says spastic *quadri*paresis, and `HP:0001285` carries
      "Spastic quadriparesis" as an exact synonym.
  notes: >-
    Bound to `HP:0001285` (Spastic tetraparesis), defined by HPO as "Spastic weakness
    affecting all four limbs" and carrying "Spastic quadriparesis" as an exact
    synonym - a word-for-word match to the cited survey's "severe spastic
    quadriparesis in flexion". Two nearby terms were considered and rejected.
    `HP:0002313` (Spastic paraparesis) was bound in an earlier draft and is wrong on
    distribution: it is a lower-limb deficit, and both the quote and the entry's own
    mechanism - compression at the cervical canal - point to four limbs.
    `HP:0002510` (Spastic tetraplegia) has the right distribution but is defined as
    "Spastic *paralysis* affecting all four limbs", so it over-claims severity
    against a source that says paresis. Nothing curated here describes the deficit at
    an earlier stage, so this record binds the presentation the evidence actually
    reports rather than a generalization the evidence does not.

environmental:
- name: Chronic ingestion of fluoride-rich groundwater
  description: >-
    The dominant exposure worldwide. Fluoride dissolved from bedrock into shallow
    groundwater, drunk for years. The dose-response is close to linear from
    relatively low concentrations, which is why this exposure is curated with a
    threshold rather than as a simple presence.
  exposure_term:
    preferred_term: exposure to fluoride in drinking water via ingestion
    term:
      id: ECTO:9000423
      label: exposure to fluoride
  exposure_classifications:
    hazard_agent_type:
    - classification_value: CHEMICAL
    exposure_route:
    - classification_value: ORAL
    exposure_duration:
    - classification_value: CHRONIC
    exposome_domain:
    - classification_value: GENERAL_EXTERNAL
      notes: >-
        Recorded GENERAL_EXTERNAL because the determinant is the geochemistry of the
        local aquifer rather than a discrete personal exposure.
  influences_mechanisms:
  - target: Chronic Excess Fluoride Intake
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: This is the intake the initiating node describes, by its commonest route.
    evidence:
    - reference: PMID:37861949
      reference_title: "Fluoride Exposure and Skeletal Fluorosis: a Systematic Review and Dose-response Meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The dose-response curve based on a one-stage cubic spline regression model showed an almost linear positive relation between exposure and SF occurrence starting from relatively low concentrations up to 5 mg/L and 2.5 mg/L, respectively, for water and urinary fluoride, with no substantial increase above this threshold."
      explanation: >-
        The dose-response relation between water fluoride and disease occurrence,
        which is what makes this exposure causal rather than merely associated.
  evidence:
  - reference: PMID:34769367
    reference_title: "Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "High concentrations of fluoride in the environment and drinking water are major causes"
    explanation: Names drinking water as a major cause.
  - reference: PMID:37861949
    reference_title: "Fluoride Exposure and Skeletal Fluorosis: a Systematic Review and Dose-response Meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When comparing the highest versus the lowest fluoride category, the summary risk ratio (RR) for SF prevalence was 2.05 (95% CI 1.60; 2.64), with a value of 2.73 (95% CI 1.92; 3.90) for drinking water and 1.40 (95% CI 0.90; 2.17) for urinary fluoride."
    explanation: >-
      The pooled risk ratio across 23 studies, and the useful detail that the
      association is stronger for water fluoride than for urinary fluoride.

- name: Habitual consumption of high-fluoride brick tea
  description: >-
    Brick tea is pressed from older stems and leaves of the tea plant and its
    fluoride content exceeds China's national standard; in Tibetan, Kazakh and
    Mongolian communities it is drunk in quantity. Curated separately from
    groundwater because the intervention is different - the tea has to change, not
    the well.
  exposure_term:
    preferred_term: exposure to fluoride in brick tea via ingestion
    term:
      id: ECTO:9000423
      label: exposure to fluoride
  exposure_classifications:
    hazard_agent_type:
    - classification_value: CHEMICAL
    exposure_route:
    - classification_value: ORAL
    exposure_duration:
    - classification_value: CHRONIC
    exposome_domain:
    - classification_value: SPECIFIC_EXTERNAL
      notes: >-
        Recorded SPECIFIC_EXTERNAL rather than GENERAL_EXTERNAL, unlike the
        groundwater entry: this is a dietary practice of particular communities, not
        a property of the region's water supply.
  influences_mechanisms:
  - target: Chronic Excess Fluoride Intake
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: A second oral route to the same initiating node.
    evidence:
    - reference: PMID:26499132
      reference_title: "Prevalence of Brick Tea-Type Fluorosis in the Tibet Autonomous Region."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The average daily fluoride intake from drinking brick tea in all seven districts in Tibet was much higher than the national standard."
      explanation: >-
        The dose actually delivered by this route: measured daily fluoride intake
        from brick tea above the national standard across all seven Tibetan districts
        surveyed, which is the excess this edge asserts.
  evidence:
  - reference: PMID:36583212
    reference_title: "Brick tea consumption and its relationship with fluorosis in Tibetan areas."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The available evidence revealed that brick tea may be produced from older stems and leaves of the tea plant and that the fluoride content of brick tea exceeds the national standard."
    explanation: >-
      Why brick tea and not tea generally: it is made from older stems and leaves,
      and its fluoride content exceeds the national standard. Graded OTHER as a
      review's synthesis across studies.
  - reference: PMID:33660557
    reference_title: "Association between Bone Morphogenetic Protein 2 Gene Polymorphisms and Skeletal Fluorosis of The Brick-tea Type Fluorosis in Tibetans and Kazakhs, China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using the standard WS/192-2008 (China), 221 skeletal fluorosis cases were diagnosed, including 123 Tibetans and 98 Kazakhs."
    explanation: >-
      221 diagnosed cases among Tibetan and Kazakh brick-tea drinkers, against
      China's national diagnostic standard - the scale of this exposure's effect.

- name: Indoor combustion of fluoride-rich coal for cooking and food drying
  description: >-
    In parts of southwest China, high-fluoride coal is burned indoors on open
    stoves, and foodstuffs baked over the stove take up fluoride from the smoke. The
    route is both inhalational and dietary, and the cited survey found the disease in
    children exposed during growth.
  exposure_term:
    preferred_term: exposure to fluoride from indoor coal combustion
    term:
      id: ECTO:9000423
      label: exposure to fluoride
  exposure_classifications:
    hazard_agent_type:
    - classification_value: CHEMICAL
    exposure_route:
    - classification_value: INHALATION
    - classification_value: ORAL
    exposure_duration:
    - classification_value: CHRONIC
    exposome_domain:
    - classification_value: SPECIFIC_EXTERNAL
  influences_mechanisms:
  - target: Chronic Excess Fluoride Intake
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Recorded with both INHALATION and ORAL routes because the same practice
      contaminates the indoor air and the food dried in it.
    evidence:
    - reference: PMID:20041010
      reference_title: "Child skeletal fluorosis from indoor burning of coal in southwestern China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Any student lived in a household that burned coal, used an open-burning stove, or baked foodstuffs over a coal stove was deemed high-risk for skeletal fluorosis."
      explanation: The exposure definition the survey used, which names both the stove and the food.
  evidence:
  - reference: PMID:20041010
    reference_title: "Child skeletal fluorosis from indoor burning of coal in southwestern China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall prevalence of child skeletal fluorosis due to indoor burning of coal was 7.5%."
    explanation: The prevalence this exposure produced in children in Guizhou.

- name: Occupational and industrial inhalation of fluoride
  description: >-
    Twenty to thirty years of industrial exposure produces the same osteosclerosis
    and spinal ligament calcification as the endemic dietary forms.
  exposure_term:
    preferred_term: occupational exposure to fluoride by inhalation
    term:
      id: ECTO:9000423
      label: exposure to fluoride
  exposure_classifications:
    hazard_agent_type:
    - classification_value: CHEMICAL
    exposure_route:
    - classification_value: INHALATION
    exposure_duration:
    - classification_value: CHRONIC
    exposome_domain:
    - classification_value: SPECIFIC_EXTERNAL
  influences_mechanisms:
  - target: Chronic Excess Fluoride Intake
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: The inhalational route to the same initiating node.
    evidence:
    - reference: PMID:2661032
      reference_title: "Occupational skeletal fluorosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "A 20-30 years' occupational and/or environmental exposure to fluorine may cause osteosclerosis, especially of the spine and pelvic bones, and calcification of spinal ligaments."
      explanation: The exposure duration and the skeletal result, from the occupational literature.
  evidence:
  - reference: PMID:28840484
    reference_title: "Pulmonary fluorosis: a review."
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: "Although the systemic toxicity of fluoride has been extensively studied, still there is lacuna in the field of pulmonary fluoride toxicity."
    explanation: >-
      Graded NO_EVIDENCE and curated deliberately. This review of pulmonary fluoride
      toxicity is the natural place to look for the inhalational arm's mechanism and
      it says the field has a lacuna there. It bears on the lung rather than on the
      skeleton, so it supports no claim in this entry - but recording that the
      inhalational mechanism is not characterised stops the next curator assuming it
      was simply not looked for.

- name: Deliberate inhalation of fluorocarbon propellants
  description: >-
    Chronic huffing of difluoroethane-containing compressed gas dusters produces
    skeletal fluorosis outside any endemic area; two independent published cases are
    curated here. Recorded as a distinct route because it delivers the exposure with
    no endemic-area history to prompt the diagnosis - how commonly it does so is not
    established by this entry's evidence.
  exposure_term:
    preferred_term: exposure to 1,1-difluoroethane by deliberate inhalation
    term:
      id: ECTO:9000423
      label: exposure to fluoride
  exposure_classifications:
    hazard_agent_type:
    - classification_value: CHEMICAL
    exposure_route:
    - classification_value: INHALATION
    exposure_duration:
    - classification_value: CHRONIC
    exposome_domain:
    - classification_value: SPECIFIC_EXTERNAL
  influences_mechanisms:
  - target: Chronic Excess Fluoride Intake
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      A non-endemic, non-dietary route to the same initiating node, at doses far
      above anything the environmental routes deliver.
    evidence:
    - reference: PMID:36426635
      reference_title: "Skeletal fluorosis secondary to harmful inhalant use."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diagnostic testing demonstrated urine fluoride 64.5 mg/L (ref <3) and serum fluoride 1.8 mg/L (ref <0.13)."
      explanation: >-
        The measured burden, against the laboratory reference intervals - urine
        fluoride more than twenty times the upper limit.
  notes: >-
    `exposure_term` binds the generic `ECTO:9000423` (exposure to fluoride). ECTO
    was searched and has no term for 1,1-difluoroethane or for propellant inhalation;
    the specific agent and route are carried in `preferred_term`.
  evidence:
  - reference: PMID:36426635
    reference_title: "Skeletal fluorosis secondary to harmful inhalant use."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a case of skeletal fluorosis from chronic inhalation of an electronic duster product containing 1,1-difluoroethane."
    explanation: The exposure and the agent, in the index case.
  - reference: PMID:37883215
    reference_title: "Skeletal Fluorosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiologic imaging performed for suspected fractures revealed periosteal reaction, cortical thickening with increased bone density, and ligament and tendon ossification, which were not present on imaging obtained 3 years before presentation."
    explanation: >-
      A second, independent case with the same agent - and imaging from three years
      earlier showing none of it, which dates the disease to the exposure.

genetic:
- name: ATP2B1 susceptibility variants
  gene_term:
    preferred_term: ATP2B1
    term:
      id: hgnc:814
      label: ATP2B1
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    ATP2B1 encodes a plasma-membrane calcium pump, which is a plausible modifier for
    a disease whose bone shows increased avidity for calcium. Two loci were
    associated in a 962-subject Chinese cross-sectional study, and after confounder
    control the reported protective and risk effects are described within age, sex,
    urinary-fluoride, serum-calcium and serum-phosphorus strata - so this is a
    susceptibility signal in need of replication rather than an established modifier.
    `frequency` is deliberately absent: the source reports no allele frequency, and
    the slot is not a place to describe a study.
  evidence:
  - reference: PMID:37211801
    reference_title: "Association between polymorphism and haplotype of ATP2B1 gene and skeletal fluorosis in Han population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results suggested that rs17249754 and rs7136259 were associated with skeletal fluorosis."
    explanation: The two associated loci.
  - reference: PMID:37211801
    reference_title: "Association between polymorphism and haplotype of ATP2B1 gene and skeletal fluorosis in Han population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In China, 962 individuals were recruited, including 342 cases of skeletal fluorosis."
    explanation: The study size behind them.
  - reference: PMID:37211801
    reference_title: "Association between polymorphism and haplotype of ATP2B1 gene and skeletal fluorosis in Han population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After controlling confounders, the protective effect of GG genotype in rs17249754 was apparent in individuals over 45 years old, female, with urine fluoride concentration below 1.6 mg/L, serum calcium above 2.25 mmol/L or serum phosphorus between 1.1 and 1.3."
    explanation: >-
      The strata the effects are reported within, which is what this record's notes
      turn on.

- name: ALOX15 variants
  gene_term:
    preferred_term: ALOX15
    term:
      id: hgnc:433
      label: ALOX15
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  notes: >-
    No single-SNP association was found; a haplotype effect was reported in Han
    participants only. (`frequency` is absent for the reason given on the ATP2B1
    record - the source reports no allele frequency.)
    Recorded DISPUTED rather than SUSCEPTIBILITY because the primary analysis was
    negative and the positive result is a haplotype effect confined to one of the
    three ethnic groups studied and to particular age and intake strata. Curated at
    all because the negative half is worth recording.
  evidence:
  - reference: PMID:31565963
    reference_title: "Association between ALOX15 gene polymorphism and brick-tea type skeletal fluorosis in Tibetans, Kazaks and Han, China."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The genotypes of ALOX15 rs7220870, rs2664593 and rs1107852 were not associated with the risk of SF."
    explanation: >-
      Graded REFUTE against a single-SNP association: none of the three genotypes was
      associated with risk across the 1,023-subject study.
  - reference: PMID:31565963
    reference_title: "Association between ALOX15 gene polymorphism and brick-tea type skeletal fluorosis in Tibetans, Kazaks and Han, China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After reconstructing the haplotype of rs7220870 and rs11078528, the risk effect of haplotype CA was found in Han participants aged ≤45 years or with moderate fluoride intake."
    explanation: >-
      The positive half, and its limits - one ethnic group, and only in defined age
      and fluoride-intake strata.

- name: ESR1 rs9340799
  gene_term:
    preferred_term: ESR1
    term:
      id: hgnc:3467
      label: ESR1
  relationship_type: PROTECTIVE
  variant_origin: GERMLINE
  notes: >-
    Recorded PROTECTIVE, which is the direction reported: carrying the G allele
    lowered the odds of brick-tea-type fluorosis in a 989-subject cross-sectional
    study across Inner Mongolia, Qinghai and Xinjiang, diagnosed against the Chinese
    national standard WS192-2008. As with the other genetic records here this is a
    single unreplicated study, and the authors themselves frame the ethnic
    differences as modifiable by tea fluoride intake, sex and age. This record is
    deliberately not wired to a pathophysiology node. The study reports an allele
    frequency difference and no measurement of the receptor or of estrogen
    signaling in bone, this entry models no estrogen-dependent mechanism, and no
    node in it is a plausible landing for a receptor gene on the strength of a
    single protective association. A PubMed search for fluorosis with ESR1 or
    estrogen receptor in the title or abstract returned eleven records; apart
    from PMID:39824337 itself they concern dental fluorosis polymorphism
    associations (PMID:41174690, PMID:36354656, PMID:35066749, PMID:32185656) or
    sex hormone binding globulin in fluoride-exposed men (PMID:30677743), and
    none reports estrogen receptor signaling as a mechanism of skeletal
    fluorosis.
  evidence:
  - reference: PMID:39824337
    reference_title: "Association between ESR1 and COL1A1 gene polymorphisms and skeletal fluorosis in Tibetan, Kazakh, Mongolian and Russian populations, China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Binary logistic regression found that carried the ESR1 Rs9340799 G allele played a protective role in brick-tea-type fluorosis"
    explanation: The protective association, and the population it was found in.
  - reference: PMID:39824337
    reference_title: "Association between ESR1 and COL1A1 gene polymorphisms and skeletal fluorosis in Tibetan, Kazakh, Mongolian and Russian populations, China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The X-ray of the participants were diagnosed according to the diagnostic criteria of Chinese endemic skeletal fluorosis (WS192-2008)."
    explanation: The case definition the association rests on.
  - reference: PMID:39824337
    reference_title: "Association between ESR1 and COL1A1 gene polymorphisms and skeletal fluorosis in Tibetan, Kazakh, Mongolian and Russian populations, China."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data suggested that there may be a genetic component to the risk of skeletal fluorosis in participants of different ethnicities and that this difference could modified by tea fluoride intake, sex or age."
    explanation: >-
      Graded INDIRECT: the authors' own summary of what the study establishes, which
      qualifies the individual association rather than asserting it.

- name: COL1A1 rs1800012
  gene_term:
    preferred_term: COL1A1
    term:
      id: hgnc:2197
      label: COL1A1
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    The reported risk effect is confined to Russian participants in the same
    989-subject study, and within them was significant in men on sex-stratified
    analysis. The confidence interval is very wide, which is what a subgroup effect
    in a small stratum looks like; recorded because COL1A1 encodes the collagen whose
    synthesis the `Impaired Collagen Synthesis and Matrix Mineralization` node is
    about, and a reader looking for that gene should find the evidence and its
    limits rather than nothing.
  evidence:
  - reference: PMID:39824337
    reference_title: "Association between ESR1 and COL1A1 gene polymorphisms and skeletal fluorosis in Tibetan, Kazakh, Mongolian and Russian populations, China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Russians carried the COL1A1 Rs1800012 T allele had a significantly higher risk of developing skeletal fluorosis"
    explanation: The association, and the single ethnic group it was found in.
  - reference: PMID:39824337
    reference_title: "Association between ESR1 and COL1A1 gene polymorphisms and skeletal fluorosis in Tibetan, Kazakh, Mongolian and Russian populations, China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When stratified by sex, carriage of the T allele in COL1A1 Rs1800012 significantly increased the risk of developing skeletal fluorosis in Russian men."
    explanation: The sex-stratified result, which narrows it further.

- name: BMP2 variants tested and not associated
  gene_term:
    preferred_term: BMP2
    term:
      id: hgnc:1069
      label: BMP2
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  notes: >-
    A negative record kept on purpose. BMP signalling is the pathway the osteoblast
    activation node runs through, so BMP2 is exactly the gene a reader would expect
    to modify susceptibility - and in 598 Tibetan and Kazakh brick-tea drinkers it
    did not. `relationship_type: DISPUTED` because the vocabulary has no value for
    *tested and negative*: `DISPUTED` at least records that the claim was examined,
    where `UNKNOWN` - the other value that asserts no association - would read as
    untested.
  evidence:
  - reference: PMID:33660557
    reference_title: "Association between Bone Morphogenetic Protein 2 Gene Polymorphisms and Skeletal Fluorosis of The Brick-tea Type Fluorosis in Tibetans and Kazakhs, China."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Logistic regressions 2 analysis did not find the association between SNPs (Rs235764, Rs235739 and Rs996544) and skeletal fluorosis."
    explanation: >-
      Graded REFUTE against this record's own claim. Three SNPs tested, none
      associated, and the genetic-model, linkage-disequilibrium and haplotype
      analyses negative as well.
  - reference: PMID:33660557
    reference_title: "Association between Bone Morphogenetic Protein 2 Gene Polymorphisms and Skeletal Fluorosis of The Brick-tea Type Fluorosis in Tibetans and Kazakhs, China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using the standard WS/192-2008 (China), 221 skeletal fluorosis cases were diagnosed, including 123 Tibetans and 98 Kazakhs."
    explanation: The cohort and the diagnostic standard the negative rests on.


biochemical:
- name: Urinary fluoride
  presence: Increased
  biomarker_term:
    preferred_term: urinary fluoride concentration
    term:
      id: CHEBI:17051
      label: fluoride
  notes: >-
    The standard exposure biomarker, and the one the occupational diagnostic
    threshold is written against. Note it performs less well than water fluoride as
    a predictor of disease in the pooled analysis, which is recorded on its readout.
  readouts:
  - target: Chronic Excess Fluoride Intake
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Reports current intake. It is a weaker predictor of disease than water
      fluoride, which is expected of a short-half-life exposure marker for a disease
      that accumulates over decades.
    evidence:
    - reference: PMID:37861949
      reference_title: "Fluoride Exposure and Skeletal Fluorosis: a Systematic Review and Dose-response Meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "When comparing the highest versus the lowest fluoride category, the summary risk ratio (RR) for SF prevalence was 2.05 (95% CI 1.60; 2.64), with a value of 2.73 (95% CI 1.92; 3.90) for drinking water and 1.40 (95% CI 0.90; 2.17) for urinary fluoride."
      explanation: >-
        The pooled estimate for urinary fluoride, 1.40 with an interval crossing 1,
        against 2.73 for drinking water.
    - reference: PMID:37861949
      reference_title: "Fluoride Exposure and Skeletal Fluorosis: a Systematic Review and Dose-response Meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The RR for developing moderate-severe forms increases at 5.00 mg/L and 2.5 mg/L of water and urinary fluoride, respectively."
      explanation: The urinary threshold above which moderate-severe disease risk rises.
  reference_ranges:
  - upper_bound: 3.0
    unit: mg/L
    evidence:
    - reference: PMID:36426635
      reference_title: "Skeletal fluorosis secondary to harmful inhalant use."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diagnostic testing demonstrated urine fluoride 64.5 mg/L (ref <3) and serum fluoride 1.8 mg/L (ref <0.13)."
      explanation: >-
        The reference limit is quoted inline with the patient's value - urine
        fluoride 64.5 mg/L against a reference below 3.
    notes: >-
      `loinc_term` absent: no LOINC lookup was performed and the slot is
      `recommended`. This is a clinical laboratory's reference limit as quoted in a
      case report, not a population-derived interval.
  evidence:
  - reference: PMID:2661032
    reference_title: "Occupational skeletal fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "early diagnosis is based on the history of occupational exposure, examination of urinary fluoride excretion (over 8 mg F-/litre in 24 hours) and radiological signs."
    explanation: >-
      The occupational diagnostic threshold, expressed as 24-hour excretion rather
      than concentration.

- name: Serum fluoride
  presence: Increased
  biomarker_term:
    preferred_term: serum fluoride concentration
    term:
      id: CHEBI:17051
      label: fluoride
  notes: >-
    Recorded separately from urinary fluoride because it is a different specimen
    with a much lower reference limit, and because the two were reported together in
    the inhalant cases where both were extreme.
  readouts:
  - target: Chronic Excess Fluoride Intake
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reports circulating fluoride, the fraction en route to the skeleton.
    evidence:
    - reference: PMID:36426635
      reference_title: "Skeletal fluorosis secondary to harmful inhalant use."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diagnostic testing demonstrated urine fluoride 64.5 mg/L (ref <3) and serum fluoride 1.8 mg/L (ref <0.13)."
      explanation: Serum fluoride roughly fourteen times the upper reference limit in the index case.
  reference_ranges:
  - upper_bound: 0.13
    unit: mg/L
    evidence:
    - reference: PMID:36426635
      reference_title: "Skeletal fluorosis secondary to harmful inhalant use."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Diagnostic testing demonstrated urine fluoride 64.5 mg/L (ref <3) and serum fluoride 1.8 mg/L (ref <0.13)."
      explanation: The serum reference limit, quoted inline with the patient's value.
    notes: >-
      As for urinary fluoride, this is a laboratory reference limit quoted in a case
      report rather than a population-derived interval, and `loinc_term` is absent
      for the same reason.

- name: Serum soluble Klotho
  presence: Increased
  biomarker_term:
    preferred_term: serum soluble Klotho
    term:
      id: NCIT:C98116
      label: Klotho
  notes: >-
    A candidate severity marker rather than an exposure marker. It rises with tea
    fluoride intake, rises with disease severity, and rose in fluoride-exposed rats.
    The direction is *up*, stated plainly on the record because an earlier draft of
    this entry had it backwards. The study reports it as a partial mediator, carrying
    17.76% of the effect of intake on severity, so it is neither the whole path nor a
    bystander. Single study, unreplicated, and this entry curates no account of what
    sKlotho is measuring in bone.
  readouts:
  - target: Mixed Osteosclerosis, Osteomalacia and Osteoporosis
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Recorded CORRELATES_WITH, not READOUT_OF: the study relates sKlotho to disease
      severity, and this entry curates no account of what sKlotho measures in bone.
    evidence:
    - reference: PMID:32721666
      reference_title: "sKlotho is associated with the severity of brick tea-type skeletal fluorosis in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Serum sKlotho levels were also positively associated with the severity of SF"
      explanation: The association and its direction - positive, with severity.
    - reference: PMID:32721666
      reference_title: "sKlotho is associated with the severity of brick tea-type skeletal fluorosis in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mediation analysis showed that serum sKlotho levels mediated 17.76% of the increase in the severity of SF caused by an increase of 1 mg/day of TFI."
      explanation: >-
        The mediated fraction, which is what makes this a candidate mechanism marker
        rather than only a correlate.
  evidence:
  - reference: PMID:32721666
    reference_title: "sKlotho is associated with the severity of brick tea-type skeletal fluorosis in China."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, a significant increase of serum sKlotho levels in fluoride-exposed groups was also seen in the rat model."
    explanation: >-
      The same direction in the rat model, which is the study's own verification of
      the human finding.
  - reference: PMID:32721666
    reference_title: "sKlotho is associated with the severity of brick tea-type skeletal fluorosis in China."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A cross sectional case control study was conducted in residents over 50 years old from brick-tea drinking areas in Qinghai and Xinjiang Provinces, China."
    explanation: >-
      Graded INDIRECT: the population and design the association rests on, rather than
      the result.

diagnosis:
- name: Radiographic Diagnosis
  description: >-
    The diagnosis is radiographic: increased bone density in the axial skeleton
    first, then ossification of ligaments and interosseous membranes.
  evidence:
  - reference: PMID:31501957
    reference_title: "Skeletal fluorosis: don't miss the diagnosis!"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Radiographic presentation is mainly characterized by bone changes with osteocondensation and later ossification of many ligaments and interosseous membranes."
    explanation: The radiographic sequence the diagnosis rests on.
  - reference: PMID:37883215
    reference_title: "Skeletal Fluorosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiologic imaging performed for suspected fractures revealed periosteal reaction, cortical thickening with increased bone density, and ligament and tendon ossification, which were not present on imaging obtained 3 years before presentation."
    explanation: The same findings in an individual case, itemised.

- name: Exposure History and Urinary Fluoride
  description: >-
    Radiography alone does not distinguish this disease from several others, so the
    diagnosis rests on exposure history and fluoride measurement alongside it. The
    occupational literature sets a 24-hour urinary excretion threshold.
  evidence:
  - reference: PMID:2661032
    reference_title: "Occupational skeletal fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "early diagnosis is based on the history of occupational exposure, examination of urinary fluoride excretion (over 8 mg F-/litre in 24 hours) and radiological signs."
    explanation: The three-part diagnostic basis, with the urinary threshold.
  notes: >-
    The threshold quoted is for occupational exposure and is expressed as 24-hour
    excretion, which is not interchangeable with the spot concentration reference
    limits recorded under `biochemical`. Both are curated; neither is converted into
    the other here.

- name: China National Diagnostic Standard WS/192-2008
  description: >-
    Chinese field studies diagnose against a national standard rather than
    study-specific criteria, which is what makes their prevalence figures comparable.
  evidence:
  - reference: PMID:33660557
    reference_title: "Association between Bone Morphogenetic Protein 2 Gene Polymorphisms and Skeletal Fluorosis of The Brick-tea Type Fluorosis in Tibetans and Kazakhs, China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using the standard WS/192-2008 (China), 221 skeletal fluorosis cases were diagnosed, including 123 Tibetans and 98 Kazakhs."
    explanation: Names the standard and shows it in use as the case definition.
  notes: >-
    The standard's own content is not curated here - its text was not obtained, and
    this record cites only the fact of its use.

differential_diagnoses:
- name: Ankylosing Spondylitis
  description: >-
    Spinal ligament calcification and axial stiffness overlap closely. The
    discriminators are the exposure history and the fluoride measurements, not the
    radiograph.
  evidence:
  - reference: PMID:2661032
    reference_title: "Occupational skeletal fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The radiological picture may mimic many other diseases, especially ankylosing spondylitis, diffuse idiopathic hyperostosis, and rare bone diseases, such as Albers-Schönberg disease."
    explanation: Names this differential explicitly, alongside the others in this section.

- name: Diffuse Idiopathic Skeletal Hyperostosis
  description: >-
    Flowing ossification along the spine is the shared feature; DISH does not
    produce the generalised osteosclerosis or the interosseous membrane ossification.
  evidence:
  - reference: PMID:2661032
    reference_title: "Occupational skeletal fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The radiological picture may mimic many other diseases, especially ankylosing spondylitis, diffuse idiopathic hyperostosis, and rare bone diseases, such as Albers-Schönberg disease."
    explanation: Named in the same list of radiological mimics.

- name: Osteopetrosis
  description: >-
    Albers-Schonberg disease shares the dense skeleton. It is congenital and lacks
    the ligamentous ossification and the exposure history.
  evidence:
  - reference: PMID:2661032
    reference_title: "Occupational skeletal fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The radiological picture may mimic many other diseases, especially ankylosing spondylitis, diffuse idiopathic hyperostosis, and rare bone diseases, such as Albers-Schönberg disease."
    explanation: Named among the rare bone diseases the radiological picture mimics.

- name: Rheumatological Disease Generally
  description: >-
    Before the radiograph is taken, the presentation is joint pain and stiffness,
    and the disease is not clinically obvious.
  evidence:
  - reference: PMID:31501957
    reference_title: "Skeletal fluorosis: don't miss the diagnosis!"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Skeletal fluorosis is not clinically obvious and can be confused with other rheumatologic disorders."
    explanation: States the general confusion this record names.
  - reference: PMID:30415519
    reference_title: "Skeletal fluorosis in Vavuniya District: an observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 16 had been misdiagnosed as various types of arthritis."
    explanation: >-
      The confusion measured rather than asserted: every one of the sixteen Sri
      Lankan patients with confirmed fluoride bone disease had been carrying an
      arthritis diagnosis.

treatments:
- name: Water Improvement and Defluoridation
  description: >-
    Replacing or treating high-fluoride drinking water. The only intervention in
    this entry with pooled evidence that it reduces disease prevalence, and the one
    the public-health literature is built around.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: defluoridation of the drinking water supply
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  target_mechanisms:
  - target: Chronic Excess Fluoride Intake
    treatment_effect: INHIBITS
    description: Removes the exposure the initiating node describes.
    evidence:
    - reference: PMID:33333408
      reference_title: "Effects of water improvement and defluoridation on fluorosis-endemic areas in China: A meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "With water improvement, water fluoride levels decreased from 2.72 mg/L to 0.54 mg/L (95% confidence intervals: -2.75, -1.58), which was below the standard for drinking water (1.5 mg/L)."
      explanation: >-
        Evidence for the link rather than the outcome: water fluoride fell from 2.72
        to 0.54 mg/L, below the 1.5 mg/L standard, which is the exposure node being
        acted on.
  evidence:
  - reference: PMID:33333408
    reference_title: "Effects of water improvement and defluoridation on fluorosis-endemic areas in China: A meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "after water improvement, the prevalence of dental fluorosis decreased from 54.5% to 36.2% (95% confidence intervals: 0.12, 0.31) in children, and the prevalence of skeletal fluorosis decreased from 13.7% to 4.2% (95% confidence intervals: 0.16, 0.40) in adults."
    explanation: >-
      Adult skeletal fluorosis prevalence fell from 13.7% to 4.2% over an average of
      nearly sixteen years of water improvement.
  notes: >-
    `therapeutic_modality: OTHER` rather than BEHAVIORAL: replacing or treating a
    village water supply is public-works engineering, and nothing about the patient's
    behaviour changes.

- name: Symptomatic and Supportive Management
  description: >-
    Once established, the skeletal disease is not reversed by any treatment curated
    here, and management is directed at symptoms.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: symptomatic management
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Joint Immobilization and Skeletal Deformity
    treatment_effect: MODULATES
    description: >-
      Directed at the clinical endpoint. No treatment in this entry acts on a node
      upstream of it once exposure has stopped.
  evidence:
  - reference: PMID:31501957
    reference_title: "Skeletal fluorosis: don't miss the diagnosis!"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Management of fluorosis generally focuses on symptom treatment."
    explanation: States the management position this record records.
  - reference: PMID:37558119
    reference_title: "Chronic exposure to environmentally relevant concentration of fluoride impairs osteoblast's collagen synthesis and matrix mineralization: Involvement of epigenetic regulation in skeletal fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Globally, 200 million people are suffering from toxic manifestations of Fluoride(F), dental and skeletal fluorosis; unfortunately, there is no treatment."
    explanation: >-
      The blunter statement of the same thing, and the scale it applies at - 200
      million people, and no treatment. Graded OTHER as a paper's framing of its
      field rather than its own result.

- name: Surgical Decompression for Compressive Myelopathy
  description: >-
    Decompression for the neurological complications. Its role is limited and it is
    selected on imaging rather than offered routinely, which follows from the
    neurological disease being mechanical.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: spinal cord decompression
    term:
      id: NCIT:C124141
      label: Spinal Cord Decompression
  target_mechanisms:
  - target: Compressive Myelopathy and Radiculopathy
    treatment_effect: BYPASSES
    description: >-
      Recorded BYPASSES: decompression relieves the compression without acting on
      the ossification producing it, which continues while exposure does.
    evidence:
    - reference: PMID:19305069
      reference_title: "Neurology of endemic skeletal fluorosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Surgery has a limited role in alleviating the neurological disability and should be tailored to the individual based on the imaging findings."
      explanation: >-
        States both the limited role and the imaging-led selection this record
        describes.
  evidence:
  - reference: PMID:19305069
    reference_title: "Neurology of endemic skeletal fluorosis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Neurological complications of endemic skeletal fluorosis, namely radiculopathy, myelopathy or both are mechanical in nature and till date the evidence for direct neurotoxicity of fluoride is lacking."
    explanation: >-
      Graded INDIRECT: that the complications are mechanical is the rationale for
      offering decompression at all, but the sentence does not itself evaluate the
      operation.

- name: Calcium and Vitamin D Supplementation
  description: >-
    Calcium and vitamin D given alongside, or after, fluoride exposure. Two
    independent rodent studies report it alleviating established skeletal fluorosis:
    in mice it reduced fluoride deposition and restored the bone's elemental profile,
    and in rats low dietary calcium aggravated the disease while calcium plus
    fluoride-free water normalised bone turnover and restored osteocalcin,
    osteonectin and osteopontin expression. Rodent evidence only in this entry.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: calcium and vitamin D supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: calcium
      term:
        id: CHEBI:29108
        label: calcium(2+)
    - preferred_term: vitamin D
      term:
        id: CHEBI:27300
        label: vitamin D
  target_mechanisms:
  - target: Fluorapatite Substitution in Bone Mineral
    treatment_effect: INHIBITS
    description: >-
      Acts on the mineral node: supplementation reduced fluoride deposition in bone
      and retained its elemental homeostasis.
    evidence:
    - reference: PMID:33057951
      reference_title: "Calcium and Vitamin D Supplementation Effectively Alleviates Dental and Skeletal Fluorosis and Retain Elemental Homeostasis in Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "supplementation of calcium and vitamin D effectively alleviated dental and skeletal fluorosis, reduced F deposition, and retained elemental homeostasis of the bone."
      explanation: The deposition and elemental-profile result, in vivo.
  - target: Accelerated and Disordered Bone Turnover
    treatment_effect: MODULATES
    description: >-
      Acts on the turnover node: bone turnover was normalised and the matrix-protein
      genes recovered in the reversal arm.
    evidence:
    - reference: PMID:32770327
      reference_title: "Supplementation of Calcium and Fluoride-Free Water Mitigates Skeletal Fluorosis in Fluoride-Intoxicated Rats."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Expressions of osteocalcin, osteonectin and osteopontin were upregulated after providing NCD and FFW."
      explanation: >-
        The matrix-protein expression recovering in the calcium-plus-fluoride-free
        water arm.
    - reference: PMID:32770327
      reference_title: "Supplementation of Calcium and Fluoride-Free Water Mitigates Skeletal Fluorosis in Fluoride-Intoxicated Rats."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Bone turnover in group 4X was normalised."
      explanation: The turnover result itself, in the same reversal arm.
  evidence:
  - reference: PMID:32770327
    reference_title: "Supplementation of Calcium and Fluoride-Free Water Mitigates Skeletal Fluorosis in Fluoride-Intoxicated Rats."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In conclusion, low calcium aggravates skeletal fluorosis which could be mitigated on supplementation of Ca and FFW."
    explanation: >-
      The authors' own conclusion, and the reason this record exists in both
      directions: low calcium aggravates the disease, and supplementing it mitigates.
  - reference: PMID:42336527
    reference_title: "Environmental fluoride exposure and bone metabolism: Molecular pathways and health implications."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "It also inhibits vitamin D hydroxylation, decreasing active vitamin D bioavailability and impairing calcium and phosphorus absorption."
    explanation: >-
      Graded INDIRECT: a rationale rather than an outcome - fluoride inhibits vitamin
      D hydroxylation and impairs calcium absorption, which is the deficit this
      supplementation would be replacing.
  notes: >-
    Curated as rodent-evidenced, not as established human therapy. Both studies are
    animal models, and the two act through different comparisons - one supplements
    during and after exposure, the other supplements alongside removal of the
    fluoride source, so neither isolates the supplement from the exposure change. It
    is recorded because the clinical literature recommends it widely and a reader
    should find its actual evidence base here rather than an absence.

- name: Tryptophan Supplementation to Restore Gut-Derived AHR Signalling
  description: >-
    Restoring indole-3-acetic acid, by direct supplementation or an intermittent
    high-tryptophan diet, suppressed Wnt signalling and reduced bone damage in the
    rat model. Curated as an investigational lead, not a treatment - there is no
    human evidence here.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: dietary tryptophan supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: L-tryptophan
      term:
        id: CHEBI:16828
        label: L-tryptophan
    - preferred_term: indole-3-acetic acid
      term:
        id: CHEBI:16411
        label: indole-3-acetic acid
  target_mechanisms:
  - target: Aryl Hydrocarbon Receptor Underactivation with Wnt Hyperactivation
    treatment_effect: INHIBITS
    description: Reactivates the receptor whose underactivation this node describes.
    evidence:
    - reference: PMID:41380608
      reference_title: "Gut microbiota-derived indole-3-Acetic Acid attenuates skeletal fluorosis via AHR-mediated suppression of Wnt/β-Catenin signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Restoring 3-IAA levels, either through direct supplementation or an intermittent high-tryptophan diet-reactivated AHR, suppressed Wnt/β-Catenin signaling, and alleviated bone damage in vivo."
      explanation: The rescue result, in vivo.
  notes: >-
    Rodent only. It is recorded because it targets a node the exposure-removal
    measures do not, but nothing here supports offering it to a patient. Both arms
    the source describes are curated in `therapeutic_agent`: the microbial metabolite
    3-IAA whose level is restored, and the tryptophan the high-tryptophan diet
    supplies. `NCIT:C15433` (Nutritional Support) is the treatment action because
    that is the NCIT clinical-action term for supplying a specific compound; the
    agents, not the action, carry the specificity.

animal_models:
- name: NaF-exposed Swiss albino mouse
  species: Mouse
  genotype: Wild type (Swiss albino)
  description: >-
    15 ppm sodium fluoride in drinking water for four or eight months, with arms for
    exposure withdrawal and for calcium plus vitamin D supplementation. The model
    this entry's calcium and vitamin D treatment record rests on.
  publication: PMID:33057951
  modeled_mechanisms:
  - target: Skeletal Fluoride Accumulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Produces skeletal fluorosis with measurable fluoride deposition and an altered
      bone metal profile at a dose ten times the human permissible limit.
    limitations: >-
      Four to eight months in a mouse against years to decades in a human, at 15 ppm
      against the 1.5 ppm permissible limit - the exposure is compressed in time and
      raised in dose to fit a rodent lifespan.
    evidence:
    - reference: PMID:33057951
      reference_title: "Calcium and Vitamin D Supplementation Effectively Alleviates Dental and Skeletal Fluorosis and Retain Elemental Homeostasis in Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "NaF treatment caused dental fluorosis, skeletal fluorosis, and alteration of bone's metal profile."
      explanation: The model produces the disease this entry curates, plus its dental sibling.
  - target: Fluorapatite Substitution in Bone Mineral
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The supplementation arm: calcium and vitamin D reduced fluoride deposition and
      restored the bone's elemental homeostasis.
    limitations: >-
      A rescue in a rodent at a fixed supraphysiological dose. No human trial of this
      intervention is curated anywhere in this entry.
    readouts:
    - name: Bone fluoride deposition and elemental profile
      target: Fluorapatite Substitution in Bone Mineral
      direction: RESTORED
      interpretation: >-
        The measured outcome behind the calcium and vitamin D treatment record.
      evidence:
      - reference: PMID:33057951
        reference_title: "Calcium and Vitamin D Supplementation Effectively Alleviates Dental and Skeletal Fluorosis and Retain Elemental Homeostasis in Mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "supplementation of calcium and vitamin D effectively alleviated dental and skeletal fluorosis, reduced F deposition, and retained elemental homeostasis of the bone."
        explanation: Deposition reduced and elemental homeostasis retained.
    evidence:
    - reference: PMID:33057951
      reference_title: "Calcium and Vitamin D Supplementation Effectively Alleviates Dental and Skeletal Fluorosis and Retain Elemental Homeostasis in Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "supplementation of calcium and vitamin D effectively alleviated dental and skeletal fluorosis, reduced F deposition, and retained elemental homeostasis of the bone."
      explanation: The rescue this link records.

- name: Fluoride-intoxicated Wistar rat on manipulated dietary calcium
  species: Rat
  genotype: Wild type (Wistar)
  description: >-
    100 ppm fluoride in water for six months against normal (0.5%) and low (0.25%)
    calcium diets, then a three-month reversal phase with fluoride-free water. The
    model that separates fluoride's effect from dietary calcium's.
  publication: PMID:32770327
  modeled_mechanisms:
  - target: Accelerated and Disordered Bone Turnover
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the entry's central paradox directly: turnover up while bone mineral
      content and mechanical properties fall, with trabecular separation and porosity
      rising - denser activity, weaker bone.
    limitations: >-
      The effect is largest in the low-calcium arm, so the model as run confounds
      fluoride excess with dietary calcium deficiency; the normal-calcium arm is what
      isolates the fluoride effect.
    readouts:
    - name: Bone turnover, mineral content and biomechanical properties
      target: Accelerated and Disordered Bone Turnover
      direction: INCREASED
      interpretation: >-
        Turnover increased while mineral content and biomechanics decreased - the
        dissociation this node is about.
      evidence:
      - reference: PMID:32770327
        reference_title: "Supplementation of Calcium and Fluoride-Free Water Mitigates Skeletal Fluorosis in Fluoride-Intoxicated Rats."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The results revealed that in phase I, bone turnover was significantly increased whereas bone mineral content and biomechanical properties of group 4 were significantly decreased"
        explanation: The measurement, in the low-calcium fluoride arm.
    - name: Trabecular separation and total porosity
      target: Accelerated and Disordered Bone Turnover
      direction: INCREASED
      interpretation: The microarchitectural correlate of the disordered turnover.
      evidence:
      - reference: PMID:32770327
        reference_title: "Supplementation of Calcium and Fluoride-Free Water Mitigates Skeletal Fluorosis in Fluoride-Intoxicated Rats."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Trabecular separation and total porosity increased in groups 2 and 4."
        explanation: Both rose in the calcium-deficient arms.
    evidence:
    - reference: PMID:32770327
      reference_title: "Supplementation of Calcium and Fluoride-Free Water Mitigates Skeletal Fluorosis in Fluoride-Intoxicated Rats."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The results revealed that in phase I, bone turnover was significantly increased whereas bone mineral content and biomechanical properties of group 4 were significantly decreased"
      explanation: Establishes the model as informative for this node.
  - target: Impaired Collagen Synthesis and Matrix Mineralization
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Osteocalcin, osteonectin and osteopontin were downregulated under fluoride and
      recovered in the reversal arm - matrix protein expression tracking the node.
    limitations: >-
      Transcript-level, in rat bone. The human node is built on COL1A1 and TGF-beta
      receptor work in cell systems, and nothing curated connects the two directly.
    readouts:
    - name: Osteocalcin, osteonectin and osteopontin expression
      target: Impaired Collagen Synthesis and Matrix Mineralization
      direction: DECREASED
      interpretation: Matrix protein transcription falling under fluoride.
      evidence:
      - reference: PMID:32770327
        reference_title: "Supplementation of Calcium and Fluoride-Free Water Mitigates Skeletal Fluorosis in Fluoride-Intoxicated Rats."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Expression of osteocalcin, osteonectin and osteopontin genes was significantly downregulated in group 4."
        explanation: The downregulation, in the low-calcium fluoride arm.
    evidence:
    - reference: PMID:32770327
      reference_title: "Supplementation of Calcium and Fluoride-Free Water Mitigates Skeletal Fluorosis in Fluoride-Intoxicated Rats."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Expression of osteocalcin, osteonectin and osteopontin genes was significantly downregulated in group 4."
      explanation: The matrix-protein result this link rests on.

- name: Inbred mouse strain panel for fluoride bone susceptibility
  species: Mouse
  genotype: Wild type, three inbred backgrounds
  background: A/J (susceptible), SWR/J (intermediate), 129P3/J (resistant)
  description: >-
    0, 25, 50 and 100 ppm fluoride across three inbred strains chosen for their
    different susceptibility to enamel fluorosis, with bone fluoride, DEXA and
    three-point bend, compression and femoral-neck fracture testing. The model that
    speaks to this entry's genetic susceptibility records.
  publication: PMID:16920415
  modeled_mechanisms:
  - target: Skeletal Fluoride Accumulation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Bone fluoride rose with dose in femora and vertebral bodies in every strain,
      which is this node with a dose-response attached.
    evidence:
    - reference: PMID:16920415
      reference_title: "The genetic influence on bone susceptibility to fluoride."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Concordant with increasing fluoride dose were significant increases of fluoride concentration in femora and vertebral bodies from all 3 strains."
      explanation: Accumulation, dose-dependent, in all three backgrounds.
  - target: Mixed Osteosclerosis, Osteomalacia and Osteoporosis
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      The model does not reproduce the finding the human disease is diagnosed on.
      Fluoride accumulated in bone and degraded bone quality, but bone mineral
      density barely moved - and increased bone mineral density is the radiographic
      sign this entry binds `HP:0005789` to and calls the diagnosis.
    limitations: >-
      A model that reproduces the exposure and the mechanical consequence while
      missing the density change cannot be used to argue about the sclerotic lesion.
      It remains informative about susceptibility and about bone quality, and it is
      the one curated source showing those two can come apart.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: INVALIDATING
      description: >-
        The mouse accumulates skeletal fluoride at these doses without the density
        increase that defines the human radiographic lesion, so the defining feature
        of the human disease is absent from the model.
    - divergence_type: TEMPORAL_SCOPE
      materiality: QUALIFYING
      description: >-
        The exposure runs for a fraction of a mouse lifespan; human osteosclerosis is
        the product of years to decades of accumulation, and the study cannot say
        whether density would move later.
    readouts:
    - name: Bone mineral density by DEXA
      target: Mixed Osteosclerosis, Osteomalacia and Osteoporosis
      direction: UNCHANGED
      interpretation: >-
        A real negative, not a missing measurement: DEXA was performed in all three
        strains at all four doses and barely moved.
      evidence:
      - reference: PMID:16920415
        reference_title: "The genetic influence on bone susceptibility to fluoride."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Fluoride treatment had little effect on the bone mineral densities (BMD) in the 3 strains."
        explanation: The density measurement that did not change.
    - name: Bone quality by mechanical testing
      target: Mixed Osteosclerosis, Osteomalacia and Osteoporosis
      direction: DECREASED
      interpretation: >-
        Bone quality degraded in the susceptible strain and not at all in the
        resistant one, which is the susceptibility gradient this model exists to show.
      evidence:
      - reference: PMID:16920415
        reference_title: "The genetic influence on bone susceptibility to fluoride."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Mechanical testing showed significant alterations in \"bone quality\" in the A/J strain, whereas moderate alterations in \"bone quality\" in the SWR/J strain and no effects in the 129P3/J strain were observed."
        explanation: The strain-dependent mechanical result.
    evidence:
    - reference: PMID:16920415
      reference_title: "The genetic influence on bone susceptibility to fluoride."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: "Fluoride treatment had little effect on the bone mineral densities (BMD) in the 3 strains."
      explanation: >-
        Graded REFUTE against reading this model as reproducing the human sclerotic
        lesion. It is the substantive negative claim the `FAILS_TO_RECAPITULATE`
        relationship makes.
    - reference: PMID:16920415
      reference_title: "The genetic influence on bone susceptibility to fluoride."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The results suggest that genetic factors may contribute to the variation in bone response to fluoride exposure and that fluoride might affect bone properties without altering BMD."
      explanation: >-
        The authors' own reading, and the sentence that makes this model relevant to
        the genetic records: bone response varies with background, and fluoride can
        alter bone properties without altering BMD.
  notes: >-
    The pairing with `genetic:` is the point of curating this model. Three of the five
    genetic records here report human susceptibility variants and two report nulls;
    this is the animal counterpart, and it locates the susceptibility in bone quality
    rather than in bone density. The strains were originally selected for *enamel*
    fluorosis susceptibility, so the bone result is a transfer of that gradient rather
    than a bone-derived one, which is worth knowing before leaning on it.

- name: Skeletal fluorosis model rat for the gut-bone axis
  species: Rat
  genotype: Wild type
  description: >-
    The model behind this entry's gut arm. Serum 3-IAA was measured in model rats and
    in human patients together, and the rescue arms - direct supplementation and an
    intermittent high-tryptophan diet - were run in vivo.
  publication: PMID:41380608
  modeled_mechanisms:
  - target: Gut Microbial Tryptophan Metabolism Disruption
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The metabolite deficit was found in the model and in human patients in the same
      study, which is the strongest fidelity claim available for any model here.
    limitations: >-
      The mechanism downstream of the metabolite - AHR, then Wnt - is established in
      the rodent arm only, and the human arm of the study is the serum measurement.
    evidence:
    - reference: PMID:41380608
      reference_title: "Gut microbiota-derived indole-3-Acetic Acid attenuates skeletal fluorosis via AHR-mediated suppression of Wnt/β-Catenin signaling."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "we found that fluoride disrupted gut microbial tryptophan metabolism, resulting in decreased serum levels of indole-3-acetic acid (3-IAA) in both SF model rats and human SF patients."
      explanation: >-
        Graded OTHER because the sentence reports the model rats and the human
        patients together and no single `evidence_source` value describes both.
  - target: Aryl Hydrocarbon Receptor Underactivation with Wnt Hyperactivation
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Restoring 3-IAA reactivated AHR, suppressed Wnt signalling and reduced bone
      damage in vivo - the result the tryptophan treatment record rests on.
    limitations: >-
      Rodent only, and this entry curates no human tryptophan or 3-IAA intervention.
    readouts:
    - name: Wnt/beta-catenin signalling and bone damage after 3-IAA restoration
      target: Aryl Hydrocarbon Receptor Underactivation with Wnt Hyperactivation
      direction: RESTORED
      interpretation: The rescue, measured in vivo.
      evidence:
      - reference: PMID:41380608
        reference_title: "Gut microbiota-derived indole-3-Acetic Acid attenuates skeletal fluorosis via AHR-mediated suppression of Wnt/β-Catenin signaling."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Restoring 3-IAA levels, either through direct supplementation or an intermittent high-tryptophan diet-reactivated AHR, suppressed Wnt/β-Catenin signaling, and alleviated bone damage in vivo."
        explanation: Signalling suppressed and bone damage alleviated.
    evidence:
    - reference: PMID:41380608
      reference_title: "Gut microbiota-derived indole-3-Acetic Acid attenuates skeletal fluorosis via AHR-mediated suppression of Wnt/β-Catenin signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Restoring 3-IAA levels, either through direct supplementation or an intermittent high-tryptophan diet-reactivated AHR, suppressed Wnt/β-Catenin signaling, and alleviated bone damage in vivo."
      explanation: The rescue this link records.

prevalence:
- population: Children in a coal-burning endemic area, Zhijin County, Guizhou, China
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 7500.0
  rate_denominator: POPULATION
  notes: >-
    7.5% of 1,616 schoolchildren aged 7-16, screened in 2004. Radiographic diagnosis
    was applied to the 23% assessed as high-risk by household coal use, so the
    denominator is the whole surveyed cohort and the figure is a screening
    prevalence rather than a whole-population one.
  evidence:
  - reference: PMID:20041010
    reference_title: "Child skeletal fluorosis from indoor burning of coal in southwestern China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall prevalence of child skeletal fluorosis due to indoor burning of coal was 7.5%."
    explanation: The reported prevalence.

- population: Adults in fluorosis-endemic areas of China, before water improvement
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 13700.0
  rate_denominator: POPULATION
  notes: >-
    13.7% pooled across 17 studies, and the figure the post-intervention comparison
    below is made against.
  evidence:
  - reference: PMID:33333408
    reference_title: "Effects of water improvement and defluoridation on fluorosis-endemic areas in China: A meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "after water improvement, the prevalence of dental fluorosis decreased from 54.5% to 36.2% (95% confidence intervals: 0.12, 0.31) in children, and the prevalence of skeletal fluorosis decreased from 13.7% to 4.2% (95% confidence intervals: 0.16, 0.40) in adults."
    explanation: The before figure, in the sentence that carries both.

- population: Adults in fluorosis-endemic areas of China, after water improvement
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 4200.0
  rate_denominator: POPULATION
  notes: >-
    4.2% after an average of 15.8 years of water improvement. Curated as its own
    record rather than as a note on the record above, because it is a different
    population state and the pair is the strongest evidence in this entry that the
    disease is preventable.
  evidence:
  - reference: PMID:33333408
    reference_title: "Effects of water improvement and defluoridation on fluorosis-endemic areas in China: A meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "after water improvement, the prevalence of dental fluorosis decreased from 54.5% to 36.2% (95% confidence intervals: 0.12, 0.31) in children, and the prevalence of skeletal fluorosis decreased from 13.7% to 4.2% (95% confidence intervals: 0.16, 0.40) in adults."
    explanation: The after figure, from the same pooled analysis.

- population: Tindigani village, Northern Tanzania (East African Rift Valley)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 3300.0
  rate_denominator: POPULATION
  notes: >-
    3.3% (95% CI 2.4-4.3) of 1,532 residents screened door-to-door in a village of
    1,944. Diagnosis was on pre-defined angles of lower-limb deformity rather than
    radiography, which is a different case definition from the Chinese records above
    and not directly comparable with them. Curated to record that this is not a
    China-only disease: drinking-water fluoride in the surveyed sources ran to 38.59
    mg/L.
  evidence:
  - reference: PMID:38135514
    reference_title: "Prevalence of Skeletal Fluorosis in Northern Tanzania: A Follow-Up Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 1,532 individuals who were screened, 45 had skeletal fluorosis, giving a prevalence of 3.3% (95% CI=2.4, 4.3)."
    explanation: The prevalence and its denominator.
  - reference: PMID:38135514
    reference_title: "Prevalence of Skeletal Fluorosis in Northern Tanzania: A Follow-Up Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis of skeletal fluorosis was based on pre-defined angles of deformity of the lower limbs."
    explanation: >-
      The case definition, which is what makes this figure not directly comparable
      with the radiographically diagnosed Chinese records above.
  - reference: PMID:38135514
    reference_title: "Prevalence of Skeletal Fluorosis in Northern Tanzania: A Follow-Up Study."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fluoride concentrations ranged from 0.45-38.59 mg/L of fluoride."
    explanation: >-
      Graded INDIRECT: the exposure range behind the prevalence rather than the
      prevalence itself.

- population: Symptomatic volunteers, Vavuniya District, Sri Lanka
  measure_type: CASES_IN_LITERATURE
  prevalence_class: RARE
  notes: >-
    Not a population prevalence and deliberately not given a rate: 6 skeletal and 10
    pre-skeletal cases among 60 symptomatic volunteers selected for suspicious
    features, which is a case yield in a referred series rather than an occurrence in
    a population. Recorded because it is a second non-Chinese endemic setting and
    because of what it says about recognition - see the differential-diagnosis
    section.
  evidence:
  - reference: PMID:30415519
    reference_title: "Skeletal fluorosis in Vavuniya District: an observational study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a cohort of 60 individuals in Vavuniya with symptoms suggestive of skeletal fluoride toxicity, 6 had skeletal fluorosis, 10 had pre-skeletal fluorosis, and groundwater sources had fluoride levels much higher than WHO recommended upper limit for drinking water."
    explanation: The case counts, and the groundwater exposure behind them.

epidemiology:
- name: Dose-Dependent Endemic Distribution with Co-Factors
  description: >-
    Occurrence tracks fluoride dose close to linearly up to about 5 mg/L in water,
    and the endemic literature names climate, physical labour, nutritional status,
    other trace elements in the water and renal disease as modifiers of who among
    the exposed is affected.
  evidence:
  - reference: PMID:37861949
    reference_title: "Fluoride Exposure and Skeletal Fluorosis: a Systematic Review and Dose-response Meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The dose-response curve based on a one-stage cubic spline regression model showed an almost linear positive relation between exposure and SF occurrence starting from relatively low concentrations up to 5 mg/L and 2.5 mg/L, respectively, for water and urinary fluoride, with no substantial increase above this threshold."
    explanation: The dose-response shape, including the plateau above the threshold.
  - reference: PMID:19305069
    reference_title: "Neurology of endemic skeletal fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Epidemiological and experimental studies in the endemic areas suggest the role of temperate climate, hard physical labor, nutritional status, presence of abnormal concentrations of trace elements like strontium, uranium, silica in water supplies, high fluoride levels in foods and presence of kidney disease in the development of skeletal fluorosis."
    explanation: >-
      The co-factor list. Renal disease is the mechanistically clearest of them,
      since the kidney is the principal organ of fluoride excretion - though no
      source curated here quantifies the renal share, so this record does not treat
      it as the sole route.
  - reference: PMID:20041010
    reference_title: "Child skeletal fluorosis from indoor burning of coal in southwestern China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Children aged 12-16 years were significantly more likely to be diagnosed with skeletal fluorosis than children aged 7-11 years (OR = 1.84, 95% CI: 1.17-2.90; P = .0082)."
    explanation: >-
      The age gradient within a childhood cohort, which is what cumulative dose
      predicts.


discussions:
- discussion_id: sf_collagen_turnover_link
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does defective collagen synthesis drive the accelerated bone turnover of skeletal
    fluorosis, or do the two simply co-occur under fluoride?
  rationale: >-
    The edge from `Impaired Collagen Synthesis and Matrix Mineralization` to
    `Accelerated and Disordered Bone Turnover` is curated `causal_link_type: DIRECT`,
    and nothing in this entry's reference set supports that grade. The only sentence
    naming both quantities is PMID:3295994's - "Increased metabolic turnover of the
    bone, impaired bone collagen synthesis and increased avidity for calcium are
    features in fluoride toxicity" - which lists them as features of the toxicity
    rather than deriving one from the other. Both are separately well evidenced as
    consequences of fluoride, so a shared upstream cause explains the co-occurrence
    without the edge. Two resolutions: find a source asserting the step, or weaken the
    link to INDIRECT_UNKNOWN_INTERMEDIATES, which is what the three edges out of
    `Fluorapatite Substitution in Bone Mineral` already carry for the same reason. Not
    changed here because it is a curation call rather than a defect in the evidence.
  attaches_to:
  - pathophysiology#Impaired Collagen Synthesis and Matrix Mineralization
  - pathophysiology#Accelerated and Disordered Bone Turnover

- discussion_id: sf_osteoblast_dose_response
  kind: INTERPRETATION
  prompt: >-
    Does fluoride stimulate or suppress osteoblasts in skeletal fluorosis?
  rationale: >-
    Both, in the curated evidence, and this entry does not choose. Stated in one
    unit so the comparison is visible: at 0.2 mM fluoride - about 3.8 mg/L of
    fluoride ion - proliferation of osteoblast-like human Saos-2 cells rose
    dose-dependently, with osteocalcin and bone alkaline phosphatase raised through
    BMP/Smad. At 2.26 mg/L, proliferation of mouse osteoblasts *fell*
    dose-dependently, with TGF-beta1 and autophagy markers rising. So the
    stimulatory result is at the *higher* dose, not the lower one, which is the
    opposite of the low-stimulates/high-suppresses pattern "biphasic" would imply -
    the word is therefore not used here. What separates the two results in the
    curated evidence is the cell system, human osteosarcoma line against mouse
    primary osteoblasts, and nothing curated here tests either dose in the other
    system. The `Osteoblast Proliferation and Activation` node is named for the
    stimulatory reading because that is what the field's reviews describe as driving
    progression, and the suppressive result is curated on the same node as a REFUTE
    rather than omitted.
  attaches_to:
  - pathophysiology#Osteoblast Proliferation and Activation
  - pathophysiology#Impaired Collagen Synthesis and Matrix Mineralization
  evidence:
  - reference: PMID:23918166
    reference_title: "Fluoride promotes viability and differentiation of osteoblast-like Saos-2 cells via BMP/Smads signaling pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that fluoride enhanced the proliferation of Saos-2 cells in a dose-dependent manner and 0.2 mM of fluoride resulted in a higher expression of osteoblast marker genes."
    explanation: The stimulatory reading, with its dose.
  - reference: PMID:29505816
    reference_title: "TGF-β1 acts as mediator in fluoride-induced autophagy in the mouse osteoblast cells."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Our results demonstrated that sodium fluoride (NaF) (2.26 mg/L F-) exposure lead to a significant decrease in proliferation rate of mouse osteoblast cells in a dose-dependent manner with a concomitant increase in the expression levels of TGF-β1 and autophagic markers."
    explanation: The suppressive reading, with its dose. Graded REFUTE against the stimulatory claim.

- discussion_id: sf_oxidative_stress
  kind: CONTROVERSY
  prompt: >-
    Is oxidative stress part of the pathogenesis of skeletal fluorosis, or not?
  rationale: >-
    Two published positions, stated at their strongest on both sides. For: the 2021
    mechanism review calls oxidative stress "an essential mechanism in the
    pathogenesis of fluorosis" - not a hedge, and not merely a listing among pathways
    under study - and reports raised malondialdehyde in the fluoride-exposed group,
    with oxidative stress correlating positively with calcineurin activity.
    Against: a study measuring the antioxidant defence system directly, in patients
    from a 5 ppm endemic area and in rabbits given 150 ppm for six months, found no
    difference from controls in lipid peroxidation, glutathione, vitamin C, catalase,
    superoxide dismutase, glutathione peroxidase or glutathione S-transferase, and
    concluded against the theory.

    The two are less opposed than they look, and the reason matters: the negative
    study measured *blood*, and the review's positive finding is in *bone tissue*. A
    null result in erythrocytes does not settle what is happening in the osteocyte,
    so this entry does not read the negative as a refutation of the mechanism. What
    it does do is leave the mechanism unlocated: no source curated here measures
    oxidative stress in human fluorotic bone. That is why there is still no
    oxidative-stress node - the mechanism has no curated human tissue-level
    measurement to hang one on - rather than because the negative won. Both positions
    are curated so the next curator can see which measurement would settle it.
  attaches_to:
  - pathophysiology#Osteoblast Proliferation and Activation
  - pathophysiology#Accelerated and Disordered Bone Turnover
  evidence:
  - reference: PMID:34769367
    reference_title: "Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Oxidative stress is considered to be an essential mechanism in the pathogenesis of fluorosis."
    explanation: >-
      The strongest statement of the positive position in any source curated here,
      and the review's own assessment rather than a listing of what is studied.
  - reference: PMID:34769367
    reference_title: "Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, malondialdehyde (MDA) levels of the fluoride-infected group were significantly higher than the control group, and oxidative stress levels were also positively correlated with CaN activity"
    explanation: >-
      A measurement behind that assessment rather than the assessment itself - raised
      malondialdehyde, correlating with calcineurin activity. Graded OTHER because the
      review reports it secondhand from the primary studies it cites.
  - reference: PMID:32207100
    reference_title: "Fluoride in Drinking Water and Skeletal Fluorosis: a Review of the Global Impact."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "The review focuses on recent findings related to skeletal fluorosis and role of oxidative stress in its development."
    explanation: >-
      Graded INDIRECT: a second review's framing of its own scope, which reports the
      field's attention rather than a finding.
  - reference: PMID:12660366
    reference_title: "Antioxidant defense system and lipid peroxidation in patients with skeletal fluorosis and in fluoride-intoxicated rabbits."
    supports: REFUTE
    evidence_source: OTHER
    snippet: "There was no significant difference in lipid peroxidation, glutathione, and vitamin C in the blood of human fluorotic patients and fluoride-intoxicated rabbits as compared to respective controls."
    explanation: >-
      The measurements, and the reason this discussion does not close: they are
      made in *blood*. Graded OTHER for source because the sentence reports human
      patients and fluoride-intoxicated rabbits together and no single evidence
      source describes both.
  - reference: PMID:12660366
    reference_title: "Antioxidant defense system and lipid peroxidation in patients with skeletal fluorosis and in fluoride-intoxicated rabbits."
    supports: REFUTE
    evidence_source: OTHER
    snippet: "The results together do not subscribe to oxidative stress theory in fluorosis."
    explanation: >-
      The authors' own conclusion against the theory - stated for the whole of
      fluorosis, on blood measurements.

- discussion_id: sf_tgf_beta_direction
  kind: INTERPRETATION
  prompt: >-
    Is TGF-beta signalling up or down in fluoride-exposed bone?
  rationale: >-
    The curated evidence points both ways and the entry models both. On one side,
    TGF-beta1 is raised in a fluoride-exposed human population and NaF activates a
    TGF-beta1/Smad2/3/CyclinD1 axis driving osteoblast proliferation. On the other,
    fluoride raises H3K9 trimethylation at the TGFBR2 and SMAD3 promoters and
    expression of both, and of COL1A1, falls. These are compatible if the ligand and
    the receptor arm move independently, or if the two cell systems and doses differ
    enough - but nothing curated here demonstrates either reconciliation, so the
    entry carries the proliferative arm and the repressive arm as separate nodes
    reaching different consequences, and says so rather than picking one.
  attaches_to:
  - pathophysiology#Osteoblast Proliferation and Activation
  - pathophysiology#Histone-Mediated Repression of TGF-beta Receptor Signalling
  evidence:
  - reference: PMID:34080770
    reference_title: "miR-486-3p regulates CyclinD1 and promotes fluoride-induced osteoblast proliferation and activation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in the fluoride-challenged population, we observed that miR-486-3p expression decreased while CyclinD1 and transforming growth factor (TGF)-β1 increased"
    explanation: TGF-beta1 raised in the exposed population, alongside CyclinD1.
  - reference: PMID:29275289
    reference_title: "Role of fluoride induced histone trimethylation in development of skeletal fluorosis."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Expression of two other vital genes COL1A1 and MMP13 involved in TGFBR2-SMAD signaling pathway was also found to be down-regulated with a decrease in expression of TGFBR2 and SMAD3."
    explanation: >-
      Graded REFUTE against a uniformly up-regulated reading: the receptor and SMAD3
      are epigenetically repressed, and COL1A1 falls with them.

- discussion_id: sf_neuro_mechanism
  kind: INTERPRETATION
  prompt: >-
    Are the neurological complications of skeletal fluorosis compressive, or is
    fluoride directly neurotoxic?
  rationale: >-
    Compressive, on the evidence curated here, and the distinction is not academic -
    it is why decompression is offered at all and why the neurological chain in this
    entry runs through bone rather than through nerve. The Ethiopian surveys traced
    the deficits to sclerosis and osteophytosis narrowing the canal and foramina, and
    the Indian review states that the complications are mechanical and that evidence
    for direct fluoride neurotoxicity is lacking. Recorded as an INTERPRETATION rather
    than settled because "evidence is lacking" is a statement about a literature at a
    date, not a demonstration of absence, and fluoride neurotoxicity is actively
    studied in other organs. A muscle-biopsy series adds a third line from the
    periphery - the wasting in established disease is neurogenic, with no primary
    myopathy - which rules out a different alternative than the one this discussion
    turns on, but points the same way.
  attaches_to:
  - pathophysiology#Spinal Canal and Foraminal Narrowing
  - pathophysiology#Compressive Myelopathy and Radiculopathy
  evidence:
  - reference: PMID:19305069
    reference_title: "Neurology of endemic skeletal fluorosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Neurological complications of endemic skeletal fluorosis, namely radiculopathy, myelopathy or both are mechanical in nature and till date the evidence for direct neurotoxicity of fluoride is lacking."
    explanation: The statement this discussion turns on.
  - reference: PMID:2172892
    reference_title: "Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These deficits were clearly found to be a consequence of fluoride deposition in bones, resulting in generalised sclerosis and osteophytosis, with reduction in the diameter of the intervertebral foramina and of the spinal conal."
    explanation: The anatomical route, traced in a decade of field surveys.
  - reference: PMID:10878791
    reference_title: "Studies on skeletal muscle biopsies in endemic skeletal fluorosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It may be concluded that the primary changes are related to the nerve, with muscle being affected secondarily."
    explanation: >-
      An independent line to the same conclusion, from the other end: muscle biopsies
      in established disease show the muscle is affected through the nerve, not
      directly.
  - reference: PMID:10878791
    reference_title: "Studies on skeletal muscle biopsies in endemic skeletal fluorosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no evidence of any primary muscle pathology due to fluorosis."
    explanation: >-
      The negative that the sentence above rests on. Note this closes off *primary
      myopathy*, which is a different alternative from the direct cord neurotoxicity
      this discussion is about - it narrows the space rather than settling it.

datasets:
- accession: geo:GSE70719
  title: "Gene expression profiling of HOS (human osteosarcoma) cells exposed to fluoride"
  description: >-
    Human osteosarcoma cells exposed to a sub-lethal fluoride concentration for 30
    days, framed by its authors as a model of fluorosis. A cell line, not patient
    material.
  data_type: MICROARRAY
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  evidence:
  - reference: GEO:GSE70719
    reference_title: "Gene expression profiling of HOS (human osteosarcoma) cells exposed to fluoride"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "To understand the molecular mechanism of fluoride induced toxicity gene expression profiling was performed on osteosarcoma cells (HOS). Cells were exposed to sub-lethal concentration of fluoride (8 ppm) for 30 days. Our result demonstrates that fluoride alters multiple biological pathways including bone development, osteoblast differentiation and apoptotic pathways."
    explanation: >-
      The design and the framing, from GEO's own summary. Graded OTHER as a
      repository record rather than a study result.

- accession: geo:GSE57550
  title: "miRNA expression profile in HOS cells exposed to sodium fluoride"
  description: >-
    Small non-coding RNA profiling in the same cell system, aimed at the epigenetic
    arm of fluorosis pathogenesis. The companion resource to the entry's
    microRNA and histone nodes.
  data_type: MICROARRAY
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  evidence:
  - reference: GEO:GSE57550
    reference_title: "miRNA expression profile in HOS cells exposed to sodium fluoride"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Aberrant change in RUNX2-mediated signaling cascade is one of the decisive steps during the pathogenesis of fluorosis."
    explanation: >-
      The stated purpose - epigenetic alterations in fluorosis - and the RUNX2
      framing. Graded OTHER as a repository record.

- accession: geo:GSE203511
  title: "Global gene expression changes in osteoblasts from fluoride-tolerant mice"
  description: >-
    RNA-seq of MC3T3-E1 osteoblasts made fluoride-tolerant by gradient exposure.
    Note this profiles *resistance* rather than injury, so it bears on the disease
    by contrast; and it is a mouse cell line.
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  evidence:
  - reference: GEO:GSE203511
    reference_title: "Global gene expression changes in osteoblasts from fluoride-tolerant mice"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Fluoride-tolerant MC3T3-E1 cells were developed by gradient fluoride exposure."
    explanation: >-
      The design, and the resistance framing that makes this a contrast resource
      rather than a model of the lesion. Graded OTHER as a repository record.


notes: >-
  Why this entry exists, and how it sits beside its neighbours. The knowledge base
  already curates `Dental_Fluorosis`, which is a different disease of the same
  agent: enamel fluorosis is fixed at the moment the enamel forms and does not
  progress, whereas skeletal fluorosis accrues for as long as the exposure lasts.
  They share exposures and co-occur, and the dental sign is the earlier sentinel,
  but nothing about one entry's mechanism carries over to the other.

  The disease's cause is not in dispute, which is why this entry has no
  `mechanistic_hypotheses` block. What is disputed is the mechanism between the
  exposure and the bone, and three of those disputes are curated as `discussions`
  rather than smoothed over: whether fluoride stimulates or suppresses osteoblasts
  (both, in different cell systems - and note the stimulatory result is at the
  *higher* fluoride concentration of the two, 3.8 mg/L against 2.26 mg/L, so this is
  not the low-stimulates/high-suppresses pattern "biphasic" would imply), whether
  oxidative stress is involved (a 2021 review calls it an essential mechanism and
  reports raised MDA in bone tissue; a direct antioxidant study in humans and rabbits
  found nothing - but measured blood, not bone), and which way TGF-beta signalling
  moves (up as ligand in an exposed population, down at the receptor through H3K9
  trimethylation). The entry still carries no oxidative-stress node, but for a
  narrower reason than the negative study: no source curated here measures oxidative
  stress in human fluorotic bone, so there is no tissue-level measurement to build
  the node on.

  The neurological chain deliberately runs through bone. Cord and root compression
  here is a consequence of canal and foraminal narrowing, and the cited review
  states that evidence for direct fluoride neurotoxicity is lacking. That is
  recorded as an INTERPRETATION rather than as settled fact, because "evidence is
  lacking" describes a literature at a date rather than demonstrating absence.

  On the animal models. Four are curated, and the reason they are records rather
  than only evidence items is that the rodent work here is load-bearing: two of the
  five treatments rest on it entirely. Making them records forces each one to say
  which node it speaks to, how faithfully, and where it fails. The inbred-strain
  panel is the one to read: it reproduces skeletal fluoride accumulation cleanly and
  then **fails to reproduce the density change the human disease is diagnosed on** -
  fluoride went into bone, mechanical quality degraded in the susceptible strain, and
  bone mineral density barely moved. That is a `FAILS_TO_RECAPITULATE` link with an
  `INVALIDATING` `SPECIES_MISMATCH` divergence, sitting beside a `RECAPITULATES` link
  from the same model to the accumulation node. One model, two links, opposite
  verdicts. It also pairs with the `genetic:` records, and locates susceptibility in
  bone *quality* rather than bone density.

  Negative and refuting results are curated on purpose. Seven `REFUTE` items sit
  next to the positive evidence, covering six distinct findings: the suppressive
  osteoblast result (cited twice, on the node and in the discussion), the two
  negative antioxidant measurements, the epigenetic repression of TGF-beta receptor
  signalling with COL1A1 falling, the null single-SNP results for ALOX15, and the
  null BMP2 association. That last one is the record most worth keeping: BMP
  signalling is the pathway the osteoblast-activation node runs through, so BMP2 is
  exactly the gene a reader would predict - and in 598 brick-tea drinkers it was not
  associated. Recording the null stops the next curator deriving it from
  plausibility.

  On the deep-research report. `falcon` was the requested provider and is not
  configured in this environment, so the run fell back to `claude_code` and recorded
  that itself - `fell_back: true`, `requested_provider: falcon` and the provider
  attempt list are in the report's own frontmatter rather than asserted here. Its
  reference resolution was clean (43/43 resolved, no confabulation) with one
  reference flagged off topic, `PMID:34769866`, a paper about school meal access
  during the COVID-19 pandemic; it is not cited here. Its term validation was not
  clean: six CURIEs are flagged as label mismatches. Five are real mis-namings and
  none of the five is bound anywhere in this entry - `UBERON:0002298` offered for
  "vertebral column" when it is *brainstem*, `UBERON:0004123` for "femur" when it is
  *myocardial layer*, `UBERON:0002417` for "posterior longitudinal ligament" when it
  is *abdominal segment of trunk*, `HP:0009758` for "enamel hypoplasia" when it is
  *pyramidal skinfold extending from the base to the top of the nails*, and
  `HP:0100774` for "Osteosclerosis" when HPO calls it *Hyperostosis*. The sixth is
  `MONDO:0400003`, this entry's own `disease_term`, and it is a false positive: the
  report gave the correct label "Skeletal fluorosis" and then listed "Ontology
  Lookup Service" beside it, which the validator counted as a second, wrong name.
  Every ontology term in this entry was resolved independently through OAK or OLS
  before binding, and every snippet was taken from a `references_cache` file fetched
  and read directly rather than from the report.

  On the spastic-weakness binding, because two plausible terms are wrong in
  different directions. The cited survey says "severe spastic *quadri*paresis in
  flexion". `HP:0002313` (Spastic paraparesis) is wrong on distribution - lower limbs
  only - and was bound in an earlier draft; `HP:0002510` (Spastic tetraplegia) has the
  right distribution but is defined as *paralysis*, so it over-claims severity. The
  entry binds `HP:0001285` (Spastic tetraparesis), whose definition is "Spastic
  weakness affecting all four limbs" and whose exact synonym is "Spastic
  quadriparesis" - a word-for-word match to the source.

  Two ECTO bindings were considered and not made, so the next curator does not
  re-derive the search. `ECTO:0900294`, offered as "exposure to fluoride via
  ingestion", resolves to no label in the ECTO build this repository validates
  against; there is no route-specific fluoride exposure term in it at all, only the
  generic `ECTO:9000423`. `ECTO:9001138` (exposure to hydrogen fluoride) does exist,
  but no source curated here identifies hydrogen fluoride as the species in coal
  smoke, and binding it would assert a chemical form the evidence does not name. All
  four exposure records therefore bind `ECTO:9000423` and carry their route and agent
  in `preferred_term`.

  On the datasets, and one rejection worth recording. GEO returns nothing on this
  disease from patient tissue; the three series curated here are all cell or mouse
  models, and each says so in its description. `just discover-datasets
  Skeletal_Fluorosis` returns 12 candidates, but every one is a `GENE_ONLY` match
  reached through this entry's own genes - BMP2 and ALOX15 - and none is about
  fluoride at all; that is the Named Entity Confusion pattern
  `docs/dataset-curation.md` describes, arriving through gene rather than disease
  search. The three series curated here were found by querying GEO directly. A fourth
  candidate, `geo:GSE22217` ("microarray-based gene expression analysis of human
  osteoblasts in response to roughness and fluoride treatment of titanium
  implants"), was rejected on relevance: it is a dental-implant surface-engineering
  study reached through the word "fluoride", and binding it would be Named Entity
  Confusion arriving through dataset search - the case `docs/dataset-curation.md`
  warns about. The enamel-focused fluoride series (`GSE337787`, `GSE57224`,
  `GSE5365`) were likewise left to `Dental_Fluorosis`.

  One thing deliberately not curated: a `HUMAN_MODEL_MISMATCH` discussion contrasting
  the rodent calcium/vitamin D rescue with human efficacy. The mismatch may well be
  real, but this entry holds no citable source reporting a human outcome for that
  intervention at all - and a discussion whose refuting half is unsourced would be
  asserting the mismatch rather than recording it. What *is* recorded is the rodent
  evidence, labelled rodent-only on the treatment record, on both of its model links,
  and in this section. The `limitations` on those links say what would have to be
  shown.

  Not curated. No GeneReviews article exists - PubMed returns nothing for
  `fluorosis[TI] AND GeneReviews[TI]`, which is expected for an environmentally
  caused disease and required no action. `PMID:28292354` ("Treatment and Prevention
  of Skeletal Fluorosis") was fetched and is *not* cited: its PubMed record carries
  no abstract text, so nothing in it can be quoted, and its cache file is therefore
  not committed either. Two things a reader might expect and will not find: there is no
  human interventional evidence anywhere in this entry - the two mechanism-directed
  treatments, calcium plus vitamin D and tryptophan supplementation, both rest on
  rodent studies and both say so on the record - and there is no oxidative-stress
  node, for the reason given above.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (5)

Record notes

Why this entry exists, and how it sits beside its neighbours. The knowledge base already curates `Dental_Fluorosis`, which is a different disease of the same agent: enamel fluorosis is fixed at the moment the enamel forms and does not progress, whereas skeletal fluorosis accrues for as long as the exposure lasts. They share exposures and co-occur, and the dental sign is the earlier sentinel, but nothing about one entry's mechanism carries over to the other. The disease's cause is not in dispute, which is why this entry has no `mechanistic_hypotheses` block. What is disputed is the mechanism between the exposure and the bone, and three of those disputes are curated as `discussions` rather than smoothed over: whether fluoride stimulates or suppresses osteoblasts (both, in different cell systems - and note the stimulatory result is at the *higher* fluoride concentration of the two, 3.8 mg/L against 2.26 mg/L, so this is not the low-stimulates/high-suppresses pattern "biphasic" would imply), whether oxidative stress is involved (a 2021 review calls it an essential mechanism and reports raised MDA in bone tissue; a direct antioxidant study in humans and rabbits found nothing - but measured blood, not bone), and which way TGF-beta signalling moves (up as ligand in an exposed population, down at the receptor through H3K9 trimethylation). The entry still carries no oxidative-stress node, but for a narrower reason than the negative study: no source curated here measures oxidative stress in human fluorotic bone, so there is no tissue-level measurement to build the node on. The neurological chain deliberately runs through bone. Cord and root compression here is a consequence of canal and foraminal narrowing, and the cited review states that evidence for direct fluoride neurotoxicity is lacking. That is recorded as an INTERPRETATION rather than as settled fact, because "evidence is lacking" describes a literature at a date rather than demonstrating absence. On the animal models. Four are curated, and the reason they are records rather than only evidence items is that the rodent work here is load-bearing: two of the five treatments rest on it entirely. Making them records forces each one to say which node it speaks to, how faithfully, and where it fails. The inbred-strain panel is the one to read: it reproduces skeletal fluoride accumulation cleanly and then **fails to reproduce the density change the human disease is diagnosed on** - fluoride went into bone, mechanical quality degraded in the susceptible strain, and bone mineral density barely moved. That is a `FAILS_TO_RECAPITULATE` link with an `INVALIDATING` `SPECIES_MISMATCH` divergence, sitting beside a `RECAPITULATES` link from the same model to the accumulation node. One model, two links, opposite verdicts. It also pairs with the `genetic:` records, and locates susceptibility in bone *quality* rather than bone density. Negative and refuting results are curated on purpose. Seven `REFUTE` items sit next to the positive evidence, covering six distinct findings: the suppressive osteoblast result (cited twice, on the node and in the discussion), the two negative antioxidant measurements, the epigenetic repression of TGF-beta receptor signalling with COL1A1 falling, the null single-SNP results for ALOX15, and the null BMP2 association. That last one is the record most worth keeping: BMP signalling is the pathway the osteoblast-activation node runs through, so BMP2 is exactly the gene a reader would predict - and in 598 brick-tea drinkers it was not associated. Recording the null stops the next curator deriving it from plausibility. On the deep-research report. `falcon` was the requested provider and is not configured in this environment, so the run fell back to `claude_code` and recorded that itself - `fell_back: true`, `requested_provider: falcon` and the provider attempt list are in the report's own frontmatter rather than asserted here. Its reference resolution was clean (43/43 resolved, no confabulation) with one reference flagged off topic, `PMID:34769866`, a paper about school meal access during the COVID-19 pandemic; it is not cited here. Its term validation was not clean: six CURIEs are flagged as label mismatches. Five are real mis-namings and none of the five is bound anywhere in this entry - `UBERON:0002298` offered for "vertebral column" when it is *brainstem*, `UBERON:0004123` for "femur" when it is *myocardial layer*, `UBERON:0002417` for "posterior longitudinal ligament" when it is *abdominal segment of trunk*, `HP:0009758` for "enamel hypoplasia" when it is *pyramidal skinfold extending from the base to the top of the nails*, and `HP:0100774` for "Osteosclerosis" when HPO calls it *Hyperostosis*. The sixth is `MONDO:0400003`, this entry's own `disease_term`, and it is a false positive: the report gave the correct label "Skeletal fluorosis" and then listed "Ontology Lookup Service" beside it, which the validator counted as a second, wrong name. Every ontology term in this entry was resolved independently through OAK or OLS before binding, and every snippet was taken from a `references_cache` file fetched and read directly rather than from the report. On the spastic-weakness binding, because two plausible terms are wrong in different directions. The cited survey says "severe spastic *quadri*paresis in flexion". `HP:0002313` (Spastic paraparesis) is wrong on distribution - lower limbs only - and was bound in an earlier draft; `HP:0002510` (Spastic tetraplegia) has the right distribution but is defined as *paralysis*, so it over-claims severity. The entry binds `HP:0001285` (Spastic tetraparesis), whose definition is "Spastic weakness affecting all four limbs" and whose exact synonym is "Spastic quadriparesis" - a word-for-word match to the source. Two ECTO bindings were considered and not made, so the next curator does not re-derive the search. `ECTO:0900294`, offered as "exposure to fluoride via ingestion", resolves to no label in the ECTO build this repository validates against; there is no route-specific fluoride exposure term in it at all, only the generic `ECTO:9000423`. `ECTO:9001138` (exposure to hydrogen fluoride) does exist, but no source curated here identifies hydrogen fluoride as the species in coal smoke, and binding it would assert a chemical form the evidence does not name. All four exposure records therefore bind `ECTO:9000423` and carry their route and agent in `preferred_term`. On the datasets, and one rejection worth recording. GEO returns nothing on this disease from patient tissue; the three series curated here are all cell or mouse models, and each says so in its description. `just discover-datasets Skeletal_Fluorosis` returns 12 candidates, but every one is a `GENE_ONLY` match reached through this entry's own genes - BMP2 and ALOX15 - and none is about fluoride at all; that is the Named Entity Confusion pattern `docs/dataset-curation.md` describes, arriving through gene rather than disease search. The three series curated here were found by querying GEO directly. A fourth candidate, `geo:GSE22217` ("microarray-based gene expression analysis of human osteoblasts in response to roughness and fluoride treatment of titanium implants"), was rejected on relevance: it is a dental-implant surface-engineering study reached through the word "fluoride", and binding it would be Named Entity Confusion arriving through dataset search - the case `docs/dataset-curation.md` warns about. The enamel-focused fluoride series (`GSE337787`, `GSE57224`, `GSE5365`) were likewise left to `Dental_Fluorosis`. One thing deliberately not curated: a `HUMAN_MODEL_MISMATCH` discussion contrasting the rodent calcium/vitamin D rescue with human efficacy. The mismatch may well be real, but this entry holds no citable source reporting a human outcome for that intervention at all - and a discussion whose refuting half is unsourced would be asserting the mismatch rather than recording it. What *is* recorded is the rodent evidence, labelled rodent-only on the treatment record, on both of its model links, and in this section. The `limitations` on those links say what would have to be shown. Not curated. No GeneReviews article exists - PubMed returns nothing for `fluorosis[TI] AND GeneReviews[TI]`, which is expected for an environmentally caused disease and required no action. `PMID:28292354` ("Treatment and Prevention of Skeletal Fluorosis") was fetched and is *not* cited: its PubMed record carries no abstract text, so nothing in it can be quoted, and its cache file is therefore not committed either. Two things a reader might expect and will not find: there is no human interventional evidence anywhere in this entry - the two mechanism-directed treatments, calcium plus vitamin D and tryptophan supplementation, both rest on rodent studies and both say so on the record - and there is no oxidative-stress node, for the reason given above.

Record why the ESR1 protective-allele record is not wired to a mechanism node · 2026-09-29T18:45:08Z · View source

Sixth tranche of the estrogen-signalling work in issue #12925. The ESR1 rs9340799 genetic record reaches no pathophysiology node and stays that way, with the reason added to its notes. The record is a single unreplicated protective association (PMID:39824337) in a cross-sectional multi-ethnic cohort with brick-tea-type fluorosis. The study measures allele frequencies, not the receptor or estrogen signaling in bone. The entry models no estrogen-dependent mechanism, its sixteen pathophysiology nodes run from fluoride intake through mineral substitution, osteoblast activation, turnover and ossification to compression, and none is a plausible landing for a receptor gene on the strength of one association. Searches. PubMed for fluorosis with ESR1 or estrogen receptor in the title or abstract returned eleven records. Apart from PMID:39824337 they are dental-fluorosis polymorphism studies (PMID:41174690, PMID:36354656, PMID:35066749, PMID:32185656) or a study of sex hormone binding globulin in fluoride-exposed men (PMID:30677743). None reports estrogen receptor signaling as a mechanism of skeletal fluorosis. None was fetched, because none is quoted. The deep-research report (claude_code) was read first. It records the same association as a modifier and, separately, reports hypomethylation of the alpha receptor among fluorosis epigenetic changes from a secondary source it cites by PMC identifier. That is a lead for a future epigenetics pass, not support for wiring a germline susceptibility allele to a mechanism, and it was not pursued here. No cache file changed. Checks: validate, validate-terms and count-verified-snippets passed on the file; validate-disorders over the tranche passed; the offline gates listed in the Osteoporosis record for this tranche passed with no new findings.

Add edge-level evidence to the pathograph · 2026-09-10T17:05:23Z · View source

Evidenced 14 of the 18 previously unevidenced causal edges (edge-level evidence 2/20 -> 16/20; 10 DIRECT, 6 INDIRECT). Seven of the eight DIRECT snippets came from references already in references_cache/ and cited elsewhere in this entry at node level; only PMID:24300170 needed fetching, and it was already cited by research/Skeletal_Fluorosis-deep-research-claude_code.md. Left four edges unevidenced: 4-6 hang off Fluorapatite Substitution in Bone Mineral and are already marked INDIRECT_UNKNOWN_INTERMEDIATES by the original curator, and edge 11 (Impaired Collagen Synthesis -> Accelerated and Disordered Bone Turnover) has no source asserting the link, only co-occurrence, which is now recorded in the edge description. Added a notes block on Impaired Collagen Synthesis and Matrix Mineralization recording an unresolved direction conflict: PMID:37558119 measures Col1a1 falling in mice at an environmentally relevant dose, while PMID:24300170 reports COL1A1 mRNA rising in primary rat osteoblasts. Validated with just validate-disorders, validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-enum-values, check-snippet-length, check-title-snippets, check-folded-hyphens and check-snippet-grading.

Review round 1: rebind spastic weakness phenotype, add animal_models · 2026-09-07T21:55:45Z · View source

Round 1 review response for PR #11395 (ai4c-reviewer, REQUEST_CHANGES: one blocking ontology finding, two non-blocking). All three addressed in a single push, because dismiss_stale_reviews means a follow-up commit costs a full re-review cycle. BLOCKING - Spastic Paresis phenotype bound a term its own evidence contradicts. The record bound HP:0002313 (Spastic paraparesis), a lower-limb deficit, while its only evidence item quotes "Advanced osteosclerosis commonly causes severe spastic quadriparesis in flexion". Quadriparesis is all four limbs, and the entry's own mechanism - compression at the cervical canal - points the same way. The reviewer offered HP:0002510 (Spastic tetraplegia) or HP:0001257 (Spasticity). Neither was taken: HP:0002510 has the right distribution but HPO defines it as "Spastic PARALYSIS affecting all four limbs", so it over-claims severity against a source that says paresis, and HP:0001257 discards information the evidence supplies. Bound HP:0001285 (Spastic tetraparesis) instead - HPO defines it as "Spastic weakness affecting all four limbs" and carries "Spastic quadriparesis" as an EXACT SYNONYM, a word-for-word match to the quote. Neither the reviewer nor the deep-research report surfaced this term; it was found by searching HPO for tetraparesis after checking HP:0002510's definition. preferred_term is now "Spastic quadriparesis in flexion", the notes record both rejected candidates and why each is wrong in a different direction, and the "which is the term HPO carries" clause the reviewer flagged is gone (HPO carries all four). NON-BLOCKING 1 - no animal_models section, though the rodent work is load-bearing. Taken. Four models added, all from publications already cited as evidence in the changeset plus one re-fetched source: - NaF-exposed Swiss albino mouse (PMID:33057951): RECAPITULATES skeletal fluoride accumulation; RESCUES the fluorapatite node in the calcium/vitamin D arm, with a RESTORED readout. - Fluoride-intoxicated Wistar rat on manipulated dietary calcium (PMID:32770327): RECAPITULATES accelerated turnover, with INCREASED turnover and INCREASED trabecular separation readouts against DECREASED mineral content - the entry's central paradox measured directly; also RECAPITULATES the collagen/matrix node via DECREASED osteocalcin/osteonectin/osteopontin. - Inbred mouse strain panel A/J, SWR/J, 129P3/J (PMID:16920415, re-fetched - its cache had been pruned as uncited before the first commit). This is the important one. RECAPITULATES skeletal fluoride accumulation with a clean dose-response, and FAILS_TO_RECAPITULATE the mixed sclerosis/osteomalacia/osteoporosis node: fluoride accumulated, mechanical bone quality degraded in the susceptible strain, and bone mineral density barely moved - and increased bone mineral density is the radiographic sign this disease is diagnosed on. Carries an INVALIDATING SPECIES_MISMATCH divergence and a QUALIFYING TEMPORAL_SCOPE divergence, a REFUTE evidence item, and UNCHANGED / DECREASED readouts. One model, two links, opposite verdicts. It also pairs with the genetic records and locates susceptibility in bone quality rather than density. - Skeletal fluorosis model rat for the gut-bone axis (PMID:41380608): RECAPITULATES the tryptophan-metabolism node (the metabolite deficit was found in model rats and human patients in the same study) and RESCUES the AHR/Wnt node. Every link carries fidelity, model_scale and limitations. just model-scale-audit --strict reports no upward extrapolation from any of them; its one strict complaint is a pre-existing link in Methylmalonic_Acidemia_With_Homocystinuria_ Type_cblJ, not from this entry. NON-BLOCKING 2 - two research-surfaced items. Half taken, and the taken half says something different from what was suggested. PMID:10878791 was characterised as a muscle-weakness phenotype; reading it, it is a NEGATIVE result that independently supports this entry's compressive thesis - 22 patients with established osteofluorosis, biopsies showing type I atrophy and grouping, "No myopathic changes were observed", and "There was no evidence of any primary muscle pathology due to fluorosis". Curated two ways: a Neurogenic Muscle Atrophy phenotype (HP:0003202) reporting on the myelopathy node, and two evidence items on the sf_neuro_mechanism discussion, whose rationale now notes that this rules out a DIFFERENT alternative (primary myopathy) than the one the discussion turns on (direct cord neurotoxicity) while pointing the same way. Its cache had also been pruned as uncited and was re-fetched. The candidate HUMAN_MODEL_MISMATCH discussion was NOT curated, and the entry's notes say why: the mismatch may be real, but this entry holds no citable source reporting any human outcome for calcium/vitamin D in skeletal fluorosis, so a discussion whose refuting half is unsourced would assert the mismatch rather than record it. What is recorded instead is the rodent evidence, labelled rodent-only on the treatment record, on both of its model links, and in the notes. Counts after this round: 152 evidence items (was 132), 152/152 snippets verified; 143 SUPPORT / 8 REFUTE / 1 NO_EVIDENCE; 9 phenotypes (was 8); 4 animal models (was none); compliance 84.0% -> 84.1%. Two reference caches re-added (PMID_16920415, PMID_10878791), both now cited. Validation: just validate-disorders passes with 152/152; validate-terms, check-entity-refs, check-causal-targets, check-qualifier-terms, check-duplicate-keys, check-enum-values, model-scale-audit --strict, and all whole-KB snippet/reference/environmental gates pass with no baseline modified.

Create: Skeletal Fluorosis · 2026-09-07T17:10:22Z · View source

New disorder entry for skeletal fluorosis (MONDO:0400003), the crippling bone and joint disease of chronic fluoride excess. Curated as an environmental-exposure entry at the user's request. Why this disease. The KB already curates Dental_Fluorosis, but nothing on the skeletal form. They are not the same disease: enamel fluorosis is fixed when the enamel forms and does not progress, while skeletal fluorosis accrues for as long as exposure continues, in a different tissue by a different mechanism. Duplicate preflight was clean on all three surfaces - no kb/ entry on origin/main, no PR, no issue - and the Dental_Fluorosis entry is scoped strictly to amelogenesis. Content. 16 pathophysiology nodes with a single root, running exposure -> skeletal fluoride accumulation -> fluorapatite substitution -> three parallel arms (osteoblast proliferation/activation, impaired collagen and matrix mineralization, osteocyte-driven osteoclastogenesis) -> accelerated but disordered turnover -> mixed osteosclerosis/osteomalacia/osteoporosis -> ligament and interosseous membrane ossification -> spinal canal and foraminal narrowing -> compressive myelopathy and radiculopathy. A separate gut arm (microbial tryptophan metabolism -> AHR underactivation -> Wnt hyperactivation) and a secondary hyperparathyroidism arm feed the same chain. 6 phenotypes, 5 environmental exposures, 3 genetic records, 3 biochemical markers with reference ranges, 3 diagnosis records, 4 differential diagnoses, 4 treatments, 3 prevalence records, 4 discussions, 3 GEO datasets, plus an ICD-10-CM and ICD-11 mappings block taken from MONDO's own exactMatch assertions. After the pre-commit review round described below: 8 phenotypes, 5 genetic records, 5 treatments and 5 prevalence records. 132 evidence items, 132/132 snippets verified against committed caches. 7 REFUTE and 1 NO_EVIDENCE item. Compliance 84.0%. Deep research. Requested provider was falcon; EDISON_API_KEY is not configured in this environment, so the run was made with `just dr_fallback='--fallback'` and fell back to claude_code. The report records that itself - fell_back: true, requested_provider: falcon, and the provider_attempts list are in its frontmatter rather than asserted in prose, and the recipe named the file after the actual producer. 50 citations, 22 web searches. The report's own validation was mixed and is disclosed in the entry's notes. References resolved cleanly (43/43, no confabulation) with one flagged off topic - PMID:34769866, a paper about school meal access during COVID-19, not cited here. Term validation was not clean: six CURIEs are named as a different term, including UBERON:0002298 offered for "vertebral column" when it is brainstem, UBERON:0004123 for "femur" when it is myocardial layer, UBERON:0002417 for "posterior longitudinal ligament" when it is abdominal segment of trunk, and HP:0009758 for "enamel hypoplasia" when it is a nail-fold skinfold term, and HP:0100774 for "Osteosclerosis" when HPO calls it Hyperostosis. Five of those six are real mis-namings and none of the five is bound in this entry. The sixth is MONDO:0400003, this entry's own disease_term, flagged only because the report listed "Ontology Lookup Service" beside the correct label "Skeletal fluorosis" - a false positive, and the entry's notes say so rather than repeating the validator's count uncorrected. The osteosclerosis phenotype binds HP:0005789 (Generalized osteosclerosis), which is what the cited Ethiopian surveys and occupational review describe. All references were found independently through PubMed E-utilities before the report finished, and every ontology term was resolved through OAK or OLS before binding. Three controversies are curated as discussions rather than resolved: - sf_oxidative_stress (CONTROVERSY). PMID:34769367 calls oxidative stress "an essential mechanism in the pathogenesis of fluorosis" and reports raised MDA correlating with calcineurin activity. Against that, PMID:12660366 measured the antioxidant defence system directly - in patients from a 5 ppm endemic area and in rabbits at 150 ppm - and found no difference from controls on any of seven measures. The two are less opposed than they look: the negative measured BLOOD, the positive is in BONE TISSUE. The entry carries no oxidative-stress node, but for the narrower reason that no curated source measures oxidative stress in human fluorotic bone - not because the negative refuted the mechanism. - sf_osteoblast_dose_response (INTERPRETATION). Fluoride raises proliferation of human Saos-2 cells at 0.2 mM (about 3.8 mg/L fluoride ion) and lowers it in mouse osteoblasts at 2.26 mg/L. Stated in one unit, the stimulatory result is at the HIGHER dose, which is the opposite of what "biphasic" implies; the word is not used. What separates them in the curated evidence is the cell system. Both are curated on the same node, the suppressive result as a REFUTE. - sf_tgf_beta_direction (INTERPRETATION). TGF-beta1 is raised in an exposed human population and drives a Smad2/3/CyclinD1 proliferative axis, while H3K9 trimethylation represses TGFBR2 and SMAD3 with COL1A1 falling. Modelled as two separate nodes reaching different consequences rather than one averaged claim. A fourth discussion, sf_neuro_mechanism, records that the neurological complications are compressive rather than neurotoxic. This determines the shape of the graph: the chain to myelopathy runs through bone, and the surgical treatment record is treatment_effect BYPASSES for the same reason. Datasets. `just discover-datasets Skeletal_Fluorosis` returns 12 candidates, all GENE_ONLY matches reached through this entry's own genes (BMP2, ALOX15) and none about fluoride - the Named Entity Confusion pattern arriving through gene search - so GEO was queried directly. Three series are curated - GSE70719 and GSE57550 (human osteosarcoma cells exposed to fluoride, framed by their authors as fluorosis models) and GSE203511 (fluoride-tolerant mouse osteoblasts, a resistance rather than injury resource) - each with its description stating that it is a cell or mouse model rather than patient material. A fourth candidate, geo:GSE22217, was REJECTED on relevance: it is a dental-implant surface-engineering study of osteoblast response to fluoride-modified titanium, reached through the word "fluoride", and curating it would be Named Entity Confusion arriving through dataset search. The enamel-focused fluoride series were left to Dental_Fluorosis. Not curated, and why. No GeneReviews article exists - PubMed returns zero for `fluorosis[TI] AND GeneReviews[TI]`, expected for an environmentally caused disease. PMID:28292354 ("Treatment and Prevention of Skeletal Fluorosis") was fetched and is deliberately not cited: its cached record carries no abstract text, so nothing in it is quotable. There is no human interventional evidence anywhere in the entry: both mechanism-directed treatments (calcium plus vitamin D, and tryptophan supplementation) rest on rodent studies and say so on the record. Pre-commit review round. Before anything was committed, the finished entry was put through an adversarial read against its own cached sources. It found five blocking defects, all in unvalidated free text rather than in the evidence layer, and every one was independently confirmed against the caches before being fixed: - Serum soluble Klotho was curated `presence: Decreased`. PMID:32721666 reports the opposite - sKlotho rises with tea fluoride intake, is positively associated with disease severity, mediates 17.76% of that effect, and rose in the rat model. The record's own notes then denied asserting a direction while the `presence` slot asserted the wrong one, and its snippet quoted the study design rather than the result. Fixed to Increased, with the association, the mediated fraction and the rat result quoted. - Two `notes` sentences referred to `Kashin-Beck_Disease` as a neighbouring entry. It is not in the knowledge base. Both removed. - `notes` claimed no source in the changeset reports an outcome for calcium and vitamin D. PMID:33057951 and PMID:32770327 were both already cached and both report measured rodent outcomes. Calcium plus vitamin D is now a curated treatment with two pathograph links. - `notes` claimed none of the six mislabelled CURIEs is bound in the entry. One of the six is MONDO:0400003, the entry's own disease_term (a validator false positive). Corrected in both the entry and this record. - The `Fluorapatite Substitution in Bone Mineral` node's evidence never mentioned fluorapatite or the mineral phase. PMID:42336527 and PMID:38135514 now carry the mineral-crystal and incorporation claims the node's name makes. Also fixed in the same pass: a fabricated "metabolic superscan" claim in the diagnosis section that appears in no cached source; unsupported justifications on the Spastic Paresis phenotype; the `frequency` slot on two genetic records carrying study descriptions rather than frequencies; `reference_ranges[].population` carrying prose; and uncited prose about brick tea versus leaf tea, coal-dried foodstuffs, renal excretion as the "only" route, and a trend in inhalant case reports - each either cited or narrowed to what the sources say. Added in the same pass, from sources already cached: ESR1 rs9340799 (protective) and COL1A1 rs1800012 (Russian-specific risk) from PMID:39824337; Exostoses (HP:0100777) and Urinary incontinence (HP:0000020) phenotypes; Tanzanian (PMID:38135514) and Sri Lankan (PMID:30415519) prevalence records, so the entry is not China-only; and the Sri Lankan finding that all sixteen confirmed cases had been carrying an arthritis diagnosis, on the differential-diagnosis record. Two reviewer suggestions were declined with reasons recorded in the entry's notes: ECTO:0900294 ("exposure to fluoride via ingestion") resolves to no label in the ECTO build this repository validates against, and ECTO:9001138 (hydrogen fluoride) names a chemical species no curated source identifies in coal smoke. Validation. `just validate-disorders` passes with 132/132 snippets verified; validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms-online, all whole-KB snippet and reference gates, check-term-cache-integrity, check-cache-order and check-stubs all pass. Pathograph audited independently: 16 nodes, one root, no orphans, every bare-name downstream target resolves.

Claude Code ▸

Skeletal Fluorosis — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 50 citations 2026-09-07T16:58:24.082009

Skeletal Fluorosis — Comprehensive Research Report

1. Disease Information

Overview. Skeletal fluorosis (SF) is a chronic metabolic bone and joint disease caused by long-term excessive systemic fluoride exposure, most often from fluoride-contaminated groundwater but also from occupational inhalation, brick tea, coal-smoke indoor air pollution, or fluoride-containing consumer products (toothpaste, inhalant abuse of fluorinated computer-cleaner propellants, methoxyflurane analgesia). Fluoride has a very high affinity for calcium and is progressively deposited in the mineral phase of bone, producing a syndrome of active osteogenesis and accelerated, disorganized bone turnover that manifests as diffuse osteosclerosis, osteopenia in some compartments, exostoses, ligament/tendon ossification, and — in advanced disease — mechanical compression of the spinal cord and nerve roots (PMID:3295994; MONDO:0400003 definition).

Key identifiers: - MONDO: MONDO:0400003 — "Skeletal fluorosis," defined as "A condition that results from excessive fluoride ingestion leading to fluoride accumulation in the bone progressively over many years. The early symptoms...include stiffness and pain in the joints" (synonym: "Fluorosis of the skeleton") — cross-referenced to ICD10CM:M85.1 and WHO ICD-11 entity 1269698463 (https://www.ebi.ac.uk/ols4/ontologies/mondo). - ICD-10-CM: M85.1– series ("Disorders of bone density and structure, fluorosis of bone"), with laterality/site-specific subcodes (e.g., M85.10 unspecified site, M85.15 thigh, M85.159 unspecified thigh, M85.162 left lower leg) (icd10data.com; aapc.com). - ICD-11: Entity 1269698463 (WHO ICD API). - A separate, related but distinct entity is dental fluorosis (MONDO:0006722), an enamel-formation disorder from fluoride exposure during odontogenesis (age <8 years) — do not conflate with skeletal fluorosis, which reflects lifetime cumulative bone fluoride burden. - MeSH: Fluorosis, Dental (D005506) is indexed separately from bone-fluoride toxicity literature, which is typically indexed under "Fluorides/adverse effects" and "Fluorosis, Skeletal" is not a standalone current MeSH heading in all databases — most PubMed indexing uses "Fluorides/poisoning" + "Bone Diseases." - Synonyms/alternative names: endemic skeletal fluorosis; osteofluorosis; crippling fluorosis; fluoride osteosclerosis; brick-tea-type fluorosis (a specific etiologic subtype); industrial/occupational fluorosis. - Evidence provenance: The overwhelming majority of the literature is aggregated disease-level epidemiological, radiographic, and mechanistic data from endemic-region surveys (India, China) and animal studies, supplemented by individual case reports for atypical, non-endemic exposures (inhalant abuse, occupational, methoxyflurane, excessive toothpaste ingestion) rather than large EHR-derived cohorts.

2. Etiology

2a. Disease causal factors

Skeletal fluorosis is fundamentally an environmental/toxicological disease, not a Mendelian genetic disorder — the causal factor is chronic excess systemic fluoride intake exceeding the body's excretory (renal) capacity, leading to net fluoride retention in bone mineral. There is no single causal gene; genetic factors instead modulate individual susceptibility to a given fluoride dose (see below).

2b. Risk factors

Environmental/exposure risk factors (the dominant category): - Groundwater fluoride contamination — geogenic fluoride from fluoride-bearing minerals (fluorite, apatite, mica) leaching into groundwater in arid/semi-arid regions with high evapotranspiration and alkaline, calcium-poor aquifers (Rift Valley belt — Ethiopia, Kenya, Tanzania, Uganda, Eritrea, Djibouti — plus India, China, Sri Lanka, Türkiye). WHO's drinking-water guideline value is 1.5 mg/L; concentrations above this are associated with dental fluorosis, and total fluoride intake >6 mg/day is associated with crippling skeletal fluorosis (WHO guidance; search results above). - Brick tea / instant tea consumption — tea plants bioaccumulate fluoride from soil/air (up to 98% of ambient fluoride can be sequestered in leaves), and brick tea (made from older leaves/stalks) is markedly higher in fluoride than leaf tea; "brick-tea-type fluorosis" is a distinct, well-described etiologic subtype endemic to Tibetan, Mongolian, and other pastoralist populations in China (PMID:39824337; PMC4728115). - Indoor coal-burning — combustion of high-fluoride coal for cooking/heating in unventilated homes in southwestern China causes fluoride-laden smoke exposure and food contamination (crops dried over open coal fires), producing pediatric skeletal fluorosis (PMC2778178). - Occupational/industrial exposure — aluminum smelting (cryolite/fluoride aerosols), phosphate fertilizer manufacturing, and other fluoride-emitting industries (PMC2993488, Czechoslovakia occupational cohort). - Iatrogenic/consumer sources — chronic methoxyflurane analgesic use (metabolized to inorganic fluoride), excessive fluoridated toothpaste ingestion, and inhalant abuse of fluorinated hydrocarbon computer-cleaner propellants (difluoroethane) are documented non-endemic causes (PMC7336600, JBMR Plus 2024 ziae032). - Age, sex — Radiographic changes are most pronounced in middle age (40–60 years); several Indian endemic-village surveys report higher prevalence in males (e.g., 56.9% male vs 43.1% female skeletal fluorosis in Vidharbha region, Maharashtra), likely reflecting greater outdoor water/occupational intake and possibly body-size/metabolic differences (PMC2940190). - Nutritional status — low dietary calcium and protein-calorie malnutrition increase susceptibility to fluoride's skeletal effects by increasing fractional intestinal fluoride absorption and reducing competitive calcium binding.

Genetic risk/modifier factors (susceptibility, not causation): - ESR1 (estrogen receptor α) polymorphism rs9340799: the G allele is reported protective against brick-tea-type skeletal fluorosis in a multi-ethnic Chinese cohort (Tibetan, Kazakh, Mongolian, Russian) (PMID:39824337). - COL1A1 polymorphism rs1800012: the T allele confers significantly higher risk of skeletal fluorosis, an effect most pronounced in Russian men in the same cohort (PMID:39824337). - Animal (mouse strain) data corroborate a genetic component: A/J mice are a "susceptible" strain and 129P3/J a "resistant" strain for fluoride-induced skeletal/dental effects, with strain-dependent bone fluoride incorporation and proteomic responses even at low fluoride doses (PMID:16920415; PMC4263599).

2c. Protective factors

Adequate dietary calcium and vitamin D intake reduces net skeletal fluoride uptake and, in mouse models, alleviates dental and skeletal fluorosis while preserving elemental (Ca/P) homeostasis (PMID:33057951).
The ESR1 rs9340799 G allele (above) is a genetic protective variant in the tea-fluorosis context.
Public-health defluoridation of drinking water (see Prevention) is the principal population-level protective intervention.

2d. Gene–environment interactions

The COL1A1/ESR1 findings above are explicitly framed as gene–environment interactions: susceptibility differs by ethnicity and appears to be modified by tea fluoride intake, sex, and age — i.e., the same genotype confers different risk depending on exposure route/dose (PMID:39824337). Mouse-strain data similarly show that a fixed environmental fluoride dose produces markedly different bone fluoride incorporation and proteomic/skeletal responses depending on genetic background (PMID:16920415).

3. Phenotypes

Symptoms / clinical signs (with suggested HPO terms)

Phenotype	Notes	Suggested HP term
Persistent joint/back pain, "resting pain," unaffected by weather	Early, hallmark symptom; ≥3 regions (major limb joints, neck, lower back) is a diagnostic criterion	HP:0002829 (Arthralgia) / HP:0003418 (Back pain)
Restricted joint mobility / stiffness	Progresses with disease stage	HP:0001376 (Limitation of joint mobility) / HP:0001387 (Joint stiffness)
Diffuse osteosclerosis	Radiographic hallmark	HP:0100774 (Osteosclerosis)
Skeletal exostoses / bony outgrowths		HP:0100777 (Exostoses)
Ligamentous/tendon ossification (interosseous membrane, posterior longitudinal ligament, ligamentum flavum)	Drives neurologic compression	HP:0011800 (Midline sternotomy) n/a — better: HP:0002758 (Osteoarthritis) not exact; consider generic HP:0040068 (Abnormality of limb bone) plus free-text for ligament ossification (no precise HPO term for DISH-like ligament calcification exists; closest is HP:0002758-adjacent or ontology gap — record as free text/qualifier)
Spinal rigidity / kyphosis		HP:0002808 (Kyphosis)
Genu valgum/varum (children)	Reported in pediatric coal-smoke fluorosis	HP:0002857 (Genu varum) / HP:0002857
Spastic quadriparesis (advanced/neurologic disease)	Due to cervical cord compression	HP:0002510 (Spastic tetraparesis)
Radiculopathy / paresthesia		HP:0009830 (Peripheral neuropathy)
Urinary incontinence (advanced neurologic disease)	Secondary to myelopathy	HP:0000020 (Urinary incontinence)
Muscle weakness	Reported on skeletal-muscle biopsy studies in endemic SF (PMID:10878791)	HP:0001324 (Muscle weakness)
Dental mottling (concurrent dental fluorosis)	Co-occurs when exposure begins before age 8	HP:0009758 (Enamel hypoplasia) / dental fluorosis-specific term outside core HPO

Laboratory abnormalities

Elevated urinary fluoride — the primary chemical biomarker; recent exposure reflected within 1–3 weeks, with reported values of ~15–20 ppm in affected humans/animals vs. 2–6 ppm normal (comparative veterinary literature; PMC search results).
Bone-ash fluoride concentration (from biopsy) — considered the gold-standard definitive diagnostic measure, but invasive and rarely performed clinically.
Elevated serum PTH with chronic fluoride exposure (secondary/tertiary hyperparathyroidism-like state; PMC8584317).
Alkaline phosphatase elevation reflecting high bone turnover.
Serum fluoride itself is not reliably diagnostic ("serum parameters rarely help in the diagnosis" — search synthesis above), because it reflects only very recent intake, not cumulative skeletal burden.

Phenotype characteristics

Onset: Adult-onset in most endemic (waterborne) cases after years to decades of cumulative exposure; pediatric-onset described in indoor coal-burning fluorosis in southwestern China (PMC2778178) and rare acute/subacute cases from inhalant abuse or methoxyflurane over months.
Severity/progression: Progressive with cumulative dose and duration; graded by China's national standard WS/T192-2021 into Grade I (symptoms, no radiographic/physical signs), Grade II (typical clinical/radiographic manifestations, retains some work capacity), and Grade III (loss of work capacity/crippling disease) (search synthesis).
Frequency of neurologic involvement: Neurologic complications (myelopathy ± radiculopathy) occur in an estimated 5–10% of skeletal fluorosis cases, typically after >4 ppm fluoride exposure for >10 years; among those with neurologic disease, myelopathy alone accounts for ~72% and myelopathy+radiculopathy ~28% (PMID:2172892, Neurology India review).

Quality of life impact

Skeletal fluorosis causes "severe crippling disease which impairs the health-related quality of life in affected subjects," with case-report literature describing prolonged, sometimes decade-long, disability (search synthesis of ScienceDirect case-series review and JBMR "Recovery from Skeletal Fluorosis" case, PMID:17014382). No disease-specific EQ-5D/SF-36 dataset was identified in this search; QoL impact is documented narratively rather than via validated instrument scores in the literature surveyed.

4. Genetic/Molecular Information

Skeletal fluorosis is not a monogenic Mendelian disease — there is no single causal gene, OMIM entry, or pathogenic-variant classification analogous to a genetic disorder. Genetic information relevant to this entry is restricted to susceptibility/modifier loci:

ESR1 (estrogen receptor alpha; HGNC:3467) — variant rs9340799 (intron 1, "PvuII" site); G allele protective in brick-tea-type fluorosis (PMID:39824337). Functional consequence: modifies estrogen-responsive transcriptional regulation of osteoblast activity, consistent with estrogen's known role in bone remodeling.
COL1A1 (collagen type I alpha 1 chain; HGNC:2197) — variant rs1800012 (Sp1 binding site polymorphism, well known in osteoporosis genetics); T allele associated with increased skeletal fluorosis risk, especially in Russian men in the Chinese multi-ethnic cohort (PMID:39824337). This is the same polymorphism long studied for osteoporotic fracture risk, consistent with a shared collagen-matrix-quality mechanism.
COL1A2 (HGNC:2198) — polymorphism rs412777 studied in relation to dental (not skeletal) fluorosis in a Tunisian population (PMC10958825) — noted here as an adjacent finding but not directly established for the skeletal phenotype.
No ClinVar/ClinGen pathogenic-variant curation applies (this is a toxic/environmental exposure disease, not a variant-driven disorder), so ACMG/AMP classification, allele-frequency-database (gnomAD), and somatic/germline-origin fields are not applicable.
Epigenetic changes (directly mechanistic, see Section 6) are the most substantive "genetic/molecular" content specific to this disease: DNA hypermethylation of p16, BMP1, METAP2, MMP11, BACH1; hypomethylation of ERα; and dysregulation of microRNAs miR-486-3p, miR-4755-5p, Let-7c-5p, miR-29a, miR-27 (PMC8584317, detailed in Section 6).
Chromosomal abnormalities: none reported; not a chromosomal disorder.

5. Environmental Information

Primary environmental factor: chronic excess fluoride ingestion, principally via drinking water with geogenic fluoride contamination exceeding WHO's 1.5 mg/L guideline (search synthesis; PMID citations above). ECTO/ENVO-relevant exposure route: ingestion of fluoride-contaminated water.
Dietary/lifestyle factor: habitual consumption of brick tea or instant tea concentrate (documented reversal after tea cessation/reduction — ScienceDirect S237606052030465X, "long-term follow-up after reduction and discontinuation of tea").
Occupational exposure: aluminum electrolytic production, phosphate fertilizer manufacture, and other fluoride/hydrogen-fluoride-emitting industrial processes (PMC2993488).
Indoor air pollution: fluoride-laden smoke from unventilated indoor coal-burning stoves, compounded by crop-drying practices over open coal fires that further contaminate food with fluoride (PMC2778178, southwestern China pediatric cohort).
Consumer product/iatrogenic exposure: difluoroethane-propelled computer-duster inhalant abuse (PMC7336600); chronic methoxyflurane analgesic use (JBMR Plus ziae032); excessive fluoridated toothpaste ingestion.
Infectious agents: not applicable — skeletal fluorosis has no infectious etiology.
Geographic/climatic modifiers: arid and semi-arid climates with high evapotranspiration concentrate fluoride in groundwater; the East African Rift Valley, the Indian subcontinent, and northern/southwestern China are the classic endemic belts (search synthesis; PMC13275634 "Global groundwater contamination by geogenic fluoride").

6. Mechanism / Pathophysiology

Ordered causal chain (initiating exposure → clinical manifestation)

Chronic excess fluoride intake (contaminated water, brick tea, coal smoke, industrial exposure, or iatrogenic source) leads to sustained elevation of systemic fluoride ion (F⁻) levels beyond renal excretory capacity.
Elevated systemic F⁻ results in progressive fluoride deposition into the hydroxyapatite mineral lattice of bone, substituting for hydroxyl groups to form fluorapatite — fluoride's high calcium affinity drives this preferential skeletal sequestration (PMID:3295994).
Bone-incorporated fluoride, together with circulating fluoride acting on bone-lining cells, triggers a shift in local signaling in osteoblasts and osteocytes: fluoride activates Wnt/β-catenin signaling (by suppressing the inhibitors SOST and Dkk-1, allowing β-catenin nuclear accumulation) and Hedgehog signaling (via increased Indian Hedgehog → Smoothened → Gli2), both converging on upregulation of Runx2, the master osteoblast transcription factor, while fluoride simultaneously suppresses Notch signaling (decreased Notch-3/Jagged-1), removing an inhibitory brake on osteoblast proliferation (PMC8584317).
This signaling shift leads to excessive, disorganized osteoblast proliferation and matrix (collagen I, alkaline phosphatase, osteonectin) synthesis, mediated in part by fluoride-induced Akt/GSK-3β phosphorylation that stabilizes β-catenin (PMID:24300170).
In parallel, elevated serum PTH (a systemic response to chronic fluoride/calcium perturbation) results in further downregulation of SOST and upregulation of RANKL, coupling excess osteoblastic activity to increased osteoclastogenesis via the osteocyte-driven RANK–JNK–NFATc1 pathway (PMID:32156525) — this is the mechanistic basis for the disease's hallmark of accelerated bone turnover rather than pure bone formation.
At high, sustained fluoride concentrations, cellular defenses are overwhelmed: fluoride induces oxidative stress (ROS accumulation overwhelming the Nrf2-ARE antioxidant response), endoplasmic reticulum stress (PERK-mediated unfolded protein response, upregulated BiP/GRP78, ATF4), and mitochondria-mediated apoptosis with increased mitophagy in osteocytes (Springer 2023 study), leading to disordered osteocyte viability and further dysregulated bone remodeling signals (PMC8584317; Springer/Biological Trace Element Research).
Concurrently, fluoride inhibits vitamin D hydroxylation, decreasing active vitamin D bioavailability and impairing intestinal calcium/phosphorus absorption, which — together with fluoride's direct calcium sequestration in bone — disturbs systemic phosphorus/calcium balance (search synthesis).
Epigenetic reprogramming accompanies and reinforces these changes: hypermethylation of the cell-cycle checkpoint gene p16 (reducing its expression and removing G1/S checkpoint control) and of BMP1, METAP2, MMP11, BACH1, alongside hypomethylation of ERα, and dysregulation of microRNAs (miR-486-3p↓, miR-4755-5p↓, Let-7c-5p↓ → increased Cyclin D1 → osteoblast proliferation; miR-29a↑ → decreased Dkk-1 → enhanced Wnt signaling; miR-27 positively correlated with β-catenin), collectively sustaining the pro-osteogenic, hyperproliferative osteoblast phenotype over years of chronic exposure (PMC8584317).
The net structural consequence — cumulative over years to decades — is diffuse osteosclerosis, cortical thickening, exostoses, and ossification of ligaments/tendons (interosseous membranes, posterior longitudinal ligament, ligamentum flavum, entheses), radiographically the disease's defining feature (search synthesis; AJR PMID reference; Radiopaedia).
In the spine specifically, this ligamentous/vertebral ossification and osteophytosis narrows the spinal canal and intervertebral foramina, which leads to (branch point) either (a) mechanical/compressive myelopathy and radiculopathy via direct cord/root compression, occurring in ~5–10% of cases after >10 years of high (>4 ppm) exposure (PMID:2172892), progressing in advanced cases to vascular/ischemic secondary injury of the cord, manifesting clinically as spastic quadriparesis, spasms, and urinary incontinence; or (b) purely peripheral musculoskeletal disease — joint stiffness, restricted mobility, and chronic pain — without neurologic compromise, in the majority of affected individuals.
In cartilage, a separate downstream branch occurs in chondrocytes: fluoride-induced oxidative stress suppresses the pentose phosphate pathway (decreased NADPH/GSH) and downregulates PI3K/Akt/mTOR while activating autophagy (increased Beclin-1, LC3) and upregulating MMP-13/RANKL, resulting in chondrocyte apoptosis and matrix degradation, contributing to joint/cartilage pathology alongside the primary bone-driven mechanism (PMID:39959228, PMID:41601087).

Detail by category

Molecular pathways (KEGG/Reactome-relevant): Wnt signaling pathway (activated), Notch signaling pathway (suppressed), Hedgehog signaling pathway (activated in osteoblasts; pro-apoptotic in chondrocytes via Bax↑/Bcl-2↓), PI3K-Akt signaling pathway (activated in osteoblasts, suppressed in chondrocytes), RANK/RANKL/OPG axis (shifted toward increased RANKL), IL-17A pathway, MAPK/NQO1/HO1 pathway, PTH/PTHrP signaling, insulin/IGF-1 signaling (PMC8584317; PubMed synthesis).
Cellular processes (GO-relevant): osteoblast proliferation and differentiation (GO:0002062 chondrocyte differentiation; GO:0030282 bone mineralization), osteoclast differentiation (GO:0030316), apoptosis (GO:0006915), autophagy (GO:0006914), mitophagy, oxidative stress response (GO:0006979), unfolded protein response/ER stress (GO:0030968), chronic inflammation.
Protein dysfunction: no single misfolded protein; instead, fluoride acts as an enzymatic/ionic perturbant — inhibiting osteoblastic acid phosphatase (proposed mitogenic mechanism, ScienceDirect 0026049589902321), altering collagen (COL1A1) matrix quality, and disrupting vitamin-D-hydroxylase enzymatic activity.
Metabolic changes: disturbed calcium-phosphorus homeostasis; impaired vitamin D activation; altered bone mineral (fluorapatite substitution for hydroxyapatite) reducing mechanical strength despite increased radiographic density.
Immune system involvement: chronic low-grade inflammation and IL-17A pathway activation are implicated but are secondary/contributory rather than primary autoimmune mechanisms (PMC8584317).
Tissue damage mechanisms: oxidative stress (ROS/MDA elevation), apoptosis, mitochondrial dysfunction/mitophagy in osteocytes, and secondary vascular/ischemic injury to compressed neural tissue.
Biochemical abnormalities: elevated PTH, altered alkaline/acid phosphatase activity, disrupted calcium/phosphate/vitamin D axis, calcineurin (CaN) activation promoting osteoclastogenesis.
Epigenetic changes: detailed above (DNA methylation of p16, BMP1, METAP2, MMP11, BACH1, ERα; miRNA dysregulation).
Molecular profiling: proteomic studies (iTRAQ, Wistar rat serum) have identified candidate serum protein biomarkers of fluorosis (PMC5085677); murine bone proteomics show 36 differentially abundant proteins even at low-dose fluoride exposure in susceptible (A/J) mice (PMC4263599). No large-scale human transcriptomic/single-cell atlas specific to skeletal fluorosis was identified in this search.

Suggested GO terms

GO:0030282 (bone mineralization)
GO:0001649 (osteoblast differentiation)
GO:0030316 (osteoclast differentiation)
GO:0060070 (canonical Wnt signaling pathway)
GO:0007219 (Notch signaling pathway)
GO:0007224 (smoothened signaling pathway, Hedgehog)
GO:0043491 (protein kinase B signaling, PI3K/Akt)
GO:0006915 (apoptotic process)
GO:0006979 (response to oxidative stress)
GO:0034976 (response to endoplasmic reticulum stress)
GO:0006914 (autophagy)

Suggested CL terms

CL:0000062 (osteoblast)
CL:0000137 (osteocyte)
CL:0000092 (osteoclast)
CL:0000138 (chondrocyte)

7. Anatomical Structures Affected

Organ level: primary — the skeletal system (axial > appendicular skeleton, especially spine, pelvis, forearm), teeth (concurrent dental fluorosis when exposure begins before age 8). Secondary/complication involvement — spinal cord and peripheral nerve roots (compressive myelopathy/radiculopathy in advanced disease), skeletal muscle (biopsy studies document muscle changes in endemic SF, PMID:10878791), and, per some reviews, renal involvement contributing to fluoride retention itself (kidneys clear fluoride; impaired renal function reduces excretion and worsens skeletal accumulation).
Body systems: skeletal, nervous (compressive), and to a lesser extent muscular systems; endocrine system implicated via PTH/vitamin D axis perturbation.
Tissue/cell level: bone (cortical and trabecular), articular/enthesis connective tissue and ligaments (interosseous membrane, posterior longitudinal ligament, ligamentum flavum — sites of pathological ossification), cartilage (chondrocyte apoptosis/matrix degradation), and spinal neural tissue (secondary compression injury).
Cell populations targeted: osteoblasts (hyperactivated), osteocytes (apoptosis/mitophagy), osteoclasts (RANK-pathway-driven differentiation), chondrocytes (apoptosis, autophagy).
Subcellular level: mitochondria (ROS generation, mitophagy in osteocytes), endoplasmic reticulum (UPR/ER stress via PERK-ATF4), nucleus (β-catenin nuclear translocation, epigenetic/DNA methylation changes).
Localization (UBERON): vertebral column (UBERON:0002298 vertebral column), pelvis, forearm bones, sacroiliac joint, spinal cord (UBERON:0002240), long bones. Ossification is generalized/bilateral rather than lateralized.

Suggested UBERON terms: UBERON:0001474 (bone element), UBERON:0002240 (spinal cord), UBERON:0002298 (vertebral column), UBERON:0002228 (rib), UBERON:0002417 (posterior longitudinal ligament — if available), UBERON:0004123 (femur), UBERON:0001103 (diaphragm — n/a, remove if not applicable).

8. Temporal Development

Onset: Typically adult-onset (years to decades of cumulative exposure) in endemic waterborne fluorosis; pediatric-onset described specifically in indoor coal-smoke fluorosis in China (PMC2778178); rare subacute-onset (months) cases from inhalant abuse or high-dose methoxyflurane exposure.
Onset pattern: Insidious/chronic in the overwhelming majority of cases; subacute in iatrogenic/abuse-related cases.
Progression / staging: Chinese national standard WS/T192-2021 defines three grades — Grade I (symptomatic, no radiographic/physical signs), Grade II (typical clinical and radiographic manifestations, retains partial work capacity), Grade III (loss of work capacity, "crippling" disease) (search synthesis). Radiographically, changes are described along a spectrum: early sand-like/granular trabecular thickening → osteosclerosis, osteopenia in some regions, diaphyseal widening, intermittent growth-arrest lines, and soft-tissue/ligamentous ossification, with the most pronounced structural changes typically appearing in middle age (40–60 years) (search synthesis of radiographic reviews).
Progression rate: Slow and dose/duration-dependent; neurologic complications generally require >10 years of exposure at >4 ppm fluoride.
Course pattern: Chronic and generally progressive with continued exposure; not classically relapsing-remitting.
Reversibility: Cessation of exposure can lead to gradual improvement/reversal of biochemical and even some radiographic abnormalities, but recovery is extremely slow — potentially requiring years to decades — consistent with fluoride's estimated ~7-year half-life in bone; a well-documented American case showed "considerable correction" only after nearly a decade of source removal (toothpaste) (PMID:17014382). No large systematic reversibility dataset exists; evidence is case-based.
Critical periods: Exposure before ~age 8 additionally risks concurrent dental fluorosis (enamel formation window); no other defined critical developmental window is described for the skeletal phenotype beyond cumulative dose-duration.

9. Inheritance and Population

Inheritance pattern: Not applicable in the Mendelian sense — skeletal fluorosis is an acquired toxic/environmental disease. "Inheritance" language does not apply; susceptibility is polygenic/multifactorial (see COL1A1/ESR1 modifiers, Section 4), analogous to a gene-by-environment susceptibility trait rather than a classic inherited disorder. Penetrance, expressivity, anticipation, germline mosaicism, founder effects, and carrier frequency are not meaningful concepts here except insofar as modifier-allele frequency (e.g., COL1A1 rs1800012, ESR1 rs9340799) differs by ethnicity, as documented in the Tibetan/Kazakh/Mongolian/Russian comparison cohort (PMID:39824337).
Epidemiology:
Global burden: UNICEF estimates fluorosis (dental + skeletal combined) is endemic in at least 25 countries, with approximately 200 million people at health risk from elevated groundwater fluoride; some reviews cite over 100 affected countries (search synthesis, PMC13275634). India and China are described as the two largest-affected countries.
India (regional surveys): Kankar district, Chhattisgarh — dental fluorosis prevalence 24.8%, skeletal fluorosis 6.0%. Vidharbha region, Maharashtra — skeletal fluorosis prevalence 56.9% in males, 43.1% in females among the surveyed endemic population (PMC2940190).
China: Fluorosis affects 28 provincial-level administrative regions and over 70,000 villages, via three main pathways — coal-burning, drinking-water contamination, and brick-tea consumption (PMC13128821).
Geographic distribution: Endemic belts include the Indian subcontinent, northern/southwestern China, the East African Rift Valley (Ethiopia, Kenya, Tanzania, Uganda, Eritrea, Djibouti), parts of the Middle East (Jordan, Lebanon, Israel), Sri Lanka, and Türkiye (search synthesis, ResearchGate distribution figure, PMC13275634).
Sex ratio: Male predominance reported in at least one Indian endemic-village study (see above); mechanistic basis (behavioral/occupational exposure vs. biological susceptibility) not fully resolved in the sources reviewed.
Age distribution: Peak radiographic severity in the 40–60 year age range, reflecting cumulative dose; pediatric cases occur specifically in the coal-smoke exposure pathway.

10. Diagnostics

Diagnostic criteria (composite): (1) residence history in a fluorosis-endemic area or a documented alternative fluoride source; (2) characteristic clinical symptoms — persistent resting pain in ≥3 regions (major limb joints, neck, lower back) unaffected by season, and/or restricted joint mobility or secondary neurologic impairment; (3) characteristic radiographic findings; (4) elevated urinary (and/or bone) fluoride. Diagnosis rests on this combination with exclusion of radiographic mimics (search synthesis).
Imaging (primary diagnostic modality):
Plain radiography remains the mainstay: hallmark findings are generalized osteosclerosis, diffuse periostitis, entheso-/ligamentous ossification (interosseous membranes, posterior longitudinal ligament, ligamentum flavum), and sacroiliac changes without erosions — distinguishing SF from inflammatory spondyloarthropathies (search synthesis; AJR classic series of 127 patients).
Early disease: sand-like/granular trabecular thickening at trabecular junctions.
A novel structured scoring system, FI-RADS (Fluorosis Imaging-Reporting and Data System), has been proposed (2026) combining imaging with clinical/biochemical analysis for standardized severity scoring (PMC13178315; PMID:42147921).
Advanced cases can radiographically mimic multiple myeloma on spinal MRI (PMC5117116).
Laboratory tests / biomarkers:
Urinary fluoride — the principal chemical biomarker of recent/ongoing exposure (elevated to ~15–20 ppm vs. 2–6 ppm normal, cross-species comparative data).
Bone-ash fluoride content (biopsy) — gold-standard definitive test but invasive, rarely performed.
Serum fluoride is generally not diagnostically useful because it reflects only very recent intake.
Elevated PTH, elevated alkaline phosphatase, and disturbed calcium/phosphorus panels are supportive but nonspecific.
Genetic testing: Not applicable as a diagnostic modality (no causal gene); COL1A1/ESR1 genotyping is a research tool for population-susceptibility studies, not clinical diagnosis.
Differential diagnosis: Ankylosing spondylitis and diffuse idiopathic skeletal hyperostosis (DISH) are the principal radiographic mimics. Distinguishing features: AS shows complete sacroiliac joint fusion and "smooth-type" anterior spinal bony bridging; DISH shows anterior/posterior bony bridging around the SI joint without fusion and "candle-wax-type" bridging. The combination of diffuse osteosclerosis with periosteal reaction plus ligament/tendon mineralization should specifically prompt consideration of skeletal fluorosis and a focused exposure history (search synthesis, PMC9892029 comparative radiology study).
Other mimics to exclude: renal osteodystrophy, osteopetrosis, Paget disease of bone, myelofibrosis, and (as noted) multiple myeloma on imaging alone.

11. Outcome / Prognosis

Mortality: No direct disease-specific mortality/survival statistics (e.g., 5-year survival) were identified — skeletal fluorosis is not typically fatal per se, but severe neurologic complications (quadriparesis) carry major morbidity and disability risk.
Morbidity/disability: Advanced (Grade III) disease causes loss of work capacity; the case-series literature explicitly frames the disease as a "continuing crippling challenge," with impaired health-related quality of life (search synthesis, ScienceDirect S2214624522000089).
Reversibility/recovery: As detailed in Section 8, cessation of the fluoride source can allow gradual clinical, biochemical, and radiographic improvement, but recovery is slow (years, potentially matching bone fluoride's ~7-year half-life), and a well-documented case required nearly a decade for substantial correction after removing a toothpaste source (PMID:17014382). There are no systematic reversibility data across cohorts — this is characterized as an evidence gap in the literature itself.
Complications: Compressive myelopathy/radiculopathy (5–10% of cases, see Section 3/6), joint ankylosis, secondary muscle changes, and (in the pediatric coal-smoke pathway) growth/limb deformities (e.g., genu varum/valgum).
Prognostic factors: Total cumulative fluoride dose and duration of exposure are described as "the single most important factor" determining clinical course (search synthesis, PubMed abstract on endemic skeletal fluorosis); early removal of the fluoride source is the dominant modifiable prognostic factor, since no pharmacologic treatment reverses established disease.

12. Treatment

There is no disease-modifying pharmacologic treatment for established skeletal fluorosis. Management is source removal plus symptomatic/supportive care.

Primary intervention: Identification and elimination of the fluoride source (switching water supply, discontinuing brick tea, ceasing occupational exposure, stopping inhalant abuse or methoxyflurane), which is the only intervention shown to allow gradual improvement (Section 8/11).
Pharmacotherapy (symptomatic):
NSAIDs for pain and inflammation control (NCIT:C15986 Pharmacotherapy; specific agent class NCIT:C275/analgesic).
Calcium and vitamin D supplementation — mixed evidence in humans (largely minimal efficacy reported in clinical literature), but effective in mouse models at alleviating dental/skeletal fluorosis, reducing bone fluoride deposition, and normalizing elemental (Ca/P) homeostasis (PMID:33057951; evidence_source: MODEL_ORGANISM for the murine result vs. HUMAN_CLINICAL for the largely negative human experience).
Surgical/interventional:
Decompressive laminectomy for relief of neurologic deficits from spinal cord/nerve root compression (NCIT:C15329 Surgical Procedure) — but note a documented case of recurrent fluorotic cervical compressive myelopathy 20 years after laminectomy, illustrating that surgery addresses mechanical compression without halting the underlying ossifying process if exposure continues (Surgical Neurology International case report).
Osteoplasty for ankylosis of appendicular joints.
Supportive/rehabilitative care: Physical therapy (NCIT:C15302) and general symptomatic musculoskeletal pain management, particularly important during a prolonged "withdrawal phase" after source removal that may last many weeks.
Experimental/research-stage: No specific ongoing registered clinical trials targeting skeletal fluorosis treatment were identified in this search (ClinicalTrials.gov search returned no disease-specific NCT records); a 2026 "China Fluorosis Cohort (CFC)" randomized trial explores drug–lifestyle interventions but targets cardiovascular-metabolic outcomes in fluorosis patients rather than the skeletal phenotype itself (Frontiers in Pharmacology, 2026).
Treatment outcomes: Human calcium/vitamin D trials show minimal efficacy in established disease; surgical decompression provides mechanical relief but does not reverse the underlying osteosclerotic process.

Suggested NCIT terms: NCIT:C15986 (Pharmacotherapy), NCIT:C15329 (Surgical Procedure), NCIT:C15302 (Physical Therapy), NCIT:C15747 (Supportive Care). Suggested CHEBI terms for the causal/therapeutic agents: CHEBI:17051 (fluoride ion, the causal agent), CHEBI:28741 (sodium fluoride), CHEBI:22984 (calcium(2+); for calcium supplementation), CHEBI:27300 (vitamin D).

13. Prevention

Primary prevention (population level):
Defluoridation of drinking water to bring fluoride concentration to WHO's guideline ≤1.5 mg/L — via technologies such as octacalcium-phosphate/fluorapatite transformation systems and household-scale defluoridators (demonstrated in Tanzania to reduce 21 mg/L source water to below the WHO limit within 2 hours) (PMC7687156, PMC6706606).
Alternative/safe water source provision in endemic villages.
Reduction/substitution of brick tea consumption in high-risk pastoralist populations, with documented reversal of biochemical/clinical parameters after tea reduction or cessation (ScienceDirect S237606052030465X).
Improved ventilation and alternative cooking fuel to reduce indoor coal-smoke exposure, plus altered crop-drying practices (not drying food over open coal fires) in the southwestern China pediatric-fluorosis context.
Occupational hygiene controls (ventilation, personal protective equipment, exposure monitoring) in fluoride-emitting industries.
Secondary prevention: Population screening in endemic areas via urinary fluoride testing and radiographic surveillance to detect early (Grade I) disease before irreversible skeletal changes accrue; public health surveys of the type reviewed above (e.g., Chhattisgarh, Vidharbha, Andhra Pradesh school-children studies) serve this function.
Tertiary prevention: Early source removal upon diagnosis to halt disease progression and permit the slow reversal process described in Sections 8/11; symptomatic management to prevent secondary complications (e.g., early recognition of neurologic signs to prompt timely decompressive surgery before irreversible cord injury).
Counseling: Public health education in endemic communities regarding water source safety and tea consumption patterns; occupational counseling in at-risk industries.
Regulatory/public health standards: WHO drinking-water guideline value of 1.5 mg/L fluoride, adopted as national standard in most countries (some countries with particular challenges set different limits) (search synthesis).

14. Other Species / Natural Disease

Taxonomy of affected species: Skeletal fluorosis occurs naturally in numerous species exposed to high-fluoride water, forage, or industrial contamination — most notably cattle (Bos taurus, NCBITaxon:9913), but also documented in horses, sheep, and other livestock, as well as wildlife in fluoride-contaminated environments (Merck Veterinary Manual; veterinaryworld.org review).
Natural disease in veterinary species (cattle): Skeletal fluorosis in cattle presents with hoof deformity, mandibular lesions, bone/joint enlargement, exostoses, ligament calcification, stiffness, and lameness, at drinking-water fluoride concentrations of ≥2.8 mg/L (search synthesis, veterinaryworld.org, cpdsolutions.co.za review). Diagnostic thresholds: bone fluoride concentration of 1605–2794 mg/kg (age-dependent) for chronic fluorosis; urinary fluoride <5 ppm normal, 20–30 ppm borderline toxicity, >35 ppm with systemic signs.
Causes in livestock: deep-well/artesian bore water, industrial (e.g., aluminum smelter, phosphate fertilizer plant) contamination of pasture/forage, and high soil fluoride affecting fodder crops.
Veterinary relevance: Fluorosis is an economically significant livestock disease in endemic regions (India, parts of Africa) causing reduced productivity, lameness, and premature culling; it is diagnosed via the same combination of history, clinical signs, radiography, and bone/urine fluoride analysis used in humans (Livesey, In Practice, 2011, doi:10.1136/inp.d6078).
Comparative pathology: The core pathophysiology — fluoride substitution into hydroxyapatite, osteosclerosis, exostosis formation, ligament calcification — is conserved across mammalian species, supporting cattle and mice as translationally relevant natural/experimental models. Dental fluorosis is separately documented as co-occurring in livestock sharing contaminated water/pasture with human populations (e.g., Gihaya Island, Lake Kivu, Rwanda cohort, PMC8686390).
Zoonotic potential: Not applicable — this is a shared environmental toxic exposure, not a transmissible infectious disease.
OMIA: No specific OMIA (Online Mendelian Inheritance in Animals) entry was identified for fluorosis in this search, consistent with its non-Mendelian, acquired-toxicological nature; direct OMIA database consultation would be needed to confirm absence of an entry.

15. Model Organisms

Mouse (Mus musculus, NCBITaxon:10090) — the dominant experimental model:
Genetic/strain models: Comparative dosing (0, 25, 50, 100 ppm F in food/water) across three inbred strains with differential enamel-fluorosis susceptibility — A/J (susceptible), 129P3/J (resistant), SWR/J (intermediate) — shows strain-dependent, dose-concordant increases in femoral and vertebral fluoride concentration, establishing a genetic-background model for susceptibility (PMID:16920415).
Proteomic follow-up: 8-week exposure to 0/10/50 ppm F in A/J vs. 129P3/J mice shows bone proteomic changes (36 differentially abundant proteins) even at low dose in the susceptible strain (PMC4263599) — useful for identifying candidate mechanistic biomarkers.
Intervention model: Calcium/vitamin D supplementation in a fluorosis mouse model effectively alleviates dental and skeletal fluorosis and retains elemental homeostasis (PMID:33057951) — the strongest available "rescue" evidence for this intervention, notably stronger than the human clinical experience, an instructive human/model discrepancy for a HUMAN_MODEL_MISMATCH-type discussion.
Method development: A murine model using hexamethyldisiloxane-facilitated diffusion with ion-selective electrode measurement enables age- and dose-dependent fluoride quantification across serum, bone, and teeth (PMID:42667223), supporting future dose-response and toxicokinetic studies.
Developmental-age model: Classic studies (PMID:1058056, PMID:1060516, PMID:1067906) examined age-of-exposure effects on incisor/bone fluoride incorporation and the influence of dietary salt intake on fluoride uptake in mice.
Rat (Rattus norvegicus, NCBITaxon:10116): Wistar rats treated with sodium fluoride used for iTRAQ-based serum proteomic biomarker discovery relevant to fluorosis mechanism/candidate biomarkers (PMC5085677); primary rat osteoblast cultures used to demonstrate fluoride-induced Wnt/β-catenin activation via Akt/GSK-3β (PMID:24300170).
Cattle (Bos taurus) as a natural disease model (Section 14) — valuable for translational relevance given spontaneous, environmentally acquired disease closely paralleling the human condition, though whole-organism veterinary studies are largely observational rather than mechanistic/genetic.
Model limitations: Rodent models require relatively high fluoride doses (tens to over 100 ppm) delivered over weeks to reproduce skeletal changes analogous to those developing over years to decades of low-level (~1.5–10 ppm water; higher via tea/coal) human exposure — a scale/dose-rate divergence to note explicitly when using rodent data to support human mechanism claims. No organoid, iPSC, zebrafish, or single-cell/spatial-transcriptomic fluorosis-specific model was identified in this search, representing an apparent gap in the current published model landscape relative to other skeletal disorders.
Resources: MGI (Mouse Genome Informatics) for strain background data; no dedicated fluorosis-specific model registry was identified.

Summary of Suggested Ontology Term Bindings

Category	Term	ID
Disease	Skeletal fluorosis	MONDO:0400003
Disease (related, distinct)	Dental fluorosis	MONDO:0006722
Phenotype	Osteosclerosis	HP:0100774
Phenotype	Exostoses	HP:0100777
Phenotype	Limitation of joint mobility	HP:0001376
Phenotype	Spastic tetraparesis	HP:0002510
Phenotype	Kyphosis	HP:0002808
Gene (modifier)	ESR1	hgnc:3467
Gene (modifier)	COL1A1	hgnc:2197
Gene (modifier, dental)	COL1A2	hgnc:2198
Chemical (causal agent)	fluoride	CHEBI:17051
Chemical	sodium fluoride	CHEBI:28741
GO (pathway)	canonical Wnt signaling pathway	GO:0060070
GO (pathway)	Notch signaling pathway	GO:0007219
GO (pathway)	response to oxidative stress	GO:0006979
Cell type	osteoblast	CL:0000062
Cell type	osteocyte	CL:0000137
Cell type	osteoclast	CL:0000092
Cell type	chondrocyte	CL:0000138
Anatomy	vertebral column	UBERON:0002298
Anatomy	spinal cord	UBERON:0002240
Treatment	Pharmacotherapy	NCIT:C15986
Treatment	Surgical Procedure	NCIT:C15329
Treatment	Physical Therapy	NCIT:C15302
Organism (model)	Mus musculus	NCBITaxon:10090
Organism (natural disease)	Bos taurus	NCBITaxon:9913

Notable Evidence Gaps (flagged for curation)

Reversibility/prognosis is documented almost entirely through single case reports (e.g., PMID:17014382), not cohort data — the literature itself states "there are no data regarding its reversibility" at a systematic level.
No specific registered clinical trials target skeletal-fluorosis treatment directly (ClinicalTrials.gov search returned none disease-specific); the one identified 2026 trial (China Fluorosis Cohort) targets cardiovascular-metabolic, not skeletal, endpoints.
Human calcium/vitamin D efficacy is discordant with the mouse model result (minimal human efficacy vs. clear murine rescue, PMID:33057951) — a candidate HUMAN_MODEL_MISMATCH discussion point.
No QoL instrument (EQ-5D/SF-36) score data specific to skeletal fluorosis were located; impact is described narratively only.
OMIA entry status for veterinary fluorosis was not confirmed/denied definitively and would need direct OMIA database consultation.

Sources: - Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis (PMC8584317 / PMID:34769866) - Environmental fluoride exposure and bone metabolism: Molecular pathways and health implications (PMID:42336527) - The continuing crippling challenge of skeletal fluorosis – Case series and review of literature - Skeletal fluorosis in humans: a review of recent progress (PMID:3295994) - MONDO:0400003 — Ontology Lookup Service - ICD-10-CM M85.1 series — icd10data.com - Effect of fluoride on osteocyte-driven osteoclastic differentiation (PMID:32156525) - Different Effects of Fluoride Exposure on the Three Major Bone Cell Types - Apoptosis and Inflammation Involved with Fluoride-Induced Bone Injuries (PMC11313706) - Fluoride Exposure and Skeletal Fluorosis: a Systematic Review and Dose-response Meta-analysis - Child Skeletal Fluorosis from Indoor Burning of Coal in Southwestern China (PMC2778178) - Predicting skeletal fluorosis severity using machine learning across diverse fluoride-exposed populations in China (PMC13128821) - Assessment of Skeletal and Non-skeletal Fluorosis in Endemic Fluoridated Areas of Vidharbha Region, India (PMC2940190) - FI-RADS: an imaging-based scoring system for skeletal fluorosis (PMC13178315 / PMID:42147921) - Endemic fluorosis of the skeleton: radiographic features in 127 patients — AJR - Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy (PMID:2172892) - Neurology of endemic skeletal fluorosis — Neurology India - Multiple Myeloma-Like Spinal MRI Findings in Skeletal Fluorosis (PMC5117116) - Fluorotic cervical compressive myelopathy, 20 years after laminectomy - Fluoride promotes osteoblastic differentiation through canonical Wnt/β-catenin signaling pathway (PMID:24300170) - Association between ESR1 and COL1A1 gene polymorphisms and skeletal fluorosis in Tibetan, Kazakh, Mongolian and Russian populations, China (PMID:39824337) - The genetic influence in fluorosis - The COL1A2 gene polymorphism among a Tunisian Population and Dental Fluorosis (PMC10958825) - Fluorosis in Cattle — veterinaryworld.org - Diagnosis and investigation of fluorosis in livestock and horses — In Practice - Fluoride Poisoning in Animals — Merck Veterinary Manual - Chronic Fluoride Exposure from Brick Tea Consumption Disrupts Bone Remodeling (PMID:42060046) - Skeletal Fluorosis Related to Habitual Tea Consumption: Long-Term Follow-Up - Prevalence of Brick Tea-Type Fluorosis in the Tibet Autonomous Region (PMC4728115) - Skeletal fluorosis from the point of view of an occupational exposure in former Czechoslovakia (PMC2993488) - Skeletal Fluorosis: An Unusual Manifestation of Computer Cleaner Inhalant Abuse (PMC7336600) - Skeletal fluorosis secondary to methoxyflurane use for chronic pain — JBMR Plus - Recovery From Skeletal Fluorosis (an Enigmatic, American Case) — JBMR (PMID:17014382) - Calcium and Vitamin D Supplementation Effectively Alleviates Dental and Skeletal Fluorosis in Mice (PMID:33057951) - Treatment and Prevention of Skeletal Fluorosis - Global groundwater contamination by geogenic fluoride (PMC13275634) - Application of Octacalcium Phosphate defluoridator prototype in East African Rift Valley communities (PMC7687156) - Defluoridation of water through transformation of octacalcium phosphate into fluorapatite (PMC6706606) - The genetic influence on bone susceptibility to fluoride (PMID:16920415) - Bone Response to Fluoride Exposure Is Influenced by Genetics (PMC4263599) - Quantification of Fluoride in Serum, Bone, and Teeth in a Murine Model (PMID:42667223) - iTRAQ-Based Proteomics Analysis of Serum Proteins in Wistar Rats Treated with Sodium Fluoride (PMC5085677) - Studies on skeletal muscle biopsies in endemic skeletal fluorosis (PMID:10878791) - Comparison of radiological characteristics between DISH and ankylosing spondylitis (PMC9892029) - Fluoride Exposure Provokes Mitochondria-Mediated Apoptosis and Increases Mitophagy in Osteocytes - Sodium fluoride accelerates apoptosis, oxidative stress and matrix degradation of condylar chondrocytes (PMID:39959228) - Pentose phosphate pathway regulates oxidative damage and apoptosis of chondrocytes induced by fluoride (PMID:41601087) - fluoride (CHEBI:17051) - Dental fluorosis among people and livestock, Gihaya Island, Lake Kivu, Rwanda (PMC8686390)

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	43
Resolved	43
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	43
On topic	30
Off topic	1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:34769866 (1 mention) - How Did School Meal Access Change during the COVID-19 Pandemic? A Two-Step Floating Catchment Area Analysis of a Large Metropolitan Area.
shared terms: change

Weighed against this report's own most characteristic terms: skeletal, fluoride, fluorosis, exposure, bone, disease, dental, endemic, synthesis, radiographic, clinical, year, chronic, change, tea, calcium, china, joint, water, via.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	58
Resolved	54
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	4
Terms whose name was checked	42
Terms named correctly	30
Terms named as a different term	6
Terms whose name is worth a second look	6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0400003 (4 mentions) - the report calls it "Skeletal fluorosis", "Ontology Lookup Service"; MONDO calls it skeletal fluorosis
HP:0100774 (2 mentions) - the report calls it "Osteosclerosis"; HP calls it Hyperostosis
HP:0009758 (1 mention) - the report calls it "Enamel hypoplasia"; HP calls it Pyramidal skinfold extending from the base to the top of the nails
UBERON:0002298 (3 mentions) - the report calls it "vertebral column"; UBERON calls it brainstem
UBERON:0002417 (1 mention) - the report calls it "posterior longitudinal ligament — if available"; UBERON calls it abdominal segment of trunk
UBERON:0004123 (1 mention) - the report calls it "femur"; UBERON calls it myocardial layer

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0002510 (2 mentions) - the report calls it "Spastic tetraparesis"; HP calls it Spastic tetraplegia
GO:0007224 (1 mention) - the report calls it "smoothened signaling pathway, Hedgehog"; GO calls it smoothened signaling pathway
GO:0043491 (1 mention) - the report calls it "protein kinase B signaling, PI3K/Akt"; GO calls it phosphatidylinositol 3-kinase/protein kinase B signal transduction, and lists "protein kinase B signaling" among its other names
UBERON:0001103 (1 mention) - the report calls it "diaphragm — n/a, remove if not applicable"; UBERON calls it diaphragm, and lists "diaphragm of thorax" among its other names
NCIT:C15302 (3 mentions) - the report calls it "Supportive/rehabilitative care: Physical therapy", "Physical Therapy"; NCIT calls it Physical Therapy**
CHEBI:17051 (5 mentions) - the report calls it "fluoride ion, the causal agent", "fluoride"; CHEBI calls it fluoride, and lists "FLUORIDE ION" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

MONDO:0400003 - called "Skeletal fluorosis", "Ontology Lookup Service"
MONDO:0006722 - called "dental fluorosis", "Dental fluorosis"
NCIT:C15302 - called "Supportive/rehabilitative care:** Physical therapy", "Physical Therapy"
CHEBI:17051 - called "fluoride ion, the causal agent", "fluoride"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ICD10CM.

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Mappings

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Prevalence

Epidemiology

Differential Diagnoses

Related Datasets

Animal Models

Source YAML

References & Deep Research

Deep Research

Skeletal Fluorosis — Comprehensive Research Report

1. Disease Information

2. Etiology

2a. Disease causal factors

2b. Risk factors

2c. Protective factors

2d. Gene–environment interactions

3. Phenotypes

Symptoms / clinical signs (with suggested HPO terms)

Laboratory abnormalities

Phenotype characteristics

Quality of life impact

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (initiating exposure → clinical manifestation)

Detail by category

Suggested GO terms

Suggested CL terms

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Suggested Ontology Term Bindings

Notable Evidence Gaps (flagged for curation)

Reference Validation

References that may not be about this subject

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver