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Osteogenesis Imperfecta (OI)

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Osteogenesis imperfecta (OI) is a group of rare systemic connective tissue disorders, most commonly caused by pathogenic variants in genes that encode type I collagen production. It is characterized by low bone mass, increased bone fragility, and a predisposition to fractures, often from minimal or no trauma.1,2

The condition is lifelong and variable in severity, ranging from mild forms with few fractures to severe cases with significant skeletal deformities and functional impairment. The estimated prevalence of OI is between 1 in 10,000 and 1 in 20,000 individuals globally.1,2

Osteogenesis imperfecta: a genetic disorder of collagen and bone matrix

This section explores the evolving classification of OI, its genetic origins, and the biological mechanisms, particularly the role of collagen and regulatory proteins like sclerostin that contribute to its complex clinical presentation.

Classification and clinical spectrum

Historically, OI was classified into four types (I–IV) based on clinical features.3 With the advent of molecular diagnostics, this classification has expanded to include types V–XXI.3,4 While genotype–phenotype correlations exist, they are not always predictive of clinical severity.5

●    Types I–IV are typically caused by dominant variants in COL1A1 or COL1A2.3
●    Type V is associated with a variant in IFITM5.3
●    Types VI–XXI involve autosomal recessive or X-linked variants in genes beyond collagen.3

In clinical practice, it is often more practical to describe OI by severity and genetic cause (e.g., “a moderate form of OI due to an autosomal recessive variant in SERPINH1”).6

Genetic origins and the role of collagen in osteogenesis imperfecta 
The majority of OI cases, approximately 80–85%, are linked to autosomal dominant variants in the COL1A1 and COL1A2 genes.7 These genes encode the α1 and α2 chains of type I collagen, respectively.4,8 Disruption in these genes results in either reduced production or structural abnormalities of collagen.4 These defects are central to the pathophysiology of collagen in OI, affecting both the quantity and quality of the bone matrix.4

More than 2,000 variants have been identified in COL1A1 and over 1,000 in COL1A2. These mutations impair the triple-helical structure of collagen, leading to a collagen defect in OI that compromises the biomechanical integrity of bone.4,7

In rarer forms of OI (types V–XXI), pathogenic variants affect genes involved in collagen processing, osteoblast differentiation, or cytoskeletal function, contributing to the broader spectrum of collagen and OI mechanisms.8,9,10

Biology, structure, and the role of sclerostin in osteogenesis imperfecta

In healthy bone, type I collagen forms the backbone of the extracellular matrix, contributing up to 90% of its organic content.8,11,12 In OI bones, pathogenic variants disrupt collagen synthesis or structure, leading to reduced bone mass, altered architecture, and increased fragility. These OI collagen abnormalities are central to the pathophysiology of OI.8,13

Bone turnover is regulated by osteoblasts, osteoclasts, and osteocytes. In OI, impaired osteoblast function and abnormal collagen production result in thinner cortices, fewer trabeculae, and increased porosity, hallmarks of OI bone fragility.13

These changes are often assessed through OI bone scan and bone density evaluations.

At the molecular level, excessive hydroxylation and glycosylation of collagen fibrils, along with increased non-enzymatic cross-linking, contribute to hypermineralisation and brittleness, key features of the collagen OI phenotype.8,13

Sclerostin, a glycoprotein secreted by osteocytes, plays a critical role in regulating bone formation. It inhibits the Wnt/β-catenin signalling pathway, suppressing osteoblast activity and promoting bone resorption.14,15

In OI, elevated sclerostin activity may further exacerbate the imbalance between bone formation and resorption, contributing to OI bone resorption and reduced bone strength.16

Targeting sclerostin is one of a number of promising therapeutic strategies. By inhibiting sclerostin, it may be possible to restore bone formation, reduce resorption, and improve the structural integrity of OI bones, a focus of ongoing clinical investigation.

Clinical manifestations of osteogenesis imperfecta

The hallmark of OI is a lifelong predisposition to fractures, often from minimal trauma. OI bones are structurally compromised, with reduced density and altered geometry. This leads to:6,17,18
●    Vertebral compression fractures
●    Long bone deformities
●    Scoliosis and short stature
●    Impaired mobility

These features are often observed in comparisons of normal bones vs people with OI. 

Extra skeletal features include:

●    Hearing loss, often progressive17,18,19
●    Dentinogenesis imperfecta, affecting up to 50% of individuals17,20,21
●    Cardiovascular abnormalities, such as aortic root dilation6,17,18,22
●    Respiratory complications, due to thoracic deformities23
●    Joint hypermobility and ligamentous laxity17,18
●    Blue sclerae, due to thin collagen in the sclera17,24

These features reflect the systemic role of collagen in OI which can significantly impact quality of life (QoL) and require multidisciplinary management.

Managing osteogenesis imperfecta: a multidisciplinary approach

Effective management of OI requires more than a single intervention; it demands a coordinated, multidisciplinary approach tailored to each individual’s needs. From early diagnosis through to adulthood, collaboration across medical, surgical, and allied health disciplines is essential to reduce fracture risk, manage pain, support growth, and preserve mobility and independence.25

Physicians, orthopedics and neurosurgeons, clinical nurses, physiotherapists, psychologists, dietitians, dentists, and social workers each play a vital role in delivering holistic care.25,26 Together, they help individuals with OI navigate the physical and emotional complexities of the condition, supporting not just clinical outcomes, but QoL.25,26

Understanding the impact of osteogenesis imperfecta (OI) on daily life

While the clinical manifestations of OI are well documented, the broader impact on daily life is complex and deeply individual. From infancy through adulthood, people living with OI face a range of physical, emotional, and social challenges.27,28

In severe forms, complications due to fractures, including tachypnea, aspiration, pneumonia, and respiratory failure can occur in utero or at birth and may be life-threatening. As individuals grow from childhood through to adulthood, acute and chronic pain, skeletal deformities, fatigue, and cardiovascular issues can significantly reduce QoL.29,30

The IMPACT survey, one of the largest patient-reported datasets in OI, highlights the persistent burden across all ages and severities. Respondents reported challenges with mobility, safety, independence, and social participation, often compounded by stigma and isolation.

Key findings include:
•    82% of adults with OI reported pain27
•    67% of adults with OI experience fatigue27 
•    81% of adults with severe OI were unable to walk independently27
•    67% of caregivers reported their children with OI had experienced a fracture27

Osteogenesis imperfecta and osteoporosis

Osteogenesis imperfecta (OI) and osteoporosis (OP) are both conditions that affect bone health, but they have distinct characteristics and underlying causes. OI is a genetic disorder, primarily caused by mutations in the COL1A1 or COL1A2 genes, leading to abnormal type I collagen.1,2 This results in brittle bones despite normal or minimally reduced bone mineral density (BMD).1 In contrast, OP is a multifactorial condition often associated with age-related bone loss, hormonal changes, and lifestyle factors, leading to reduced bone mass and microarchitectural deterioration.31

OI typically presents at birth or in early childhood, while OP usually occurs postmenopausally in women and in men over 70 years of age.1,32 The primary defect in OI is the abnormal structure or quantity of type I collagen, whereas in OP the defect is reduced bone mass and compromised bone architecture.31,33 Bone quality in OI is poor due to defective collagen, leading to brittle bones, while in OP, the bone mineral and collagen matrix are normal but reduced in quantity.31,32

Bone turnover in OI can vary, whereas in OP, it is generally increased, especially in postmenopausal women.32 Fractures in OI are due to structurally defective bone matrix, while in OP, they are due to decreased bone mass and compromised architecture.31,32

OI often has extra skeletal features such as blue sclerae, dentinogenesis imperfecta, hearing loss, ligamentous laxity, and short stature, which are rare in OP.1,32 Histologically, OI shows woven bone, abnormal lamellar organization, and reduced osteoid thickness, while OP shows thinned trabeculae, reduced connectivity, and increased cortical porosity.1,31,32

The genetic contribution in OI is strong with identified monogenic causes, mainly in collagen-related genes, whereas in OP, it is minor and polygenic unless secondary to genetic disorders.32,33 Treatment response in OI to bisphosphonates is inconclusive for fracture benefit, but emerging therapies like sclerostin and TGF-β inhibition show promise.1,32 In OP, bisphosphonates and anabolic agents like teriparatide are effective in appropriate populations.32

Mereo's commitment to osteogenesis imperfecta

At Mereo, we are focused on finding new therapeutic options to improve the lives of people living with rare conditions. Our development program in OI is driven by a deep understanding of bone biology and a commitment to unlocking the potential of therapies that address the underlying mechanisms of disease. We work in close partnership with healthcare professionals, researchers, and people living with OI to ensure that our work is clinically meaningful and ethically grounded.

MEREO(HR)1462

Abbreviations

BMD, bone mineral density; OI, osteogenesis imperfecta; OP, osteoporosis; QoL, Quality of Life.

References
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  2. Forlino A et al. Lancet. 2016;387(10028):1657–1671.
  3. Nijhuis WH et al. J Child Orthop. 2019;13(1):1-11.
  4. El-Gazzar A et al. Int J Mol Sci. 2021;22(2):625.
  5. Maioli M et al. Eur J Hum Genet. 2019;27(7):1090-1100.
  6. Van Dijk FS et al. Am J Med Genet A. 2014;164A(6):1470-1481.
  7. Marini JC et al. Endotext [Internet]: Osteogenesis Imperfecta. South Dartmouth (MA): MDText.com, Inc; 2000.
  8. Brizola E et al. Pediatr Phys Ther. 2014;26(2):245-252.
  9. National Organization for Rare Disorders. Osteogenesis imperfecta. National Organization for Rare Disorders. Updated July, 2021. Accessed August, 2025. https://rarediseases.org/rare-diseases/osteogenesis-imperfecta.
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  16. Bishop N et al. Orbit: a randomized, double-blind, placebo-controlled, phase 2/3 study to assess the efficacy and safety of setrusumab in pediatric and young adult participants with osteogenesis imperfecta. Presented at: American Society for Bone and Mineral Research (ASBMR) Annual Meeting; September 9-12, 2022; Austin, TX.
  17. Etich J et al. Mol Cell Pediatr. 2020;7:9. 
  18. Sam JE et al. Indian J Endocrinol Metab. 2017;21(6):903-908.
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  21. Folkestad L et al. J Bone Miner Res. 2017;32(1):125-134.
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  24. Das S at al. Kerala Journal of Ophthalmology. 29(3):240.
  25. Marr C et al. J Multidiscip Healthc. 2017;10:145-155.
  26. Osteogenesis Imperfecta Foundation. Exercise and activity: key elements in the management of OI. Osteogenesis Imperfecta Foundation. Updated November, 2022. Accessed August, 2025. https://oif.org/wp-content/uploads/2019/08/Exercise___Activity.pdf.
  27. Westerheim I at al. Orphanet J Rare Dis. 2024;19:128.
  28. Welzenis TV at al. BMC Public Health. 24:3318.1-16.
  29. Murali CN et al. Clin Genet. 2021;99(6):772-779.
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  32. Compston JE et al. Lancet. 2019; 393(10169):364–376.
  33. Seeman E et al. N Engl J Med. 2006;354(21):2250–2261.
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