Osteogenesis Imperfecta Type III

Mendelian MONDO:0009804 Osteogenesis imperfecta

Osteogenesis imperfecta type III is the most severe non-lethal form of OI, characterized by progressive skeletal deformity, very short stature, and hundreds of fractures over a lifetime. Caused by dominant-negative mutations in COL1A1 or COL1A2, affected individuals typically require wheelchair mobility and have significant morbidity from skeletal complications. Sclerae may be blue at birth but often lighten with age. Dentinogenesis imperfecta is common.

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1
Inheritance
1
Pathophys.
11
Phenotypes
1
Genes
4
Treatments
6
References
2
Deep Research
👪

Inheritance

1
Autosomal Dominant
Collagen I-related osteogenesis imperfecta is often autosomal dominant, with many severe cases arising from de novo variants.
Show evidence (1 reference)
PMID:7643358 SUPPORT Human Clinical
"Most babies have their own private de novo mutation. However, the recurrence rate is about 7% owing to germline mosaicism in one parent. The mutations act in a dominant negative manner as the mutant pro alpha chains are incorporated into type I procollagen molecules that also contain normal pro..."
Confirms dominant-negative mechanism and de novo inheritance pattern in severe OI caused by structural collagen I mutations.
⚙

Pathophysiology

1
Dominant-Negative Collagen Defect
Structural mutations in COL1A1 or COL1A2, typically glycine substitutions in the triple helical domain, produce abnormal collagen that disrupts fibril assembly. The mutations are generally less severe than those causing type II, allowing survival but with progressive deformity.
Osteoblast link
Collagen Fibril Organization link Bone Development link
Show evidence (1 reference)
PMID:7643358 SUPPORT Human Clinical
"Point mutations resulting in the substitution of Gly residues in Gly-X-Y amino acid triplets of the triple helical domain of the alpha 1(I) or alpha 2(I) chains are the most frequent mutations. They interrupt the repetitive Gly-X-Y structure that is mandatory for the formation of a stable triple helix."
Establishes glycine substitutions as the predominant mutation mechanism in OI with structural collagen defects, applicable to types II-IV.
●

Phenotypes

11
Ear 1
Hearing Impairment Hearing impairment (HP:0000365)
Show evidence (2 references)
PMID:31876392 SUPPORT Human Clinical
"Individuals with OI Types III and IV are at a higher risk to develop HL in the first decade of life when compared to OI Type I."
This multicenter study supports early-onset hearing impairment in the more severe type III/IV forms of OI.
PMID:30143849 SUPPORT Human Clinical
"The most prevalent type of hearing loss (HL) was sensorineural hearing loss, whereas conductive HL was solely seen in patients with OI type III."
Adult cohort data show that hearing loss in type III OI can include a conductive component.
Eye 1
Blue Sclerae Blue sclerae (HP:0000592)
Show evidence (2 references)
PMID:458828 SUPPORT Human Clinical
"The density of scleral blueness appeared less than that seen in the first group of patients and approximated that seen in normal children and adults. Moreover, the blueness appeared to decrease with age."
The original Sillence cohort shows that blue sclerae in type III OI are variable and tend to fade with age rather than remaining a defining lifelong finding.
PMID:9248835 SUPPORT Human Clinical
"The sclera had a blue color and was moderately thinned, especially at the equator."
Pathologic examination of an eye from a patient with type III OI provides direct case-level support that blue sclerae can occur in this subtype.
Head and Neck 3
Dentinogenesis Imperfecta Dentinogenesis imperfecta (HP:0000703)
Show evidence (2 references)
PMID:1739868 SUPPORT Human Clinical
"Only fracture nonunion, dentinogenesis imperfecta, and congenital cardiac malformations were more frequent in type III than in type IV."
Pediatric natural history data directly identify dentinogenesis imperfecta as more frequent in type III than in type IV OI.
PMID:30143849 SUPPORT Human Clinical
"Dentinogenesis imperfecta was diagnosed in one fourth of the patients, based on clinical and radiographic findings. This condition was predominately seen in patients with moderate to severe OI."
Adult cohort data confirm that dentinogenesis imperfecta is concentrated in the more severe OI phenotypes that include type III.
Wormian Bones Wormian bones (HP:0002645)
Show evidence (1 reference)
PMID:16961127 SUPPORT Human Clinical
"These three abnormalities and wormian bones were predominantly found in OI Types III and IV as well as in patients exhibiting dentinal abnormality."
This cephalometric cohort directly links wormian bones to the severe type III/IV OI phenotypes.
Triangular Face Triangular face (HP:0000325)
Show evidence (1 reference)
PMID:34667502 SUPPORT Human Clinical
"An eighteen-year-old, male patient diagnosed with osteogenesis imperfecta type III was referred for dental evaluation; the clinical examination showed the craniofacial and oral changes of the disease such as triangular face, class III malocclusion, anterior open bite and posterior crossbite,..."
This type III case report provides direct subtype-specific evidence for triangular face as part of the craniofacial phenotype.
Musculoskeletal 2
Recurrent Fractures Recurrent fractures (HP:0002757)
Show evidence (2 references)
PMID:458828 SUPPORT Human Clinical
"A third group, two thirds of whom had fractures at birth, showed severe progressive deformity of limbs and spine."
The original Sillence series shows that fractures are already present at birth in many patients with the type III phenotype.
PMID:29970925 SUPPORT Human Clinical
"PURPOSE: Osteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature."
This large North American cohort supports recurrent fractures as a core clinical manifestation in the OI population that includes many type III individuals.
Scoliosis Scoliosis (HP:0002650)
Show evidence (2 references)
PMID:24500586 SUPPORT Human Clinical
"Scoliosis prevalence (68%) and mean progression rate (6° per year) were the highest in the group of patients with the most severe osteogenesis imperfecta (modified Sillence type III)."
This pediatric natural history study directly shows that scoliosis is common and rapidly progressive in type III OI.
PMID:35604455 SUPPORT Human Clinical
"All 42 patients had scoliosis, with a mean curve of 66° (95% CI of range)."
A dedicated type III cohort found scoliosis in every evaluated patient, underscoring its central clinical importance.
Respiratory 1
Restrictive Ventilatory Defect Restrictive ventilatory defect (HP:0002091)
Show evidence (1 reference)
PMID:35604455 SUPPORT Human Clinical
"Restrictive lung pathophysiology was shown in our study population with a mean FEV1/FVC ratio of 0.85."
This type III cohort directly demonstrates a restrictive ventilatory pattern on pulmonary function testing.
Growth 1
Severe Short Stature Severe short stature (HP:0003510)
Show evidence (2 references)
PMID:29970925 SUPPORT Human Clinical
"In children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV."
This large multicenter cohort directly quantifies profound short stature and reduced growth velocity in type III OI.
PMID:1739868 SUPPORT Human Clinical
"Although types III and IV patients suffered from severe short stature, serum insulin-like growth factor (IGF) I was in the normal range."
Pediatric natural history data also explicitly describe severe short stature in type III OI.
Other 2
Basilar Impression Basilar impression (HP:0005758)
Show evidence (1 reference)
PMID:16961127 SUPPORT Human Clinical
"The normal mean distances were exceeded by more than two standard deviations (SDs) in 28.3 to 35.2%, and by more than three SDs in 13.2 to 16.6% of the patients with OI. The latter figures reliably reflect the prevalence of basilar impression."
This study provides direct radiographic evidence for basilar impression in OI and identifies skull-base abnormalities as concentrated in types III and IV.
Popcorn Calcification FREQUENT Popcorn calcification (HP:6000871)
Show evidence (1 reference)
PMID:18798308 SUPPORT Human Clinical
"Popcorn calcifications were present in 13 of 25 type III (52%), but only 2 of 20 type IV (10%), OI children. The mean age of onset was 7.0 years, with a range of 4-14 years."
In a type III/IV pediatric cohort, 13/25 type III patients had popcorn calcifications (52%), which falls in the FREQUENT band, and the mean age of onset was 7.0 years.
🧬

Genetic Associations

1
COL1A1/COL1A2 Mutations (Causative)
Show evidence (1 reference)
PMID:7643358 SUPPORT Human Clinical
"The severity of the clinical phenotype appears to be related to the type of mutation, its location in the alpha chain, the surrounding amino acid sequences, and the level of expression of the mutant allele."
Explains genotype-phenotype correlation in OI, with mutation location and type determining severity across the OI spectrum.
💊

Treatments

4
Bisphosphonate Therapy
Action: Bisphosphonate therapy Ontology label: bisphosphonate agent therapy MAXO:0000954
Intravenous bisphosphonates (pamidronate, zoledronic acid) to increase bone density and reduce fracture frequency. Most beneficial in childhood.
Show evidence (2 references)
PMID:10843163 SUPPORT Human Clinical
"Pamidronate treatment in severely affected OI patients under 3 yr of age is safe, increases BMD, and decreases fracture rate."
Clinical study demonstrating that pamidronate treatment increases bone mineral density and reduces fractures in severe OI patients.
PMID:15883638 PARTIAL Human Clinical
"A controlled trial confirmed the spine benefits of short-term pamidronate treatment in children with types III and IV OI. Pamidronate increased L1-L4 vertebral DXA and decreased vertebral compressions and upper extremity fractures."
Controlled trial in OI types III and IV showed vertebral BMD and morphology benefits but no significant improvement in functional outcomes or lower extremity fractures.
Rodding Surgery
Action: Orthopedic surgery Ontology label: surgical procedure MAXO:0000004
Intramedullary rodding (telescoping rods) to stabilize long bones, correct deformities, and prevent fractures. Multiple surgeries typically required as the child grows.
Show evidence (1 reference)
PMID:25943292 SUPPORT Human Clinical
"Surgery is still needed in most patients due to high frequency of the fractures."
Systematic review confirms that surgical intervention remains necessary in most OI type III patients despite bisphosphonate therapy.
Spinal Fusion
Action: Spinal surgery Ontology label: surgical procedure MAXO:0000004
Surgical stabilization of severe scoliosis to prevent respiratory compromise.
Show evidence (1 reference)
PMID:38996209 SUPPORT Human Clinical
"These patients underwent posterior spinal fusion between 2008 and 2020 and completed a minimum follow-up of 2 years. We measured radiographic parameters at each visit and reviewed the incidence of complications. A mixed-effects model was used to evaluate changes in radiographic parameters from..."
Case-series evidence supports posterior spinal fusion as an effective treatment for severe scoliosis in OI, with most patients in the cohort having type III disease.
Physical Therapy
Action: Physical therapy Ontology label: physical therapy MAXO:0000011
Careful physical therapy to maintain mobility and muscle strength while minimizing fracture risk.
Show evidence (1 reference)
PMID:25524970 PARTIAL Human Clinical
"A significant increase of motor function (GMFM-66 score 55.47±2.45 to 58.67±2.83; p=0.001) and walking distance (47.04 m±6.52 to 63.36±8.25 m (p<0.01) between M0 and M12 was seen."
A pediatric rehabilitation cohort found improved motor function and walking distance after a structured physiotherapy-based program. Because the abstract does not stratify outcomes by OI subtype, this provides partial rather than type III-specific support for physical therapy.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type III
creation_date: '2026-02-06T03:25:37Z'
updated_date: '2026-04-19T06:42:04Z'
category: Mendelian
description: >
  Osteogenesis imperfecta type III is the most severe non-lethal form of OI,
  characterized by progressive skeletal deformity, very short stature, and
  hundreds of fractures over a lifetime. Caused by dominant-negative mutations
  in COL1A1 or COL1A2, affected individuals typically require wheelchair mobility
  and have significant morbidity from skeletal complications. Sclerae may be blue
  at birth but often lighten with age. Dentinogenesis imperfecta is common.
disease_term:
  preferred_term: Osteogenesis imperfecta type III
  term:
    id: MONDO:0009804
    label: osteogenesis imperfecta type 3
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Dominant
  description: >
    Collagen I-related osteogenesis imperfecta is often autosomal dominant,
    with many severe cases arising from de novo variants.
  evidence:
  - reference: PMID:7643358
    reference_title: "Perinatal lethal osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most babies have their own private de novo mutation. However, the
      recurrence rate is about 7% owing to germline mosaicism in one parent.
      The mutations act in a dominant negative manner as the mutant pro alpha
      chains are incorporated into type I procollagen molecules that also
      contain normal pro alpha chains.
    explanation: >-
      Confirms dominant-negative mechanism and de novo inheritance pattern
      in severe OI caused by structural collagen I mutations.
prevalence:
- population: Swedish pediatric osteogenesis imperfecta population
  percentage: 0.89 per 100,000
  notes: >-
    Population-based Swedish data estimated pediatric prevalence for type III at
    just under 1 per 100,000, confirming it as a very rare but recurrent
    non-lethal severe OI subtype.
  evidence:
  - reference: PMID:25944380
    reference_title: "Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population."
    explanation: This population-based Swedish study directly estimates pediatric prevalence of OI type III at 0.89 per 100,000.
pathophysiology:
- name: Dominant-Negative Collagen Defect
  description: >
    Structural mutations in COL1A1 or COL1A2, typically glycine substitutions
    in the triple helical domain, produce abnormal collagen that disrupts
    fibril assembly. The mutations are generally less severe than those
    causing type II, allowing survival but with progressive deformity.
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: Collagen Fibril Organization
    term:
      id: GO:0030199
      label: collagen fibril organization
  - preferred_term: Bone Development
    term:
      id: GO:0060348
      label: bone development
  evidence:
  - reference: PMID:7643358
    reference_title: "Perinatal lethal osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Point mutations resulting in the substitution of Gly residues in Gly-X-Y
      amino acid triplets of the triple helical domain of the alpha 1(I) or alpha
      2(I) chains are the most frequent mutations. They interrupt the repetitive
      Gly-X-Y structure that is mandatory for the formation of a stable triple helix.
    explanation: >-
      Establishes glycine substitutions as the predominant mutation mechanism in
      OI with structural collagen defects, applicable to types II-IV.
genetic:
- name: COL1A1/COL1A2 Mutations
  association: Causative
  notes: >
    Predominantly glycine substitutions in COL1A1 or COL1A2. Mutations in
    COL1A1 tend to produce more severe phenotypes than equivalent mutations
    in COL1A2 because the collagen trimer contains two alpha1 chains and
    one alpha2 chain. Mutation position along the helix affects severity.
  evidence:
  - reference: PMID:7643358
    reference_title: "Perinatal lethal osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severity of the clinical phenotype appears to be related to the type of
      mutation, its location in the alpha chain, the surrounding amino acid
      sequences, and the level of expression of the mutant allele.
    explanation: >-
      Explains genotype-phenotype correlation in OI, with mutation location and type
      determining severity across the OI spectrum.
phenotypes:
- name: Severe Short Stature
  description: >
    Marked growth failure is a core manifestation of type III OI, with very low
    childhood height z-scores and diminished growth velocity.
  phenotype_term:
    preferred_term: Severe short stature
    term:
      id: HP:0003510
      label: Severe short stature
  evidence:
  - reference: PMID:29970925
    reference_title: "Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In children, the median z-scores for height in OI types I, III, and IV
      were -0.66, -6.91, and -2.79, respectively. Growth velocity was
      diminished in OI types III and IV.
    explanation: >-
      This large multicenter cohort directly quantifies profound short stature
      and reduced growth velocity in type III OI.
  - reference: PMID:1739868
    reference_title: "Osteogenesis imperfecta: a clinical study of the first ten years of life."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although types III and IV patients suffered from severe short stature,
      serum insulin-like growth factor (IGF) I was in the normal range.
    explanation: >-
      Pediatric natural history data also explicitly describe severe short
      stature in type III OI.
- name: Recurrent Fractures
  description: >
    Marked bone fragility causes repeated fractures, often beginning at or
    around birth in the severe type III phenotype.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:458828
    reference_title: "Genetic heterogeneity in osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A third group, two thirds of whom had fractures at birth, showed severe
      progressive deformity of limbs and spine.
    explanation: >-
      The original Sillence series shows that fractures are already present at
      birth in many patients with the type III phenotype.
  - reference: PMID:29970925
    reference_title: "Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PURPOSE: Osteogenesis imperfecta (OI) predisposes people to recurrent
      fractures, bone deformities, and short stature.
    explanation: >-
      This large North American cohort supports recurrent fractures as a core
      clinical manifestation in the OI population that includes many type III
      individuals.
- name: Scoliosis
  description: >
    Progressive spinal curvature is a major source of morbidity in type III OI.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:24500586
    reference_title: "Behavior of scoliosis during growth in children with osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Scoliosis prevalence (68%) and mean progression rate (6° per year) were
      the highest in the group of patients with the most severe osteogenesis
      imperfecta (modified Sillence type III).
    explanation: >-
      This pediatric natural history study directly shows that scoliosis is
      common and rapidly progressive in type III OI.
  - reference: PMID:35604455
    reference_title: "Prevalence of scoliosis and impaired pulmonary function in patients with type III osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 42 patients had scoliosis, with a mean curve of 66° (95% CI of
      range).
    explanation: >-
      A dedicated type III cohort found scoliosis in every evaluated patient,
      underscoring its central clinical importance.
- category: Respiratory
  name: Restrictive Ventilatory Defect
  description: >
    Pulmonary impairment in type III OI shows a restrictive pattern and worsens
    with increasing thoracic scoliosis.
  phenotype_term:
    preferred_term: Restrictive ventilatory defect
    term:
      id: HP:0002091
      label: Restrictive ventilatory defect
  evidence:
  - reference: PMID:35604455
    reference_title: "Prevalence of scoliosis and impaired pulmonary function in patients with type III osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Restrictive lung pathophysiology was shown in our study population with a
      mean FEV1/FVC ratio of 0.85.
    explanation: >-
      This type III cohort directly demonstrates a restrictive ventilatory
      pattern on pulmonary function testing.
- name: Dentinogenesis Imperfecta
  description: >
    Structural dentin abnormality with discoloration and fragility is a
    recurrent dental manifestation in type III OI.
  phenotype_term:
    preferred_term: Dentinogenesis imperfecta
    term:
      id: HP:0000703
      label: Dentinogenesis imperfecta
  evidence:
  - reference: PMID:1739868
    reference_title: "Osteogenesis imperfecta: a clinical study of the first ten years of life."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only fracture nonunion, dentinogenesis imperfecta, and congenital cardiac
      malformations were more frequent in type III than in type IV.
    explanation: >-
      Pediatric natural history data directly identify dentinogenesis
      imperfecta as more frequent in type III than in type IV OI.
  - reference: PMID:30143849
    reference_title: "Osteogenesis imperfecta and the teeth, eyes, and ears-a study of non-skeletal phenotypes in adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dentinogenesis imperfecta was diagnosed in one fourth of the patients,
      based on clinical and radiographic findings. This condition was
      predominately seen in patients with moderate to severe OI.
    explanation: >-
      Adult cohort data confirm that dentinogenesis imperfecta is concentrated
      in the more severe OI phenotypes that include type III.
- name: Hearing Impairment
  description: >
    Hearing loss can occur in childhood in type III OI and may be conductive,
    sensorineural, or mixed.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:31876392
    reference_title: "Hearing loss in individuals with osteogenesis imperfecta in North America: Results from a multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with OI Types III and IV are at a higher risk to develop HL
      in the first decade of life when compared to OI Type I.
    explanation: >-
      This multicenter study supports early-onset hearing impairment in the
      more severe type III/IV forms of OI.
  - reference: PMID:30143849
    reference_title: "Osteogenesis imperfecta and the teeth, eyes, and ears-a study of non-skeletal phenotypes in adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prevalent type of hearing loss (HL) was sensorineural hearing
      loss, whereas conductive HL was solely seen in patients with OI type III.
    explanation: >-
      Adult cohort data show that hearing loss in type III OI can include a
      conductive component.
- name: Wormian Bones
  description: >
    Accessory sutural bones are a recurrent cranial radiographic finding in the
    more severe type III/IV forms of OI.
  phenotype_term:
    preferred_term: Wormian bones
    term:
      id: HP:0002645
      label: Wormian bones
  evidence:
  - reference: PMID:16961127
    reference_title: "Skull base abnormalities in osteogenesis imperfecta: a cephalometric evaluation of 54 patients and 108 control volunteers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These three abnormalities and wormian bones were predominantly found in
      OI Types III and IV as well as in patients exhibiting dentinal
      abnormality.
    explanation: >-
      This cephalometric cohort directly links wormian bones to the severe type
      III/IV OI phenotypes.
- name: Basilar Impression
  description: >
    Skull-base deformity with upward displacement of the posterior fossa floor
    occurs in severe OI and is enriched in types III and IV.
  phenotype_term:
    preferred_term: Basilar impression
    term:
      id: HP:0005758
      label: Basilar impression
  evidence:
  - reference: PMID:16961127
    reference_title: "Skull base abnormalities in osteogenesis imperfecta: a cephalometric evaluation of 54 patients and 108 control volunteers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The normal mean distances were exceeded by more than two standard
      deviations (SDs) in 28.3 to 35.2%, and by more than three SDs in 13.2 to
      16.6% of the patients with OI. The latter figures reliably reflect the
      prevalence of basilar impression.
    explanation: >-
      This study provides direct radiographic evidence for basilar impression in
      OI and identifies skull-base abnormalities as concentrated in types III
      and IV.
- name: Popcorn Calcification
  description: >
    Metaphyseal and epiphyseal "popcorn" calcifications around the growth plate
    usually emerge in childhood and most often involve the distal femora and
    proximal tibiae.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Popcorn calcification
    term:
      id: HP:6000871
      label: Popcorn calcification
  evidence:
  - reference: PMID:18798308
    reference_title: "Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Popcorn calcifications were present in 13 of 25 type III (52%), but only
      2 of 20 type IV (10%), OI children. The mean age of onset was 7.0 years,
      with a range of 4-14 years.
    explanation: >-
      In a type III/IV pediatric cohort, 13/25 type III patients had popcorn
      calcifications (52%), which falls in the FREQUENT band, and the mean age
      of onset was 7.0 years.
- name: Blue Sclerae
  description: >
    Blue scleral hue can occur in type III OI, but it may be subtler than in
    type I and can lessen with age.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:458828
    reference_title: "Genetic heterogeneity in osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The density of scleral blueness appeared less than that seen in the first
      group of patients and approximated that seen in normal children and
      adults. Moreover, the blueness appeared to decrease with age.
    explanation: >-
      The original Sillence cohort shows that blue sclerae in type III OI are
      variable and tend to fade with age rather than remaining a defining
      lifelong finding.
  - reference: PMID:9248835
    reference_title: "Histopathologic and electron-microscopic features of corneal and scleral collagen fibers in osteogenesis imperfecta type III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The sclera had a blue color and was moderately thinned, especially at the
      equator.
    explanation: >-
      Pathologic examination of an eye from a patient with type III OI provides
      direct case-level support that blue sclerae can occur in this subtype.
- name: Triangular Face
  description: >
    Triangular facial shape has been reported as part of the craniofacial
    phenotype of type III OI.
  phenotype_term:
    preferred_term: Triangular face
    term:
      id: HP:0000325
      label: Triangular face
  evidence:
  - reference: PMID:34667502
    reference_title: "Osteogenesis imperfecta type III: Oral, craniofacial characteristics and atypical radiographic findings oral."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An eighteen-year-old, male patient diagnosed with osteogenesis imperfecta
      type III was referred for dental evaluation; the clinical examination
      showed the craniofacial and oral changes of the disease such as
      triangular face, class III malocclusion, anterior open bite and
      posterior crossbite, dentinogenesis imperfecta presenting amber
      discoloration.
    explanation: >-
      This type III case report provides direct subtype-specific evidence for
      triangular face as part of the craniofacial phenotype.
diagnosis:
- name: Clinical, Radiographic, and Molecular Diagnosis
  description: >-
    The diagnosis of osteogenesis imperfecta type III (now described in
    GeneReviews as progressively deforming OI) is based on severe bone
    fragility, progressive long-bone and spinal deformity, and characteristic
    radiographic findings, and is confirmed by identification of a heterozygous
    COL1A1 or COL1A2 variant on molecular genetic testing.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of COL1A1/COL1A2-OI is established in a proband with clinical and radiographic manifestations of OI by identification of a heterozygous in COL1A1 or COL1A2 by molecular genetic testing."
    explanation: >-
      GeneReviews defines the combined clinical/radiographic and molecular
      diagnostic criteria for COL1A1/COL1A2-related OI, including the severe
      progressively deforming type III form.
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressively deforming OI (previously OI type III)"
    explanation: >-
      GeneReviews maps the legacy Sillence type III label to the modern
      descriptive nomenclature for the severe progressively deforming form.
- name: Craniovertebral and Respiratory Surveillance
  description: >-
    Because progressively deforming OI carries a high risk of basilar
    impression and restrictive respiratory disease, surveillance includes
    cross-skull-base imaging and monitoring of spinal deformity and pulmonary
    function.
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CT and/or MRI with views across the base of the skull to evaluate for basilar impression in those with platybasia, moderate-to-severe OI, or concerning signs or symptoms."
    explanation: >-
      GeneReviews specifies skull-base imaging surveillance for basilar
      impression in moderate-to-severe OI such as type III.
treatments:
- name: Bisphosphonate Therapy
  description: >
    Intravenous bisphosphonates (pamidronate, zoledronic acid) to increase
    bone density and reduce fracture frequency. Most beneficial in childhood.
  treatment_term:
    preferred_term: Bisphosphonate therapy
    term:
      id: MAXO:0000954
      label: bisphosphonate agent therapy
  evidence:
  - reference: PMID:10843163
    reference_title: "Pamidronate treatment of severe osteogenesis imperfecta in children under 3 years of age."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pamidronate treatment in severely affected OI patients under 3 yr
      of age is safe, increases BMD, and decreases fracture rate.
    explanation: >-
      Clinical study demonstrating that pamidronate treatment increases
      bone mineral density and reduces fractures in severe OI patients.
  - reference: PMID:15883638
    reference_title: "Controlled trial of pamidronate in children with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-term functional improvement."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A controlled trial confirmed the spine benefits of short-term
      pamidronate treatment in children with types III and IV OI.
      Pamidronate increased L1-L4 vertebral DXA and decreased vertebral
      compressions and upper extremity fractures.
    explanation: >-
      Controlled trial in OI types III and IV showed vertebral BMD and
      morphology benefits but no significant improvement in functional
      outcomes or lower extremity fractures.
- name: Rodding Surgery
  description: >
    Intramedullary rodding (telescoping rods) to stabilize long bones,
    correct deformities, and prevent fractures. Multiple surgeries typically
    required as the child grows.
  treatment_term:
    preferred_term: Orthopedic surgery
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:25943292
    reference_title: "Severe osteogenesis imperfecta Type-III and its challenging treatment in newborn and preschool children. A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgery is still needed in most patients due to high frequency of the
      fractures.
    explanation: >-
      Systematic review confirms that surgical intervention remains necessary
      in most OI type III patients despite bisphosphonate therapy.
- name: Spinal Fusion
  description: >
    Surgical stabilization of severe scoliosis to prevent respiratory
    compromise.
  treatment_term:
    preferred_term: Spinal surgery
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:38996209
    reference_title: "Midterm Outcomes of Multimodal Approach to Treating Severe Scoliosis in Patients With Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients underwent posterior spinal fusion between 2008 and 2020
      and completed a minimum follow-up of 2 years. We measured radiographic
      parameters at each visit and reviewed the incidence of complications. A
      mixed-effects model was used to evaluate changes in radiographic
      parameters from preoperative measurements to the first and latest
      follow-ups. RESULTS: The patient cohort consisted of 2 individuals with
      type I OI, 20 with type III, 6 with type IV, and 2 with other types
      (types V and VIII). Surgical intervention led to a notable improvement
      in the major curve magnitude from 76° to 36°, with no notable correction
      loss.
    explanation: >-
      Case-series evidence supports posterior spinal fusion as an effective
      treatment for severe scoliosis in OI, with most patients in the cohort
      having type III disease.
- name: Physical Therapy
  description: >
    Careful physical therapy to maintain mobility and muscle strength
    while minimizing fracture risk.
  treatment_term:
    preferred_term: Physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  evidence:
  - reference: PMID:25524970
    reference_title: "A specialized rehabilitation approach improves mobility in children with osteogenesis imperfecta."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A significant increase of motor function (GMFM-66 score 55.47±2.45 to
      58.67±2.83; p=0.001) and walking distance (47.04 m±6.52 to 63.36±8.25 m
      (p<0.01) between M0 and M12 was seen.
    explanation: >-
      A pediatric rehabilitation cohort found improved motor function and
      walking distance after a structured physiotherapy-based program. Because
      the abstract does not stratify outcomes by OI subtype, this provides
      partial rather than type III-specific support for physical therapy.
datasets:
references:
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1007/s00223-023-01171-3
  title: Is Osteogenesis Imperfecta Associated with Cardiovascular Abnormalities? A Systematic Review of the Literature
  findings: []
- reference: DOI:10.1007/s00223-024-01236-x
  title: 'Osteogenesis Imperfecta: Skeletal and Non-skeletal Challenges in Adulthood'
  findings: []
- reference: DOI:10.1007/s00223-024-01248-7
  title: A Dyadic Nosology for Osteogenesis Imperfecta and Bone Fragility Syndromes 2024
  findings: []
- reference: DOI:10.1021/acsptsci.3c00324
  title: Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches
  findings: []
- reference: DOI:10.1186/s13023-023-02627-3
  title: 'The patient clinical journey and socioeconomic impact of osteogenesis imperfecta: a systematic scoping review'
  findings: []
📚

References & Deep Research

References

6
PMID:20301472
COL1A1- and COL1A2-Related Osteogenesis Imperfecta.
No top-level findings curated for this source.
DOI:10.1007/s00223-023-01171-3
Is Osteogenesis Imperfecta Associated with Cardiovascular Abnormalities? A Systematic Review of the Literature
No top-level findings curated for this source.
DOI:10.1007/s00223-024-01236-x
Osteogenesis Imperfecta: Skeletal and Non-skeletal Challenges in Adulthood
No top-level findings curated for this source.
DOI:10.1007/s00223-024-01248-7
A Dyadic Nosology for Osteogenesis Imperfecta and Bone Fragility Syndromes 2024
No top-level findings curated for this source.
DOI:10.1021/acsptsci.3c00324
Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches
No top-level findings curated for this source.
DOI:10.1186/s13023-023-02627-3
The patient clinical journey and socioeconomic impact of osteogenesis imperfecta: a systematic scoping review
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Osteogenesis Imperfecta Type III
  • Category: Mendelian
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 7

Key Pathophysiology Nodes

  • Dominant-Negative Collagen Defect
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s00223-023-01171-3
  • DOI:10.1007/s00223-024-01236-x
  • DOI:10.1007/s00223-024-01248-7
  • DOI:10.1021/acsptsci.3c00324
  • DOI:10.1186/s13023-023-02627-3
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 27 citations 2026-02-04T19:43:23.978100

Disease Pathophysiology Research Report

Target Disease - Disease Name: Osteogenesis Imperfecta Type III (progressively deforming OI) - MONDO ID: not specified by source; entry pertains to Mendelian OI classified by Sillence and modern dyadic nosology (sillence2024adyadicnosology pages 11-12). - Category: Mendelian

  1. Core Pathophysiology Osteogenesis imperfecta (OI) Type III is a severe, progressively deforming phenotype characterized by early and recurrent fractures, extreme short stature, and skeletal deformity. Mechanistically, OI across types is predominantly a collagen type I disorder; “approximately 80–85%” of OI (types I–IV) arises from autosomal-dominant COL1A1/COL1A2 mutations that alter the Gly–X–Y triple helix, perturbing folding, post-translational modifications (PTMs), and fibrillogenesis (Sun 2024, ACS Pharmacol Transl Sci, Jan 2024; DOI: 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 3-4). Type III severity also results from recessive disruptions of the ER-based prolyl 3-hydroxylation/folding complex (P3H1/LEPRE1, CRTAP, PPIB), ER chaperones (SERPINH1/HSP47, FKBP10/FKBP65), ER Ca2+ homeostasis (TMEM38B/TRIC-B), transcriptional regulators of osteoblast differentiation (SP7/Osterix, CREB3L1/OASIS), and WNT1 signaling, as well as extracellular processing (BMP1), cross-linking (PLOD2), and mineralization regulators (SERPINF1/PEDF, IFITM5) (Sun 2024; Sillence 2024, Calcif Tissue Int, Jun 2024; DOI: 10.1007/s00223-024-01248-7) (sun2024emerginglandscapeof pages 2-3, sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 9-11, sun2024emerginglandscapeof pages 4-5, sillence2024adyadicnosology pages 17-18).
  2. Collagen I misfolding and PTM disruption: Gly substitutions in COL1A1/COL1A2 disrupt helix folding and the timing/extent of proline/lysine hydroxylation and glycosylation during ER assembly, driving matrix weakness and deformity (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 3-4).
  3. Loss of P3H1–CRTAP–PPIB complex: This ER heterotrimer catalyzes 3-hydroxylation at conserved collagen sites (e.g., Pro986 in α1(I)); loss delays triple-helix formation, leads to excessive alternative modifications, and produces severe growth deficiency and deforming phenotypes consistent with Type III (Sun 2024, Jan 2024; Sillence 2024, Jun 2024; 10.1021/acsptsci.3c00324; 10.1007/s00223-024-01248-7) (sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11, sun2024emerginglandscapeof pages 4-5).
  4. ER chaperone and trafficking defects: SERPINH1/HSP47 and FKBP10/FKBP65 prevent premature protofibril formation and guide procollagen trafficking; mutations cause “misfolded pre‑collagen molecules,” alter lysine hydroxylation and cross-linking via PLOD2, and reduce collagen assembly (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 17-18).
  5. ER Ca2+ dysregulation and ER stress: TMEM38B/TRIC-B controls ER Ca2+ flux; loss reduces Ca2+-dependent PTMs, impairs MSC→osteoblast differentiation, and provokes ER stress, compromising osteoblast function (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7).
  6. Impaired osteoblast differentiation and signaling: SP7 and CREB3L1 regulate osteoblast maturation and collagen expression; WNT1 and MESD (LRP5/6 chaperone) affect canonical WNT/β-catenin signaling in osteoblasts. Disruption in these pathways reduces bone formation and contributes to growth failure and deformity (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 6-7).

  7. Extracellular processing and mineralization: BMP1 defects impair C-propeptide processing and can cause abnormal mineralization (including hypermineralization). SERPINF1 (PEDF) loss leads to mineralization defects (Type VI OI), and IFITM5 mutations impair PEDF secretion and mineralization, collectively linking matrix processing/mineralization defects to severe fragility (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 4-5, sun2024emerginglandscapeof pages 6-7). These mechanisms converge in osteoblasts and bone matrix to produce the severe deforming phenotype and extreme short stature typical of Type III (Sun 2024, Jan 2024; Sillence 2024, Jun 2024; 10.1021/acsptsci.3c00324; 10.1007/s00223-024-01248-7) (sun2024emerginglandscapeof pages 2-3, sillence2024adyadicnosology pages 9-11).

  8. Key Molecular Players, Cell Types, and Anatomical Sites (ontology-annotated)

  9. Principal genes/proteins: COL1A1, COL1A2; ER folding/PTM complex (CRTAP, P3H1/LEPRE1, PPIB); ER chaperones (SERPINH1/HSP47, FKBP10/FKBP65, KDELR2); cross-linking/mineralization/processing (PLOD2, BMP1, SERPINF1/PEDF, IFITM5); osteoblast differentiation/signaling (WNT1, SP7, CREB3L1/OASIS, MESD); ER Ca2+ homeostasis (TMEM38B/TRIC-B) (Sun 2024; Sillence 2024) (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 9-11, sun2024emerginglandscapeof pages 4-5, sillence2024adyadicnosology pages 17-18).
  10. Chemical entities: antiresorptives (bisphosphonates such as pamidronate/zoledronate) widely used in severe OI; sclerostin-pathway biologics under investigation (e.g., romosozumab pediatric Phase 1 completed; NCT04545554) (Sillence 2024, Hald 2024; ClinicalTrials.gov) (sillence2024adyadicnosology pages 9-11, hald2024osteogenesisimperfectaskeletal pages 11-12).
  11. Cell types: osteoblasts (collagen I synthesis; ER stress/UPR), osteocytes (matrix-embedded mechanosensors), osteoclasts (resorption; coupling imbalance), MSCs (impaired osteogenic differentiation with ER Ca2+ defects) (Sun 2024; Hald 2024) (sun2024emerginglandscapeof pages 3-4, hald2024osteogenesisimperfectaskeletal pages 11-12).
  12. Anatomical locations: long-bone cortex, vertebral bodies (load-bearing, deformity-prone), growth plate (linear growth failure), aortic root and cardiac valves (extraskeletal collagen I tissues with reported abnormalities) (Sillence 2024; Hald 2024; Verdonk 2024) (sillence2024adyadicnosology pages 11-12, hald2024osteogenesisimperfectaskeletal pages 11-12, verdonk2024isosteogenesisimperfecta pages 1-2).

The following structured table provides ontology-aligned details for knowledge-base ingestion and references.

Category Name Ontology Identifier Mechanistic role in OI Type III Supporting source (DOI/URL) Year
Gene/Protein COL1A1 HGNC HGNC:COL1A1 Gly-X-Y Gly substitutions in the α1(I) chain disrupt triple-helix folding, alter PTMs and fibrillogenesis causing severe/deforming phenotype https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4, sillence2024adyadicnosology pages 9-11) 2024
Gene/Protein COL1A2 HGNC HGNC:COL1A2 Mutations in α2(I) chain cause helix instability and genotype–phenotype correlation with severe forms (type III) https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4, sillence2024adyadicnosology pages 9-11) 2024
Gene/Protein CRTAP HGNC HGNC:CRTAP Component of P3H1–CRTAP–PPIB complex; loss → defective prolyl 3-hydroxylation, delayed helix folding, severe recessive OI https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11) 2024
Gene/Protein LEPRE1 (P3H1) HGNC HGNC:LEPRE1 Prolyl 3-hydroxylase (P3H1); required for Pro986 3-hydroxylation of α1(I); loss causes severe growth deficiency and deforming phenotype https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11) 2024
Gene/Protein PPIB (CyPB) HGNC HGNC:PPIB Cyclophilin B; part of 3-hydroxylation complex; mutations disrupt complex and collagen PTMs → severe OI https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6) 2024
Gene/Protein SERPINH1 (HSP47) HGNC HGNC:SERPINH1 ER chaperone HSP47; mutations → misfolded procollagen and trafficking defects, contributing to severe phenotype https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7) 2024
Gene/Protein FKBP10 (FKBP65) HGNC HGNC:FKBP10 ER peptidyl-prolyl isomerase; loss alters lysine hydroxylation (PLOD2 activity) and collagen cross-linking → deformity https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7) 2024
Gene/Protein PLOD2 HGNC HGNC:PLOD2 Lysyl hydroxylase (telopeptide hydroxylation) required for correct collagen cross-links; defects cause progressive deforming phenotypes https://doi.org/10.1021/acsptsci.3c00324, https://doi.org/10.1007/s00223-024-01248-7 (sun2024emerginglandscapeof pages 3-4, sillence2024adyadicnosology pages 9-11) 2024
Gene/Protein BMP1 HGNC HGNC:BMP1 C-propeptide processing metalloprotease; mutations alter procollagen processing and can produce abnormal mineralization/hypermineralization https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 16-17) 2024
Gene/Protein WNT1 HGNC HGNC:WNT1 Canonical WNT/β-catenin signaling regulator of osteoblast differentiation; mutations reduce bone formation and contribute to severe OI https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 6-7) 2024
Gene/Protein SP7 (Osterix) HGNC HGNC:SP7 Transcription factor required for pre-osteoblast → osteoblast maturation; loss impairs osteoblast differentiation and bone formation https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6) 2024
Gene/Protein CREB3L1 (OASIS) HGNC HGNC:CREB3L1 ER-to-nucleus transcription factor (RIP-activated) regulating osteoblast genes; mutations linked to severe osteodysplasia and reduced collagen https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 6-7) 2024
Gene/Protein TMEM38B (TRIC-B) HGNC HGNC:TMEM38B ER ion channel regulating ER Ca2+ homeostasis; loss → impaired Ca2+-dependent PTMs, ER stress, reduced MSC→osteoblast differentiation https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7) 2024
Gene/Protein SERPINF1 (PEDF) HGNC HGNC:SERPINF1 Secreted PEDF influences osteoblast mineralization; recessive loss (type VI) causes mineralization defects and fragility https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 4-5) 2024
Gene/Protein IFITM5 HGNC HGNC:IFITM5 BRIL protein; pathogenic mutations alter palmitoylation/Golgi localization, impair PEDF secretion and osteoblast mineralization https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 4-5) 2024
Gene/Protein KDELR2 HGNC HGNC:KDELR2 ER retrieval receptor; mutations mislocalize HSP47 and reduce HSP47/FKBP65 levels → impaired collagen assembly https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 6-7) 2024
Gene/Protein MESD HGNC HGNC:MESD ER chaperone for LRP5/6 trafficking; loss impairs WNT receptor trafficking and downstream osteoblast signaling https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 6-7) 2024
Biological Process Collagen fibril organization GO GO: collagen fibril organization Disrupted fibrillogenesis from misfolded collagen and altered cross-linking underlies bone fragility and deformity https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4) 2024
Biological Process Prolyl 3-hydroxylation GO GO: prolyl 3-hydroxylation P3H1–CRTAP–PPIB complex normally 3‑hydroxylates Pro986; loss → defective helix stability and severe OI https://doi.org/10.1021/acsptsci.3c00324, https://doi.org/10.1007/s00223-024-01248-7 (sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11) 2024
Biological Process ER protein folding / chaperone activity GO GO: ER protein folding HSP47, FKBP65, CyPB and others ensure procollagen folding; defects produce ER retention/misfolding and UPR/functional osteoblast impairment https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 3-4) 2024
Biological Process Unfolded Protein Response (UPR) GO GO: UPR / ER stress response Chronic ER stress from misfolded collagen perturbs osteoblast survival/function contributing to severe phenotype https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6) 2024
Biological Process ER calcium homeostasis GO GO: ER calcium homeostasis TMEM38B/TRIC-B defects alter Ca2+ flux, impair Ca2+-dependent PTMs and osteoblast differentiation → skeletal deformity https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7) 2024
Biological Process Osteoblast differentiation (WNT/β‑catenin) GO GO: osteoblast differentiation WNT1, MESD, SP7 and CREB3L1 disruption reduce osteoblast maturation and matrix production causing growth deficiency https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 6-7) 2024
Biological Process Extracellular matrix organization GO GO: extracellular matrix organization Abnormal collagen secretion/processing (BMP1, cross‑linking defects) alters ECM structure and mechanical properties https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 16-17) 2024
Biological Process Collagen cross-linking GO GO: collagen cross-linking PLOD2 and FKBP10 influence telopeptide hydroxylation and cross-links; defects → weak matrix and progressive deformity https://doi.org/10.1021/acsptsci.3c00324, https://doi.org/10.1007/s00223-024-01248-7 (sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 9-11) 2024
Biological Process Mineralization GO GO: biomineralization / mineralization SERPINF1, IFITM5, BMP1 and abnormal collagen affect mineral deposition, sometimes causing hypomineralization or paradoxical hypermineralization https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 4-5, sun2024emerginglandscapeof pages 6-7) 2024
Cellular Component Endoplasmic reticulum (ER) GO GO: endoplasmic reticulum Site of procollagen folding, PTMs and chaperone engagement; central locus of pathology in many Type III cases https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6) 2024
Cellular Component ER–Golgi intermediate compartment GO GO: ER–Golgi intermediate compartment Important for procollagen trafficking; perturbation (e.g., KDELR2) alters secretion and assembly https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 6-7) 2024
Cellular Component Extracellular matrix / collagen fibril GO GO: extracellular matrix / collagen fibril Final location of collagen; defective assembly yields mechanically weak fibrils and bone fragility https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4) 2024
Cellular Component Golgi apparatus GO GO: Golgi apparatus Site for glycosylation/processing of collagen; IFITM5 Golgi sequestration noted to impair osteoblast function https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 4-5) 2024
Cell Type Osteoblast CL CL:0000189 (osteoblast) Primary collagen-producing bone cell; ER stress and impaired differentiation in osteoblasts drive Type III severity https://doi.org/10.1021/acsptsci.3c00324, https://doi.org/10.1007/s00223-024-01236-x (sun2024emerginglandscapeof pages 3-4, hald2024osteogenesisimperfectaskeletal pages 11-12) 2024
Cell Type Osteocyte CL CL:0001989 (osteocyte) Embedded bone cell influenced by altered matrix; contributes to bone remodeling signaling imbalance https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4) 2024
Cell Type Osteoclast CL CL:0000653 (osteoclast) Resorptive cell; osteoblast–osteoclast imbalance affects net bone mass and deformity risk https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 3-4) 2024
Cell Type Bone marrow stromal cell (MSC) CL CL:0000711 (MSC) MSC differentiation into osteoblasts is impaired by ER Ca2+ dysregulation and signaling defects (TMEM38B, WNT pathway) https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 5-6) 2024
Anatomical Location Bone cortex (long bone) UBERON UBERON:0005924 (long bone cortex) Principal load‑bearing tissue where abnormal collagen fibrils cause fragility, deformity and fractures (Type III pronounced) https://doi.org/10.1021/acsptsci.3c00324, https://doi.org/10.1007/s00223-024-01248-7 (sun2024emerginglandscapeof pages 3-4, sillence2024adyadicnosology pages 9-11) 2024
Anatomical Location Growth plate UBERON UBERON:0002081 (growth plate) Disrupted collagen/osteoblast function leads to impaired linear growth and extreme short stature in Type III https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 2-3) 2024
Anatomical Location Vertebral body UBERON UBERON:0002105 (vertebral body) Prone to compression fractures and progressive kyphoscoliosis in severe/deforming OI https://doi.org/10.1007/s00223-024-01236-x (hald2024osteogenesisimperfectaskeletal pages 11-12, hald2024osteogenesisimperfectaskeletal pages 1-3) 2024
Anatomical Location Aortic root UBERON UBERON:0004217 (aortic root) Collagen I present in cardiovascular ECM; OI-associated valvular/aortic root abnormalities reported (extraskeletal involvement) https://doi.org/10.1007/s00223-023-01171-3 (verdonk2024isosteogenesisimperfecta pages 1-2) 2024
Chemical/Drug Bisphosphonates (pamidronate, zoledronate) CHEBI CHEBI:23688 (bisphosphonate class) Anti-resorptive therapy widely used to reduce fracture rates and improve mobility in severe OI; long-term adult effects under study https://doi.org/10.1007/s00223-024-01248-7, https://doi.org/10.1007/s00223-024-01236-x (sillence2024adyadicnosology pages 9-11, hald2024osteogenesisimperfectaskeletal pages 11-12) 2024
Chemical/Drug Sclerostin pathway agents (e.g., romosozumab class) CHEBI CHEBI: not specific (sclerostin antibody class) Anabolic/sclerostin-targeting approaches are under investigation to increase bone formation in OI (clinical studies ongoing) NCT04545554 (romosozumab pediatric study) and reviews https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 18-18, sun2024emerginglandscapeof pages 3-4) 2024

Table: Concise ontology‑annotated table mapping genes, processes, components, cell types, anatomical sites and therapies implicated in Osteogenesis Imperfecta Type III, with mechanistic roles and 2023–2024 supporting sources (context IDs). This table is designed for knowledge‑base annotation and rapid reference.

  1. Biological Processes (candidate GO annotations)

  2. Collagen fibril organization; extracellular matrix organization; collagen biosynthetic process; prolyl 3-hydroxylation; collagen cross-linking; ER protein folding; ER Ca2+ homeostasis; unfolded protein response; osteoblast differentiation (WNT/β-catenin); bone mineralization (Sun 2024; Sillence 2024) (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11, sun2024emerginglandscapeof pages 4-5).

  3. Cellular Components

  4. Endoplasmic reticulum; ER–Golgi intermediate compartment; Golgi apparatus; extracellular matrix and collagen fibril; osteoblast/osteocyte lacuno-canalicular system (Sun 2024; Sillence 2024) (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11).

  5. Disease Progression: Sequence of Events

  6. Initiation: Genetic variants affecting collagen I (COL1A1/COL1A2) or collagen processing/folding (CRTAP, P3H1, PPIB; SERPINH1/FKBP10; TMEM38B; BMP1; PLOD2) or osteoblast signaling/differentiation (WNT1, SP7, CREB3L1) (Sun 2024; Sillence 2024) (sun2024emerginglandscapeof pages 3-4, sillence2024adyadicnosology pages 9-11).
  7. Cellular dysfunction: Misfolded collagen and delayed helix formation; abnormal PTMs and cross-linking; ER retention and ER stress/UPR; reduced osteoblast differentiation and ECM production; aberrant mineralization (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7, sun2024emerginglandscapeof pages 4-5).
  8. Tissue-level consequences: Weak collagen fibrils and disorganized ECM lead to frequent fractures, vertebral compression, progressive deformity, and growth plate dysfunction with extreme short stature—defining the Type III phenotype (Sillence 2024, Jun 2024; 10.1007/s00223-024-01248-7) (sillence2024adyadicnosology pages 11-12, sillence2024adyadicnosology pages 9-11).
  9. Systemic/extra-skeletal: Collagen I defects extend to cardiovascular tissues; a systematic review found “valvular disease, heart failure, atrial fibrillation, and hypertension” more prevalent in OI, with “a larger aortic root” vs controls; abnormalities occur “in all types of OI and at all ages,” though progression is unclear (Verdonk 2024, Jan 2024; 10.1007/s00223-023-01171-3) (verdonk2024isosteogenesisimperfecta pages 1-2).

  10. Modern outcomes: Historically high pediatric respiratory mortality in severe OI has been markedly reduced with multidisciplinary care and cyclic IV bisphosphonates (pre-bisphosphonate era estimate: “60% of children died from respiratory failure before their 18th birthday”) (Sillence 2024, Jun 2024; 10.1007/s00223-024-01248-7) (sillence2024adyadicnosology pages 11-12).

  11. Phenotypic Manifestations and Clinical Correlates

  12. Core skeletal: Severe, progressively deforming bone disease with recurrent fractures, extreme short stature, and kyphoscoliosis/vertebral compression (Sillence 2024; Hald 2024) (sillence2024adyadicnosology pages 11-12, hald2024osteogenesisimperfectaskeletal pages 11-12).
  13. Spine and joints: Scoliosis reported in 26–76% across ages; ligament laxity and early osteoarthritis contribute to pain and disability (Hald 2024, Jun 2024; 10.1007/s00223-024-01236-x) (hald2024osteogenesisimperfectaskeletal pages 3-4, hald2024osteogenesisimperfectaskeletal pages 8-10).
  14. Extraskeletal: Hearing loss, dental anomalies (dentinogenesis imperfecta), ocular signs (blue sclerae), cardiopulmonary involvement likely beyond skeletal deformity effects (Hald 2024; Verdonk 2024) (hald2024osteogenesisimperfectaskeletal pages 11-12, verdonk2024isosteogenesisimperfecta pages 1-2).
  15. Patient-reported burden and adult outcomes: Cross-sectional data report 41.8% chronic pain and ~65% at least moderate fatigue; health-related quality of life reduction is mainly physical; median lifespan 72.4 years (men) and 77.4 years (women) (Hald 2024, Jun 2024; 10.1007/s00223-024-01236-x) (hald2024osteogenesisimperfectaskeletal pages 6-8, hald2024osteogenesisimperfectaskeletal pages 1-3).

Expert Opinions and 2023–2024 Reviews - Dyadic nosology emphasizes pairing genotype with Sillence phenotypes to reflect matrix biology and genomic complexity (>40 OI/bone fragility genes), providing a modern classification framework (Sillence 2024, Jun 2024; 10.1007/s00223-024-01248-7) (sillence2024adyadicnosology pages 11-12). - Contemporary adult-focused review argues OI is a systemic disease with significant adult musculoskeletal and extraskeletal morbidity and calls for longitudinal registries to define cardiovascular and other risks (Hald 2024, Jun 2024; 10.1007/s00223-024-01236-x) (hald2024osteogenesisimperfectaskeletal pages 1-3, hald2024osteogenesisimperfectaskeletal pages 11-12, hald2024osteogenesisimperfectaskeletal pages 6-8). - Mechanistic synthesis (Sun 2024) highlights convergence of collagen I misfolding, ER proteostasis (folding/PTMs, Ca2+ homeostasis), extracellular processing/cross-linking, and osteoblast differentiation signaling (WNT1/SP7/CREB3L1) as drivers of severe deforming phenotypes with growth deficiency (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 18-18, sun2024emerginglandscapeof pages 6-7, sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 3-4). - Cardiovascular systematic review recommends “low-threshold” cardiology referral given increased prevalence of valvular disease, heart failure, AF, hypertension, and larger aortic root, but notes lack of longitudinal progression data (Verdonk 2024, Jan 2024; 10.1007/s00223-023-01171-3) (verdonk2024isosteogenesisimperfecta pages 1-2).

Current Applications and Real-world Implementations - Pharmacologic: Cyclic IV bisphosphonates remain standard in severe pediatric OI within multidisciplinary programs, improving mobility and survival (Sillence 2024, Jun 2024; Hald 2024, Jun 2024) (sillence2024adyadicnosology pages 11-12, hald2024osteogenesisimperfectaskeletal pages 11-12). Adult long-term effects and antifracture efficacy remain under evaluation (Hald 2024) (hald2024osteogenesisimperfectaskeletal pages 3-4). - Anabolic/sclerostin pathway: Pediatric Phase 1 study of romosozumab in OI completed (NCT04545554; ClinicalTrials.gov), reflecting translational application of WNT pathway biology; broader efficacy/safety across subtypes (including Type III) remain areas of active research (sun2024emerginglandscapeof pages 18-18). - Multisystem care: Adult care increasingly addresses cardiopulmonary, neuromuscular, dental/oral, and women’s health domains in addition to bone, with emphasis on registries and standardized outcomes (Hald 2024; Rapoport 2023, Orphanet J Rare Dis, Feb 2023; 10.1186/s13023-023-02627-3) (hald2024osteogenesisimperfectaskeletal pages 11-12, hald2024osteogenesisimperfectaskeletal pages 8-10).

Selected Direct Quotes - “Approximately 80–85%” of OI (types I–IV) arise from autosomal‑dominant COL1A1/COL1A2 variants disrupting the triple-helix (Sun 2024, Jan 2024; 10.1021/acsptsci.3c00324) (sun2024emerginglandscapeof pages 3-4). - “Valvular disease, heart failure, atrial fibrillation, and hypertension appear to be more prevalent in OI… [and] a larger aortic root was observed in OI compared to controls” (Verdonk 2024, Jan 2024; 10.1007/s00223-023-01171-3) (verdonk2024isosteogenesisimperfecta pages 1-2). - “In the pre-bisphosphonate era, 60% of children died from respiratory failure before their 18th birthday” (Sillence 2024, Jun 2024; 10.1007/s00223-024-01248-7) (sillence2024adyadicnosology pages 11-12).

Ontology Annotations (examples) - Genes/Proteins (HGNC): COL1A1; COL1A2; CRTAP; LEPRE1/P3H1; PPIB; SERPINH1; FKBP10; PLOD2; BMP1; WNT1; SP7; CREB3L1; TMEM38B; SERPINF1; IFITM5 (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sun2024emerginglandscapeof pages 6-7, sillence2024adyadicnosology pages 9-11). - Biological Processes (GO): collagen fibril organization; prolyl 3‑hydroxylation; ER protein folding; UPR; ER Ca2+ homeostasis; osteoblast differentiation (WNT/β‑catenin); ECM organization; collagen cross-linking; mineralization (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11, sun2024emerginglandscapeof pages 4-5). - Cellular Components (GO): endoplasmic reticulum; ER–Golgi intermediate compartment; Golgi apparatus; extracellular matrix/collagen fibril (sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 5-6, sillence2024adyadicnosology pages 9-11). - Cell Types (CL): osteoblast (CL:0000189); osteocyte (CL:0001989); osteoclast (CL:0000653); bone-marrow stromal cell (CL:0000711) (sun2024emerginglandscapeof pages 3-4, hald2024osteogenesisimperfectaskeletal pages 11-12). - Anatomical Locations (UBERON): long bone cortex (UBERON:0005924); vertebral body (UBERON:0002105); growth plate (UBERON:0002081); aortic root (UBERON:0004217) (sillence2024adyadicnosology pages 11-12, hald2024osteogenesisimperfectaskeletal pages 11-12, verdonk2024isosteogenesisimperfecta pages 1-2). - Chemical Entities (CHEBI): bisphosphonates (CHEBI:23688); sclerostin‑pathway monoclonal antibodies (class) (sillence2024adyadicnosology pages 9-11, hald2024osteogenesisimperfectaskeletal pages 11-12).

References (URLs and dates) - Sun Y et al. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS Pharmacol Transl Sci. Jan 2024. https://doi.org/10.1021/acsptsci.3c00324 (sun2024emerginglandscapeof pages 18-18, sun2024emerginglandscapeof pages 6-7, sun2024emerginglandscapeof pages 4-5, sun2024emerginglandscapeof pages 3-4, sun2024emerginglandscapeof pages 2-3, sun2024emerginglandscapeof pages 5-6). - Sillence DO. A Dyadic Nosology for Osteogenesis Imperfecta and Bone Fragility Syndromes 2024. Calcif Tissue Int. Jun 2024. https://doi.org/10.1007/s00223-024-01248-7 (sillence2024adyadicnosology pages 11-12, sillence2024adyadicnosology pages 9-11, sillence2024adyadicnosology pages 16-17, sillence2024adyadicnosology pages 17-18). - Hald JD et al. Osteogenesis imperfecta: skeletal and non-skeletal challenges in adulthood. Calcif Tissue Int. Jun 2024. https://doi.org/10.1007/s00223-024-01236-x (hald2024osteogenesisimperfectaskeletal pages 11-12, hald2024osteogenesisimperfectaskeletal pages 8-10, hald2024osteogenesisimperfectaskeletal pages 1-3, hald2024osteogenesisimperfectaskeletal pages 6-8, hald2024osteogenesisimperfectaskeletal pages 3-4). - Verdonk SJE et al. Is Osteogenesis Imperfecta Associated with Cardiovascular Abnormalities? Calcif Tissue Int. Jan 2024. https://doi.org/10.1007/s00223-023-01171-3 (verdonk2024isosteogenesisimperfecta pages 1-2). - Rapoport M et al. The patient clinical journey and socioeconomic impact of osteogenesis imperfecta: a systematic scoping review. Orphanet J Rare Dis. Feb 2023. https://doi.org/10.1186/s13023-023-02627-3 (hald2024osteogenesisimperfectaskeletal pages 8-10). - ClinicalTrials.gov. Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta (NCT04545554). Status: Completed. https://clinicaltrials.gov/study/NCT04545554 (sun2024emerginglandscapeof pages 18-18).

Limitations and evidence gaps - Quantitative measurements of ER stress/UPR activation and specific pathway fluxes in human Type III osteoblasts remain limited in 2023–2024 sources reviewed here; most evidence integrates genetic mechanisms, cellular models, and clinical correlation (Sun 2024; Hald 2024) (sun2024emerginglandscapeof pages 18-18, hald2024osteogenesisimperfectaskeletal pages 11-12). Longitudinal cardiovascular risk trajectories lack robust data, despite higher observed prevalences (Verdonk 2024) (verdonk2024isosteogenesisimperfecta pages 1-2).

References

  1. (sun2024emerginglandscapeof pages 18-18): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  2. (sun2024emerginglandscapeof pages 3-4): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  3. (sun2024emerginglandscapeof pages 2-3): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  4. (hald2024osteogenesisimperfectaskeletal pages 11-12): Jannie Dahl Hald, Bente Langdahl, Lars Folkestad, Lena Lande Wekre, Riley Johnson, Sandesh C. S. Nagamani, Cathleen Raggio, Stuart H. Ralston, Oliver Semler, Laura Tosi, and Eric Orwoll. Osteogenesis imperfecta: skeletal and non-skeletal challenges in adulthood. Calcified Tissue International, 115:863-872, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01236-x, doi:10.1007/s00223-024-01236-x. This article has 12 citations and is from a peer-reviewed journal.

  5. (hald2024osteogenesisimperfectaskeletal pages 8-10): Jannie Dahl Hald, Bente Langdahl, Lars Folkestad, Lena Lande Wekre, Riley Johnson, Sandesh C. S. Nagamani, Cathleen Raggio, Stuart H. Ralston, Oliver Semler, Laura Tosi, and Eric Orwoll. Osteogenesis imperfecta: skeletal and non-skeletal challenges in adulthood. Calcified Tissue International, 115:863-872, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01236-x, doi:10.1007/s00223-024-01236-x. This article has 12 citations and is from a peer-reviewed journal.

  6. (verdonk2024isosteogenesisimperfecta pages 1-2): Sara J. E. Verdonk, Silvia Storoni, Dimitra Micha, Joost G. van den Aardweg, Paolo Versacci, Luca Celli, Ralph de Vries, Lidiia Zhytnik, Otto Kamp, Marianna Bugiani, and Elisabeth M. W. Eekhoff. Is osteogenesis imperfecta associated with cardiovascular abnormalities? a systematic review of the literature. Calcified Tissue International, 114:210-221, Jan 2024. URL: https://doi.org/10.1007/s00223-023-01171-3, doi:10.1007/s00223-023-01171-3. This article has 17 citations and is from a peer-reviewed journal.

  7. (hald2024osteogenesisimperfectaskeletal pages 1-3): Jannie Dahl Hald, Bente Langdahl, Lars Folkestad, Lena Lande Wekre, Riley Johnson, Sandesh C. S. Nagamani, Cathleen Raggio, Stuart H. Ralston, Oliver Semler, Laura Tosi, and Eric Orwoll. Osteogenesis imperfecta: skeletal and non-skeletal challenges in adulthood. Calcified Tissue International, 115:863-872, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01236-x, doi:10.1007/s00223-024-01236-x. This article has 12 citations and is from a peer-reviewed journal.

  8. (sillence2024adyadicnosology pages 11-12): David Owen Sillence. A dyadic nosology for osteogenesis imperfecta and bone fragility syndromes 2024. Calcified Tissue International, 115:873-890, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01248-7, doi:10.1007/s00223-024-01248-7. This article has 29 citations and is from a peer-reviewed journal.

  9. (sun2024emerginglandscapeof pages 5-6): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  10. (sun2024emerginglandscapeof pages 6-7): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  11. (sillence2024adyadicnosology pages 9-11): David Owen Sillence. A dyadic nosology for osteogenesis imperfecta and bone fragility syndromes 2024. Calcified Tissue International, 115:873-890, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01248-7, doi:10.1007/s00223-024-01248-7. This article has 29 citations and is from a peer-reviewed journal.

  12. (sun2024emerginglandscapeof pages 4-5): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  13. (sillence2024adyadicnosology pages 17-18): David Owen Sillence. A dyadic nosology for osteogenesis imperfecta and bone fragility syndromes 2024. Calcified Tissue International, 115:873-890, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01248-7, doi:10.1007/s00223-024-01248-7. This article has 29 citations and is from a peer-reviewed journal.

  14. (hald2024osteogenesisimperfectaskeletal pages 3-4): Jannie Dahl Hald, Bente Langdahl, Lars Folkestad, Lena Lande Wekre, Riley Johnson, Sandesh C. S. Nagamani, Cathleen Raggio, Stuart H. Ralston, Oliver Semler, Laura Tosi, and Eric Orwoll. Osteogenesis imperfecta: skeletal and non-skeletal challenges in adulthood. Calcified Tissue International, 115:863-872, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01236-x, doi:10.1007/s00223-024-01236-x. This article has 12 citations and is from a peer-reviewed journal.

  15. (sillence2024adyadicnosology pages 16-17): David Owen Sillence. A dyadic nosology for osteogenesis imperfecta and bone fragility syndromes 2024. Calcified Tissue International, 115:873-890, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01248-7, doi:10.1007/s00223-024-01248-7. This article has 29 citations and is from a peer-reviewed journal.

  16. (hald2024osteogenesisimperfectaskeletal pages 6-8): Jannie Dahl Hald, Bente Langdahl, Lars Folkestad, Lena Lande Wekre, Riley Johnson, Sandesh C. S. Nagamani, Cathleen Raggio, Stuart H. Ralston, Oliver Semler, Laura Tosi, and Eric Orwoll. Osteogenesis imperfecta: skeletal and non-skeletal challenges in adulthood. Calcified Tissue International, 115:863-872, Jun 2024. URL: https://doi.org/10.1007/s00223-024-01236-x, doi:10.1007/s00223-024-01236-x. This article has 12 citations and is from a peer-reviewed journal.