Osteogenesis imperfecta—pathophysiology and therapeutic options

Abstract

Osteogenesis imperfecta (OI) is a rare congenital disease with a wide spectrum of severity characterized by skeletal deformity and increased bone fragility as well as additional, variable extraskeletal symptoms. Here, we present an overview of the genetic heterogeneity and pathophysiological background of OI as well as OI-related bone fragility disorders and highlight current therapeutic options. The most common form of OI is caused by mutations in the two collagen type I genes. Stop mutations usually lead to reduced collagen amount resulting in a mild phenotype, while missense mutations mainly provoke structural alterations in the collagen protein and entail a more severe phenotype. Numerous other causal genes have been identified during the last decade that are involved in collagen biosynthesis, modification and secretion, the differentiation and function of osteoblasts, and the maintenance of bone homeostasis. Management of patients with OI involves medical treatment by bisphosphonates as the most promising therapy to inhibit bone resorption and thereby facilitate bone formation. Surgical treatment ensures pain reduction and healing without an increase of deformities. Timely remobilization and regular strengthening of the muscles by physiotherapy are crucial to improve mobility, prevent muscle wasting and avoid bone resorption caused by immobilization. Identification of the pathomechanism for SERPINF1 mutations led to the development of a tailored mechanism-based therapy using denosumab, and unraveling further pathomechanisms will likely open new avenues for innovative treatment approaches.

Impact of Intrinsic Muscle Weakness on Muscle–Bone Crosstalk in Osteogenesis Imperfecta

“…Roughly 85% of OI cases are the result of autosomal dominant variants resulting in qualitative (dominant negative) or quantitative (haplo-insufficient) defects in type I collagen due to mutations in the type I collagen genes, COL1A1 and COL1A2 [ 1 , 2 , 10 , 12 ]. The remaining approximate 15% of cases are the result of either autosomal dominant, autosomal recessive or X-linked mutations in genes implicated in bone mineralization, posttranslational modifications, folding, and secretion of type I collagen, as well as those involved in osteoblast maturation and function [ 1 , 2 , 13 ].…”

“…As might be expected from the vast number of disease-causing OI mutations affecting multiple genes exhibiting unique functions, the clinical severity ranges considerably; from asymptomatic to perinatal lethality [ 1 , 2 , 13 , 14 ]. Classically, there are four subtypes of OI (Sillence classification; I–IV) with type I being the most mild form of the disease, type II being the most severe (resulting in perinatal lethality), type III being the most severe viable form (often resulting in the non-ambulation of patients), and type IV being of moderate severity [ 14 ].…”

“…Classically, there are four subtypes of OI (Sillence classification; I–IV) with type I being the most mild form of the disease, type II being the most severe (resulting in perinatal lethality), type III being the most severe viable form (often resulting in the non-ambulation of patients), and type IV being of moderate severity [ 14 ]. As the genetic understanding and the number of novel OI causing mutations has expanded, there has been a shift in the classification of OI with 20 types currently recognized in the Online Mendelian Inheritance in Man (OMIM) database [ 13 , 15 , 16 ]. Despite the large number of OI types described by the OMIM database and the 2019 revision of the Nosology and Classification of Genetic Skeletal Disorders highlighting five OI types based on phenotype rather than genetic origin [ 17 ], for clinical management and genetic counseling the Sillence classification remains clinically relevant.…”

“…While currently there remains no cure for OI, its genetic and clinical heterogeneity presents a challenge for treatment, preventing a generalized use of a “one size fits all” approach. This has forced physicians to be focused more on mitigating symptoms, with current treatments predominately targeted to reducing skeletal fragility with little to no consideration of the muscle weakness [ 2 , 13 ]. These therapeutic approaches often use bone antiresorptive and osteoanabolic pharmaceutical compounds, physical therapy, and surgical interventions, including the use of intermedullary rodding in pediatric patients [ 2 , 13 , 18 , 19 , 20 , 21 ].…”

“…The current standard of treatment in OI includes administration of intravenous or oral bone antiresorptive bisphosphonate therapy, which improve bone mineral density (BMD), although their efficacy in fracture reduction remains controversial and the safety and efficacy in pediatric patients remains unclear [ 12 , 13 , 19 , 22 ]. Additionally, long-term use of bisphosphonates may have an overall detrimental effect on bone due to decreased bone remodeling, increased accumulation of microfractures, thus compromising the bone integrity, and potential association with osteonecrosis of the jaw [ 12 , 18 , 22 , 23 , 24 ].…”