Pharmacological and biological therapeutic strategies for osteogenesis imperfecta

Abstract

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility, low bone mass, and bone deformities. The majority of cases are caused by autosomal dominant pathogenic variants in the COL1A1 and COL1A2 genes that encode type I collagen, the major component of the bone matrix. The remaining cases are caused by autosomal recessively or dominantly inherited mutations in genes that are involved in the post-translational modification of type I collagen, act as type I collagen chaperones, or are members of the signaling pathways that regulate bone homeostasis. The main goals of treatment in OI are to decrease fracture incidence, relieve bone pain, and promote mobility and growth. This requires a multi-disciplinary approach, utilizing pharmacological interventions, physical therapy, orthopedic surgery, and monitoring nutrition with appropriate calcium and vitamin D supplementation. Bisphosphonate therapy, which has become the mainstay of treatment in OI, has proven beneficial in increasing bone mass, and to some extent reducing fracture risk. However, the response to treatment is not as robust as is seen in osteoporosis, and it seems less effective in certain types of OI, and in adult OI patients as compared to most pediatric cases. New pharmacological treatments are currently being developed, including anti-resorptive agents, anabolic treatment, and gene- and cell-therapy approaches. These therapies are under different stages of investigation from the bench-side, to pre-clinical and clinical trials. In this review, we will summarize the recent findings regarding the pharmacological and biological strategies for the treatment of patients with OI. © 2016 Wiley Periodicals, Inc.

Denosumab: an Emerging Therapy in Pediatric Bone Disorders

“…Common types result from autosomal dominant COL1A1/1A2 mutations leading to defects in type 1 collagen, while rarer forms result from autosomal recessive mutations in genes responsible for collagen processing or osteoblast function [38]. Bisphosphonates improve bone density, pain, and mobility in OI, and are frequently prescribed for patients with moderate to severe forms [39]. Type 6 OI, due to SERPINF1 mutations, is autosomal recessive with distinct histologic features including prominent unmineralized osteoid, and a typically poor response to bisphosphonates [40].…”

Severely Impaired Bone Material Quality in Chihuahua Zebrafish Resembles Classical Dominant Human Osteogenesis Imperfecta

“…Conventional measures including musculoskeletal exercise are therefore often combined with pharmacological approaches widely based on antiresorptive bisphosphonate therapy . However, given the particularly wide age range of patients in addition to the large clinical variability and the genetic diversity of OI, the success of such therapies often remains inconclusive …”

A Multicenter Observational Cohort Study to Evaluate the Effects of Bisphosphonate Exposure on Bone Mineral Density and Other Health Outcomes in Osteogenesis Imperfecta

“…Osteogenesis imperfecta (OI), otherwise known as brittle bone disease, is a Mendelian disorder characterized by low bone mass and bone fragility . The majority of individuals with OI have pathogenic variants in COL1A1 or COL1A2 , which encode for α1 and α2 chains of type I collagen, respectively . Although advances in identifying the genetic bases of OI over the past 15 years have greatly expanded the genetic heterogeneity of OI, most individuals can still be classified into the 1979 Sillence clinical classification of mild (type I), perinatally lethal (type II), severe (type III), and moderate (type IV) forms .…”

“…(2) Although advances in identifying the genetic bases of OI over the past 15 years have greatly expanded the genetic heterogeneity of OI, most individuals can still be classified into the 1979 Sillence clinical classification of mild (type I), perinatally lethal (type II), severe (type III), and moderate (type IV) forms. (2)(3)(4) Most individuals with type I OI (OI-1) have haploinsufficiency of type I collagen, whereas the majority with types II, III, and IV OI have a qualitative abnormality of type I collagen. (5) Bisphosphonates (BPNs), a class of drugs that inhibit osteoclast function and decrease bone resorption, are commonly used to treat OI.…”