Osteoporosis

Osteoporosis is defined clinically by reduced bone strength, typically reflected by low bone mineral density and increased fracture susceptibility. The clinical spectrum extends from severe rare monogenic low bone mass disorders such as with congenital or infantile onset to common age-related (postmenopausal or senile) osteoporosis of multifactorial pathogenesis, with substantial pathogenetic overlap between these poles.

Early-onset primary osteoporosis (EOOP) affects children, premenopausal women, and men (often defined as <50 years of age, although this age threshold is pragmatic and not strictly defined); presentation typically includes reduced bone mineral density, low-trauma vertebral or peripheral fractures, and frequently a positive family history of skeletal fragility. EOOP is classified as primary only after exclusion of secondary causes such as chronic illness, long-term medication, and nutritional deficiency.

Age-related osteoporosis predominates after age 50, with peak incidence in postmenopausal women due to oestrogen withdrawal and continued senile bone loss in both sexes thereafter; vertebral compression fractures, hip fractures, and distal forearm fractures are the principal clinical manifestations.

Rare germline variants in bone-fragility genes are detected in a subset of adults with primary low bone mass after exclusion of secondary causes, with reported detection rates of up to 20%.

Although a large number of genes have been associated with osteoporosis, the most frequently identified forms of monogenic forms across studies involve defects in type I collagen or in the canonical WNT signalling pathway, represented by heterozygous germline variants in COL1A1 or COL1A2 (associated with mild or low bone mass), as well as variants in LRP5 (WNT co-receptor) and WNT1 (WNT ligand). However, in a substantial proportion of cases no causative variant is identified, suggesting that bone fragility in these individuals is likely to result from more complex mechanisms, including polygenic and multifactorial influences.