This is a mechanism module, not a specific disease. Do NOT create an "Ischemic Bone Necrosis" Disease entry; the disease entries are Osteonecrosis (MONDO:0005380), Osteochondrosis (MONDO:0018381), Kummell_Disease, Osteochondritis_of_Tarsal_Metatarsal_Bone, Avascular_Necrosis_Of_Femoral_Head_Primary_2 and their relatives. Disorder entries reference individual nodes via conforms_to, for example "ischemic_bone_necrosis_and_repair#Resorption-Dominant Revascularization and Creeping Substitution".
Arm scoping. Conformance is per node, so an entry takes only the arm that applies to it. An adult femoral-head, vertebral-body or navicular necrosis conforms at the trigger, at Ischemic Osteocyte and Marrow Cell Death, and at the shared repair and failure nodes. A growing-epiphysis disorder additionally conforms at Epiphyseal Cartilage-Canal Ischemic Chondronecrosis and at Growth Plate Injury and Delayed Endochondral Ossification; it may also conform at the osteocyte-death node, because the secondary ossification centre of a child's epiphysis contains bone and marrow that die too. The two epiphyseal nodes must not be declared by an adult entry, and the apophyseal and physeal families of Osteochondrosis (Osgood-Schlatter, Sever, Scheuermann) must not conform anywhere in this module: they are traction and compression lesions of growth cartilage without an ischemic trigger, and the Osteochondrosis entry keeps them on separate chains for that reason.
Disorder-specific substitutions at the trigger. Glucocorticoid or alcohol exposure with endothelial dysfunction and hypofibrinolysis (Osteonecrosis), a displaced femoral neck fracture or dislocation (traumatic osteonecrosis), sickled erythrocytes or nitrogen emboli (sickle cell disease, dysbaric osteonecrosis), compromise of the basivertebral microcirculation after a minor compression fracture (Kummell disease), endothelial calcium overload and microvascular thrombosis downstream of a TRPV4 gain-of-function variant (Avascular_Necrosis_Of_Femoral_Head_Primary_2), and the idiopathic, probably mechanically induced, interruption of the cartilage-canal supply to the capital femoral epiphysis (Legg-Calve-Perthes). The etiology-specific amplifier of glucocorticoid and alcohol osteonecrosis, marrow adipogenesis and lipotoxicity, is deliberately NOT a module node: it does not recur in the traumatic, vertebral or paediatric conformers, so it stays in the Osteonecrosis entry.
What the module does not settle. Why the capital femoral epiphysis loses its supply in Legg-Calve-Perthes is unresolved; the 64-article systematic review (PMID:30918798) finds no decisive hypothesis, and that question is curated as the perthes_etiology_undetermined knowledge gap on the Osteochondrosis entry, not here. The classical repeated-infarction model of Perthes disease is likewise not asserted by the module's causal spine: an entry that wants it should carry it as a mechanistic_hypothesis with EMERGING status. The paediatric repair nodes rest on piglet, foal, rat and mouse ischemia models with human histology and perfusion imaging as the translational anchor; see the HUMAN_MODEL_MISMATCH discussion before treating them as established human mechanism.
Ontology bindings. Nodes bind GO, CL and UBERON only, per the create-module skill. The central effector's ossification DECREASED binding is read as net new bone formation falling behind resorption during repair, not as a systemic ossification defect. No module_categories value is declared: the trigger node is a vascular event rather than a toxicant exposure, so TOXICOLOGY would assert more than the module claims even though glucocorticoid-induced osteonecrosis is its commonest adult conformer; a wrong pill is worse than no pill. No Xogenesis anchor: the terminal output is loss and collapse of a structure, not formation of a pathological one.
Do the growth-plate injury, DAMP-driven repair bias and resorption-dominant repair measured after surgically induced femoral head ischemia in piglets, foals, rats and mice reproduce what happens in children with Legg-Calve-Perthes disease and the other articular osteochondroses, whose ischemia is idiopathic, possibly repeated, and never total?
HUMAN MODEL MISMATCH
OPEN
gap_paediatric_repair_nodes_rest_on_animal_ischemia_models
Attached to:
Growth Plate Injury and Delayed Endochondral Ossification
Necrotic Bone DAMP Release and Inflammatory Repair Bias
Resorption-Dominant Revascularization and Creeping Substitution
The paediatric arm's quantitative claims come from models in which the whole femoral head is infarcted at once by ligating the neck or transecting canal vessels, then followed for weeks. The human anchors are real but thinner: histology of ischemic chondronecrosis and chondroclast-rich repair at predilection sites in children's knees, perfusion MRI of epiphyseal ischemia and revascularization pattern, raised IL-6 in the synovial fluid of children with juvenile ischemic osteonecrosis. No human study measures growth-plate zone thickness, necrotic bone fluid DAMP content or the RANKL/OPG ratio in the affected epiphysis, and the piglet authors themselves qualify growth disruption as occurring "in some children". The repair-biology claims and the two drug-target patterns should therefore be read as MODEL_ORGANISM evidence with human clinical correlates, not as established human mechanism; a conforming entry that states them for a human disease should keep the evidence_source distinction visible and may want to record the IL-6-blockade and antiresorptive leads as proposed rather than curated treatments. The Osteochondrosis entry's osteochondrosis_animal_ischemia_human_translation discussion frames the same question for the chondronecrosis node; this one extends it to the repair nodes the module adds.
Bone Vascular Supply Interruption
trigger
The initiating event is loss of perfusion to a segment of bone. The interruption may be mechanical (vessel disruption by fracture or dislocation, transection of cartilage-canal vessels in a growing epiphysis), occlusive (microvascular thrombosis, sickled erythrocytes, gas emboli) or the product of endothelial dysfunction, coagulopathy and failed angiogenesis in a chronic inflammatory milieu, as with glucocorticoid and alcohol exposure. Bones with a precarious or non-collateralised supply, the femoral head, the capital femoral epiphysis before its transphyseal vessels mature, the tarsal navicular, the vertebral body around the basivertebral foramen, are the recurrent sites. Dynamic contrast-enhanced MRI detects the resulting epiphyseal ischemia in children directly.
Used by disorders
Osteonecrosis
as Vascular supply disruption and microvascular injury
Downstream
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Ischemic Osteocyte and Marrow Cell Death
Loss of perfusion deprives the bone and marrow of the segment of oxygen and nutrients; osteocytes and marrow cells die by apoptosis and necrosis.
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Epiphyseal Cartilage-Canal Ischemic Chondronecrosis
In a growing epiphysis the same interruption, when it affects cartilage-canal vessels, kills the chondrocytes of the epiphyseal growth cartilage before bone has formed at that site. This edge applies only to skeletally immature conformers.
Show evidence (5 references)
"Osteonecrosis of the femoral head (ONFH), a condition characterized by the presence of a necrotic bone lesion in the femoral head, is caused by a disruption in the blood supply."
States the defining causal claim of the trigger node for the commonest adult conformer: the necrotic lesion follows interruption of the blood supply. Graded OTHER because the source is a narrative review.
"Continuous stimulation by many variables causes a chronic inflammatory milieu, with clinical repercussions including endothelial dysfunction, leading to thrombosis, coagulopathy, and poor angiogenesis."
Names the non-traumatic route to supply interruption, endothelial dysfunction with thrombosis and failed angiogenesis, which is what the endothelial cell type and the DECREASED angiogenesis binding on this node describe.
"DGS MRI allows early detection of epiphyseal ischaemia and accurate analysis of the different revascularisation patterns."
Direct human perfusion evidence for the paediatric conformer: epiphyseal ischemia in Legg-Calve-Perthes disease is imaged in children, so the trigger is not inferred from animal work alone.
+ 2 more references
Ischemic Osteocyte and Marrow Cell Death
effector
Disrupted perfusion kills the osteocytes of the affected trabeculae and the haematopoietic and stromal cells of the marrow between them. This is the defining cellular lesion of osteonecrosis and the state histology confirms when a necrotic vertebral body or femoral head is biopsied: empty lacunae and necrotic marrow in a segment whose mineralised matrix is still intact. The necrotic bone cannot remodel itself, which is why what happens next depends on cells recruited from the viable margin. Dying cells also release the damage-associated molecular patterns that bias the subsequent repair.
Downstream
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Necrotic Bone DAMP Release and Inflammatory Repair Bias
Dying bone and marrow cells release HMGB1, RANKL and other damage-associated molecular patterns into the necrotic segment, and inflammatory cytokines rise with time; this is what sets the repair response toward resorption and fibrosis.
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Resorption-Dominant Revascularization and Creeping Substitution
The necrotic segment cannot remodel itself; repair arrives as vessels and osteoclasts invading from the viable margin, so revascularization and resorption of dead bone are coupled.
Show evidence (4 references)
"Osteonecrosis of the femoral head (ONFH) is a disabling disease characterized by the disruption of the blood supply to the femoral head, leading to the apoptosis and necrosis of bone cells and subsequent joint collapse."
Ties the trigger to this node: interrupted supply leads to apoptosis and necrosis of bone cells, the INCREASED apoptotic process binding.
"Osteonecrosis of the femoral head is characterised by compromised blood flow to the femoral head leading to bone cell apoptosis and its eventual collapse."
The inherited-osteonecrosis family study restates the same human clinical sequence in its introduction; it is the conformer Avascular_Necrosis_Of_Femoral_Head_Primary_2's source for its Osteocyte Death node.
"In Legg-Calvé-Perthes disease (LCPD), a loss of blood supply to the juvenile femoral head leads to extensive cell death and release of damage-associated molecular patterns (DAMPs)."
States the paediatric form of the same lesion, extensive cell death in the juvenile femoral head, and names the DAMP release that is the handoff to the amplifier node. The sentence is the piglet study's framing of the human disease, hence HUMAN_CLINICAL with BACKGROUND.
+ 1 more reference
Epiphyseal Cartilage-Canal Ischemic Chondronecrosis
effector
During growth the secondary ossification centre of an epiphysis is supplied through vessels running in cartilage canals, and the growth cartilage around it depends on them. Focal failure or transection of these vessels kills the chondrocytes and the canal endothelium of the supplied growth cartilage before any bone has mineralised at that site. The sequence was reproduced causally by transecting cartilage-canal vessels in foals, and histologically identical lesions, confirmed to represent cartilage-canal supply failure, were found at the predilection sites for juvenile osteochondritis dissecans in human paediatric knees. This node is specific to the skeletally immature conformers and is the reason a module built from the adult picture alone would misdescribe them.
Downstream
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Growth Plate Injury and Delayed Endochondral Ossification
Necrotic growth cartilage cannot be converted to bone, so endochondral ossification is focally delayed at the lesion and, when the physis shares the lost supply, its proliferative and hypertrophic zones thin.
Show evidence (2 references)
"Transection of blood vessels within epiphyseal cartilage canals resulted in necrosis of vessels and chondrocytes, i.e., ischaemic chondronecrosis, in foals."
The causal experiment behind the node: surgical interruption of cartilage-canal vessels is sufficient to produce ischemic chondronecrosis in a growing epiphysis.
"Changes identical to osteochondrosis in animals were detected at predilection sites for JOCD in children, and confirmed to represent failure of the cartilage canal blood supply and ischemic chondronecrosis in histological sections."
The human translation of the foal experiment: the same lesion, with the same histological signature, at the sites where juvenile osteochondritis dissecans occurs in children.
Growth Plate Injury and Delayed Endochondral Ossification
effector
The ischemic epiphysis fails to ossify on schedule. Necrotic growth cartilage is not converted to bone, producing a focal delay in endochondral ossification that is the defining feature of osteochondrosis, and when the physis is within the ischemic territory its proliferative and hypertrophic zones thin and the primary spongiosa beneath it is lost. In the piglet model of Legg-Calve-Perthes disease these changes appear within two days of inducing ischemia, and metaphyseal abnormalities are seen on perfusion MRI in children. Because the growth plate is both injured and still growing, the paediatric disease is a growth disturbance as well as a necrosis, and its outcome is staged on reossification and remodelling, which has no adult equivalent.
Used by disorders
Osteochondrosis
as Delayed Endochondral Ossification and Necrotic Fragmentation
Downstream
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Resorption-Dominant Revascularization and Creeping Substitution
Repair of the unossified, necrotic epiphysis proceeds by revascularization with chondroclast and osteoclast removal of dead tissue while new bone formation lags, the same resorption-dominant phase the adult arm reaches.
Show evidence (3 references)
"Alterations to the growth plate zones and metaphysis occurred by 2 days post-ischemia and persisted at 7 days post-ischemia."
Measured growth-plate injury after femoral head ischemia in the large-animal model of the paediatric disease; the basis for the growth plate cartilage chondrocyte binding and for treating physeal injury as part of the chain rather than a late complication.
"Areas of ischaemic chondronecrosis were associated with a focal delay in enchondral ossification (OC) in foals examined 21 days or more after transection, and pathological cartilage fracture (OCD) in one foal examined 42 days after transection."
Links the chondronecrosis node to this one causally: the necrotic area becomes a focal delay in endochondral ossification, the DECREASED binding, and in one animal went on to the pathological fracture modelled downstream.
"Total agreement between both techniques was noted in the depiction of epiphyseal necrosis (kappa=1), and metaphyseal abnormalities (kappa=0.9)."
Human imaging evidence that the metaphysis across the physis is involved in Legg-Calve-Perthes disease, the clinical counterpart of the growth-plate and primary-spongiosa changes measured in the piglet.
Necrotic Bone DAMP Release and Inflammatory Repair Bias
amplifier
The fluid of a necrotic femoral head contains HMGB1, biglycan, 4-hydroxynonenal and RANKL, and its IL-1, IL-6 and TNF content rises with the progression of necrosis. These damage-associated molecular patterns and cytokines act on the cells recruited to repair the segment: they inhibit osteoblastic differentiation of mesenchymal stem cells while driving their proliferation and fibrogenic differentiation, raise the RANKL/OPG ratio, and polarise macrophages toward an M1 phenotype through TLR4. In children with juvenile ischemic osteonecrosis IL-6 is raised in hip synovial fluid, and in Kummell disease the same cytokines are raised in vertebral blood. The result is a repair response that produces osteoclasts and fibrous tissue in preference to bone, which is why the reparative phase is itself destructive.
Downstream
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Resorption-Dominant Revascularization and Creeping Substitution
A raised RANKL/OPG ratio, M1 macrophages and suppressed osteoblastic differentiation tip the repair phase toward resorption over formation.
Show evidence (8 references)
"Western blot analysis of the NBF revealed the presence of prototypic DAMP, high mobility group box 1 (HMGB1), and other previously described DAMPs: biglycan, 4-hydroxynonenal (4-HNE), and receptor activator of NF-κB ligand (RANKL)."
Identifies the DAMPs actually present in necrotic bone fluid flushed from ischemic piglet femoral heads in vivo, including RANKL, the osteoclastogenic signal the INCREASED osteoclast differentiation binding refers to.
"NBF inhibited osteoblastic differentiation of MSCs with significantly decreased OSX expression (p = 0.008) and Von Kossa/Alizarin Red staining for mineralization."
The effect of that fluid on cultured mesenchymal stem cells: osteoblastic differentiation and mineralisation are suppressed, the DECREASED osteoblast differentiation binding. Graded IN_VITRO because the differentiation assay is in primary porcine MSC culture.
"In summary, our findings show that DAMPs and the inflammatory cytokines present in the necrotic femoral head inhibit osteogenesis and promote fibrogenesis of MSCs, potentially contributing to impaired bone regeneration following ischemic osteonecrosis as observed in LCPD."
The study's own statement of the repair bias this node names: osteogenesis down, fibrogenesis up. The fibrogenesis half is why repair produces fibrous tissue rather than bone.
+ 5 more references
Resorption-Dominant Revascularization and Creeping Substitution
central effector
Repair of necrotic bone proceeds by creeping substitution: vessels sprout into the dead segment from the viable margin, bringing osteoclasts (and chondroclasts in an unossified epiphysis) that resorb necrotic bone and granulation tissue that fills the space, while osteoblasts lay down new bone on the remaining scaffold. In ischemic osteonecrosis this phase is unbalanced: resorption predominates and new bone formation is delayed, so the segment loses trabecular bone exactly when it is being repaired, and in children this produces the fragmented radiographic appearance of the Waldenstrom fragmentation stage. The extent and pattern of revascularization varies between individuals and governs prognosis; where angiogenesis-osteogenesis coupling is damaged, as under glucocorticoids, the capacity for reconstruction is reduced. This is the key conformance target: every conformer, adult or paediatric, femoral, vertebral or tarsal, passes through it, and it is the step the antiresorptive drug-target pattern acts on.
Used by disorders
Osteonecrosis
as Resorption-dominant repair of the necrotic segment
Downstream
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Structural Failure of Necrotic Bone under Mechanical Load
Resorption of necrotic trabeculae ahead of new bone formation leaves the segment mechanically weakest during repair, and continued weight-bearing fractures it.
Show evidence (5 references)
"Increased bone resorption and delayed new bone formation, in combination with continued mechanical loading of the hip, contribute to the pathogenesis of the femoral head deformity."
The formation-versus-resorption imbalance stated directly, with its consequence under load; the INCREASED bone resorption and DECREASED ossification bindings encode exactly this sentence.
"The development of FHD in LCPD is closely associated with the repair process, characterized by a predominance of bone resorption in its early stage that produces a fragmented appearance and collapse of the femoral head."
Identifies the repair process itself, not the initial infarction, as the source of deformity in the human disease: resorption predominates early and produces the fragmentation stage. The sentence is the piglet study's introduction describing the clinical disease, hence BACKGROUND.
"Intra-cartilaginous secondary responses comprising proliferation of adjacent chondrocytes and vessels were detected in six and two lesions, whereas intra-osseous responses including accumulation of chondroclasts and formation of granulation tissue occurred in 10 and six lesions, respectively."
Human histology of the repair response at paediatric lesions: vessel ingrowth, chondroclast accumulation and granulation tissue, the cellular content of creeping substitution in an epiphysis.
+ 2 more references
Structural Failure of Necrotic Bone under Mechanical Load
effector
The necrotic, partly resorbed segment cannot bear physiological load. In the adult femoral head a subchondral fracture develops and the articular surface collapses; in the child's epiphysis the head flattens and fragments and, in osteochondritis dissecans, an osteochondral fragment separates; in the vertebral body delayed collapse opens an intravertebral vacuum cleft of nonunion; in the tarsal navicular the bone sclerosses, flattens and fragments. The femoral head's lack of collateral supply and the immature head's mechanical weakening after necrosis are why the failure is so often there. Load is the variable: in the piglet model unloading reduces deformity even though it does not improve the underlying repair.
Downstream
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Residual Articular Deformity and Secondary Osteoarthritis
A collapsed or flattened articular surface is incongruent; the deformity that persists after repair produces degenerative joint disease.
Show evidence (4 references)
"Osteonecrosis of the femoral head (ONFH) is a refractory orthopedic condition characterized by bone cell ischemia, necrosis, bone trabecular fracture, and clinical symptoms such as pain, femoral head collapse, and joint dysfunction that can lead to disability."
Names trabecular fracture and femoral head collapse as the structural outcome of the necrosis in the adult conformer.
"Experimental studies have revealed that the immature femoral head is mechanically weakened following ischemic necrosis."
The mechanical premise of the node for the paediatric arm: the necrotic immature head is weaker, so load that a normal head tolerates deforms it.
"The femoral head lacks collateral blood vessels, increasing risk for subchondral fracture and collapse."
Why the subchondral region of the femoral head is the recurrent site of failure, the basis for the node's location binding.
+ 1 more reference
Antiresorptive Therapy during the Resorptive Repair Phase (Bisphosphonate or RANKL Inhibition)
Platform:
Small molecule
Because the deformity develops during the resorption-dominant repair phase rather than at infarction, suppressing osteoclastic resorption while the necrotic segment is revascularised is the module's drug-target pattern. In the piglet model of total femoral head infarction, RANKL inhibition with osteoprotegerin-Fc and local ibandronate both preserved epiphyseal height and trabecular structure, and ibandronate combined with BMP-2 added new bone formation that the antiresorptive alone lacks. In adults bisphosphonates are among the pharmacological options for pre-collapse osteonecrosis. The systematic review of bisphosphonate therapy in Legg-Calve-Perthes disease found only three level IV clinical studies with inconsistent patient groups and drug protocols, so the human evidence for the paediatric indication is inconclusive and the pattern rests on the preclinical work. Conforming entries substitute the agent actually used (ibandronate or zoledronate clinically, OPG-Fc experimentally) and the stage at which it was given.
Evidence: 4
CHEBI:41060 is ChEBI's only term for the ibandronate active moiety and its canonical label is the upper-case string IBANDRONATE, copied as returned by OLS. OLS searches of ChEBI for `ibandron` and `ibandronic` on 2026-10-04 returned only this term and CHEBI:756152 (ibandronate sodium, the salt); ChEBI has no curated ibandronic acid entry, so the imported-style label is not a sign of a better term being available.
Mechanical Unloading and Containment of the Necrotic Segment
Because structural failure requires load on a weakened segment, reducing or redistributing that load is the module's non-pharmacological pattern: protected weight-bearing and, in Legg-Calve-Perthes disease, containment of the femoral head within the acetabulum by bracing or osteotomy so that it remodels against a spherical mould. In the piglet model, enforced non-weight-bearing decreased femoral head deformity, but it did so without improving the repair itself: resorption increased and formation did not, which is why unloading acts on the structural failure node and not on the central effector, and why it is combined with antiresorptive or anabolic therapy experimentally. In older children the current operative and non-operative containment treatments have only modest success in producing a spherical head.
Evidence: 2