VOLUME 6 - NUMBER 1 - 2026

Early-onset osteoporosis: diagnostic and therapeutic implications of WNT1 variants

  • Gemma Marcucci
  • Concise reviews, 14-21
  • Full text PDF

  • Early-onset osteoporosis (EOOP) is a rare but clinically important condition affecting children and young adults, characterized by low bone mass, impaired bone quality, and increased fracture risk. Unlike age-related osteoporosis, which is primarily driven by accelerated bone loss after attainment of peak bone mass, EOOP more often reflects impaired skeletal development, defective peak bone mass acquisition, or primary abnormalities of bone remodeling. While secondary causes must be excluded, a substantial proportion of EOOP cases are now recognized as monogenic in origin. Among these, pathogenic variants in WNT1 have emerged as a paradigmatic cause of primary EOOP. Heterozygous WNT1 variants result in autosomal dominant EOOP with variable expressivity, low bone mass, and fragility fractures, frequently associated with low-turnover bone remodeling, whereas biallelic variants cause a severe osteogenesis imperfecta-like phenotype. This review summarizes current concepts in the diagnosis of EOOP, highlighting clinical red flags that should prompt genetic evaluation, and provides an updated synthesis of WNT1-related bone fragility, histomorphometric findings, and therapeutic responses reported to date. Emerging evidence suggests that conventional antiresorptive therapies may be suboptimal in WNT1-related EOOP, whereas anabolic and Wnt-targeted strategies may represent a more rational approach in selected patients. Persistent gaps in evidence regarding fracture outcomes and long-term management underscore the need for future studies.

  • KEY WORDS: Early-onset osteoporosis, Wnt signaling, WNT1, monogenic osteoporosis, bone fragility.