Osteogenesis imperfecta in children
1Academic Unit of Child Health, Sheffield Children's Hospital, Department of Oncology and Metabolism, University of Sheffield, S10 2TH, UK.
Insights
Osteogenesis imperfecta (OI) causes brittle bones and other issues. Bisphosphonates help children reduce fractures and improve mobility, but adult treatment efficacy is unclear. New therapies aim to increase bone mass.
Area of Science:
- Bone biology and genetics
- Skeletal dysplasias
- Pharmacological interventions
Background:
- Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility, abnormal bone structure, and increased bone turnover.
- Soft tissue abnormalities, including sarcopenia, are increasingly recognized in OI patients.
- Current multidisciplinary treatment approaches primarily involve bisphosphonates, used for two decades.
Purpose of the Study:
- To review the current understanding of Osteogenesis imperfecta (OI) pathogenesis, treatment efficacy, and emerging therapeutic strategies.
- To evaluate the effectiveness of bisphosphonates in OI across different age groups and disease severity.
- To explore novel therapeutic targets and approaches for managing OI.
Main Methods:
- Review of meta-analyses on bisphosphonate efficacy in OI.
- Analysis of current research on OI genetics and pathophysiology.
- Assessment of preclinical data for novel therapeutic strategies.
Main Results:
- Bisphosphonates show clear benefits for children with OI, reducing fracture risk and improving bone and motor function.
- Anti-fracture efficacy of bisphosphonates in adults is equivocal, with ongoing research into long-term benefits.
- The fundamental pathophysiology linking bone brittleness to other systemic changes in OI remains unclear, despite insights into ER stress and inflammation.
Conclusions:
- Bisphosphonates are effective in pediatric OI, but adult treatment requires further investigation.
- New therapies focusing on increasing bone mass, enhancing autophagy, or stem cell transplantation show promise.
- Understanding the complex pathophysiology, including TGFb signaling, is crucial for developing targeted OI treatments.
Abstract:
Osteogenesis imperfecta (OI) is a disease characterised by altered bone tissue material properties together with abnormal micro and macro-architecture and thus bone fragility, increased bone turnover and hyperosteocytosis. Increasingly appreciated are the soft tissue changes, sarcopenia in particular. Approaches to treatment are now multidisciplinary, with bisphosphonates having been the primary pharmacological intervention over the last 20 years. Whilst meta-analyses suggest that anti-fracture efficacy across the life course is equivocal, there is good evidence that for children bisphosphonates reduce fracture risk, increase vertebral size and improve vertebral shape, as well as improving motor function and mobility. The genetics of OI continues to provide insights into the molecular pathogenesis of the disease, although the pathophysiology is less clear. The complexity of the multi-scale interactions of bone tissue with cellular function are gradually being disentangled, but the fundamental question of why increased tissue brittleness should be associated with so many other changes is unclear; ER stress, pro-inflammatory cytokines, accelerated senesence and altered matrix component release might all contribute, but a unifying hypothesis remains elusive. New approaches to therapy are focussed on increasing bone mass, following the paradigm established by the treatment of postmenopausal osteoporosis. For adults, this brings the prospect of restoring previously lost bone - for children, particularly at the severe end of the spectrum, the possibility of further reducing fracture frequency and possibly altering growth and long term function are attractive. The alternatives that might affect tissue brittleness are autophagy enhancement (through the removal of abnormal type I collagen aggregates) and stem cell transplantation - both still at the preclinical stage of assessment. Preclinical assessment is not supportive of targeting inflammatory pathways, although understanding why TGFb signalling is increased, and whether that presents a treatment target in OI, remains to be established.
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