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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-? 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.

SUBMITTER: Rossi V

PROVIDER: S-EPMC7017716 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Osteogenesis imperfecta: advancements in genetics and treatment.

Rossi Vittoria V Lee Brendan B Marom Ronit R

Current opinion in pediatrics 20191201 6

<h4>Purpose of review</h4>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.<h4>Recent findings</h4>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 sequenci ...[more]

PMID: 31693577

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Project description:Adults with osteogenesis imperfecta (OI) have a high risk of fracture. Currently, few treatment options are available, and bone anabolic therapies have not been tested in clinical trials for OI treatment.79 adults with OI were randomized to receive 20 ?g recombinant human parathyroid hormone (teriparatide) or placebo for 18 months in a double-blind, placebo-controlled trial. The primary endpoint was the percent change in areal bone mineral density (aBMD) of the lumbar spine (LS), as determined by dual-energy X-ray absorptiometry. Secondary endpoints included percent change in bone remodeling markers and vertebral volumetric BMD (vBMD) by quantitative computed tomography, estimated vertebral strength by finite element analysis, and self-reported fractures.Compared with the placebo group, the teriparatide group showed increased LS aBMD (6.1% ± 1.0% vs. 2.8% ± 1.0% change from baseline; P < 0.05) and total hip aBMD (2.6% ± 1.0% vs. -2.4% ± 1.0% change; P < 0.001). Vertebral vBMD and strength improved with teriparatide therapy (18% ± 6% and 15% ± 3% change, respectively), but declined with placebo (-5.0% ± 6% and -2.0% ± 3% change; P < 0.05 for both comparisons). Serum procollagen type 1 N-terminal propeptide (P1NP) and urine collagen N-telopeptide (NTx) levels increased with teriparatide therapy (135% ± 14% and 64% ± 10% change, respectively). Teriparatide-induced elevation of P1NP levels was less pronounced in severe forms of OI (type III/IV) compared with the milder form (type I). Type I OI patients exhibited robust BMD increases with teriparatide; however, there was no observed benefit for those with type III/IV OI. There was no difference in self-reported fractures between the 2 groups.Adults with OI, particularly those with less severe disease (type I), displayed a teriparatide-induced anabolic response, as well as increased hip and spine aBMD, vertebral vBMD, and estimated vertebral strength. Trial registration. Clinicaltrials.gov NCT00131469. Funding. The Osteoporosis Imperfecta Foundation, Eli Lilly and Co., the National Center for Advancing Translational Science (NCATS) at the NIH (grant no. UL1RR024140), and the Baylor College of Medicine General Clinical Research Center (grant no. RR00188).

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Osteogenesis imperfecta: advancements in genetics and treatment.

Publications

Osteogenesis imperfecta: advancements in genetics and treatment.

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