Osteogenesis imperfecta: advancements in genetics and treatment

Abstract

Purpose of review: The purpose of this review is to outline the current understanding of the molecular mechanisms and natural history of osteogenesis imperfecta, and to describe the development of new treatments for this disorder.

Recent findings: The introduction of next-generation sequencing technology has led to better understanding of the genetic cause of osteogenesis imperfecta and enabled cost-effective and timely diagnosis via expanded gene panels and exome or genome sequencing. Clinically, despite genetic heterogeneity, different forms of osteogenesis imperfecta share similar features that include connective tissue and systemic manifestations in addition to bone fragility. Thus, the goals of treatment in osteogenesis imperfecta extend beyond decreasing the risk of fracture, to include the maximization of growth and mobility, and the management of extraskeletal complications. The standard of care in pediatric patients is bisphosphonates therapy. Ongoing preclinical studies in osteogenesis imperfecta mouse models and clinical studies in individuals with osteogenesis imperfecta have been instrumental in the development of new and targeted therapeutic approaches, such as sclerostin inhibition and transforming growth factor-β inhibition.

Summary: Osteogenesis imperfecta is a skeletal dysplasia characterized by bone fragility and extraskeletal manifestations. Better understanding of the mechanisms of osteogenesis imperfecta will enable the development of much needed targeted therapies to improve the outcome in affected individuals.

Conflict of interest statement

Conflicts of interests

None.

Figures

Figure 1:

Pharmacologic interventions in OI and their target within the bone. Anti-resorptive agents include the bisphosphonates that reside in the bone matrix and inhibit osteoclast activity, and denosumab which targets the receptor activator of nuclear factor kappa-B ligand (RANKL that stimulates osteoclast formation and function). Anabolic therapies include teriparatide (a PTH analogue) that is promoting osteoblast differentiation and activity, and sclerostin inhibitory antibodies (Scl-Ab) that increase bone formation via Wnt signaling. TGF beta inhibition is a new approach designed to target the excessive activation of TGF beta signaling within the bone matrix which is thought to contribute to the bone fragility.