International Journal of Physical Medicine & Rehabilitation
Open Access

Advancements in the Molecular Pathophysiology of Osteogenesis Imperfecta

Yusuf Khan^{* *}Correspondence: Yusuf Khan, Department of Physical Therapy and Rehabilitation, University of Uludag, Bursa, Turkey, Email:

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Description

Osteogenesis Imperfecta (OI), colloquially known as brittle bone disease, presents a compelling example of how a single gene defect can reverberate through nearly every dimension of human function—molecular, structural, developmental, and psychosocial. While it has long been understood as a collagen-related genetic disorder affecting bone strength, recent discoveries in molecular biology, genomics, and tissue remodeling have expanded our understanding of its pathophysiology. This condition, while rare, serves as a paradigm for how genetically mediated skeletal fragility influences medical management, physical function, and quality of life. Moreover, it exemplifies the vital role rehabilitation professionals play in managing chronic musculoskeletal conditions.

Osteogenesis Imperfecta is primarily associated with mutations in the COL1A1 and COL1A2 genes, responsible for encoding type I collagen—a major structural protein in bone, skin, tendons, and sclera. These mutations either reduce the amount of normal collagen produced (haploinsufficiency) or result in structurally defective collagen. The resulting abnormal bone matrix undermines mechanical integrity, making bones prone to frequent fractures from minor trauma, or even spontaneously. However, OI is not a homogeneous disorder. The Sillence classification, historically based on clinical severity, ranges from type I (mild) to type II (perinatal lethal) and includes intermediate forms (types III and IV), with newer genetic classifications further expanding the spectrum to more than 15 identified subtypes. Each form varies in its genetic etiology, clinical presentation, and response to therapy.

In clinical practice, one of the greatest challenges is balancing fracture prevention with mobility promotion. Historically, there was a tendency to overprotect patients with OI, often discouraging weight-bearing and physical activity for fear of injury. However, it is now widely recognized that muscle strengthening, controlled mechanical loading, and functional mobility are essential not only for musculoskeletal development but also for cardiovascular health, psychological well-being, and social participation. Consequently, rehabilitation medicine has shifted from a reactive to a proactive paradigm, emphasizing early and sustained engagement in physical therapy tailored to individual capabilities and risks.

Pharmacologic treatment has also undergone significant evolution. The introduction of bisphosphonates, particularly intravenous pamidronate and zoledronate, marked a major breakthrough in the management of OI. These agents inhibit osteoclast-mediated bone resorption, leading to increased bone mineral density and, in many cases, a reduction in fracture rates. In pediatric populations, bisphosphonates have shown promise in improving vertebral morphology and supporting ambulation. However, their long-term efficacy in reducing adult fracture risk, especially in milder forms of OI, remains a subject of ongoing research. Moreover, questions persist regarding optimal dosing regimens, potential side effects such as osteonecrosis of the jaw, and the appropriate timing of treatment initiation and discontinuation.

More recently, attention has turned to targeted molecular therapies. Agents such as teriparatide, a recombinant parathyroid hormone analog, stimulate osteoblast activity and bone formation and have shown some efficacy in adult OI patients, particularly those with less severe forms. Sclerostin inhibitors, which act through the WNT signaling pathway to promote bone formation, are also under investigation for their utility in genetic bone disorders. Experimental gene-editing approaches using CRISPR/Cas9 have demonstrated success in correcting collagen gene mutations in vitro and in animal models, but clinical application remains distant. Nevertheless, these advances represent an exciting frontier in precision medicine for bone fragility.

One of the underappreciated aspects of OI is its psychosocial burden. Children and adults living with the condition often face not only physical limitations but also significant emotional and social challenges. Repeated fractures, surgeries, and physical therapy can be emotionally exhausting. Many patients experience school absenteeism, bullying, depression, or social isolation. The fear of fracture or overprotection by caregivers can hinder development of autonomy, self-confidence, and social engagement. For these reasons, psychological support, social work services, and peer support networks are essential components of comprehensive care. Likewise, educational accommodations, such as modified physical education, accessible school environments, and individualized learning plans, are critical for children with OI to thrive academically and socially.