Bone fragility and osteoporosis in children and young adults

Abstract

Osteoporosis is a metabolic bone disorder which increases fragility fracture risk. Elderly individuals, especially postmenopausal women, are particularly susceptible to osteoporosis. Although rare, osteoporosis in children and young adults is becoming increasingly evident, highlighting the need for timely diagnosis, management and follow-up. Early-onset osteoporosis is defined as the presence of a low BMD (Z-score of ≤ -2.0 in individuals aged < 20 years; T-score of ≤ -2.5 in those aged between 20 to 50 years) accompanied by a clinically significant fracture history, or the presence of low-energy vertebral compression fractures even in the absence of osteoporosis. Affected children and young adults should undergo a thorough diagnostic workup, including collection of clinical history, radiography, biochemical investigation and possibly bone biopsy. Once secondary factors and comorbidities are excluded, genetic testing should be considered to determine the possibility of an underlying monogenic cause. Defects in genes related to type I collagen biosynthesis are the commonest contributors of primary osteoporosis, followed by loss-of-function variants in genes encoding key regulatory proteins of canonical WNT signalling (specifically LRP5 and WNT1), the actin-binding plastin-3 protein (encoded by PLS3) resulting in X-linked osteoporosis, and the more recent sphingomyelin synthase 2 (encoded by SGMS2) which is critical for signal transduction affecting sphingomyelin metabolism. Despite these discoveries, genetic causes and underlying mechanisms in early-onset osteoporosis remain largely unknown, and if no causal gene is identified, early-onset osteoporosis is deemed idiopathic. This calls for further research to unravel the molecular mechanisms driving early-onset osteoporosis that consequently will aid in patient management and individualised targeted therapy.

Keywords: Bone mass; DXA; Early-onset osteoporosis; Fragility fractures; Genetic testing; Idiopathic osteoporosis; Osteogenesis imperfecta; Secondary osteoporosis.

Fig. 1

Flowchart showing the diagnostic workup of a growing child or young adult with suspected early-onset osteoporosis. DXA dual-energy X-ray absorptiometry, VFA vertebral fracture assessment, QCT quantitative computed tomography, HTS High-throughput sequencing, WES whole-exome sequencing, WGS whole-genome sequencing. Figure created using BioRender (https://biorender.com)

Fig. 2

Proposed prevention strategies and targeted treatment options for children and young adults with early-onset osteoporosis