Second-to-Fourth Digit (2D:4D) Ratio as A Risk Factor for Osteoporosis and Osteoarthritis: A Systematic Review.

BACKGROUND: The second-to-fourth digit (2D:4D) ratio is an established marker of prenatal sex hormone exposure and has been associated with various health outcomes across the lifespan. Increasing evidence suggests that developmental factors reflected by the 2D:4D ratio may contribute to susceptibility to musculoskeletal disorders, including osteoarthritis (OA) and osteoporosis (OP). AIM: This systematic review aimed to synthesize the available evidence regarding the association between 2D:4D ratio and the risk of OA and OP. METHODS: This systematic review was conducted according to the PRISMA guidelines and registered in PROSPERO (CRD420261439840). A comprehensive literature search was performed in PubMed, Web of Science, and Scopus between April and May 2026. Observational studies investigating the relationship between 2D:4D ratio and OA or OP related outcomes were included. Study selection, data extraction, and methodological quality assessment were independently performed by three reviewers. Methodological quality was evaluated using the Joanna Briggs Institute critical appraisal tools. RESULTS: Nine studies met the inclusion criteria, comprising eight studies on OA and one study on OP. Most studies reported that lower 2D:4D ratios or Type III finger patterns were associated with increased OA risk, greater radiographic severity, and a higher likelihood of severe knee OA requiring joint replacement. Associations were particularly evident for knee and hand OA, with several studies reporting stronger associations in women than in men. In contrast, evidence regarding OP was limited, as only one eligible study specifically investigated OP. Methodological heterogeneity was observed across studies regarding digit ratio assessment methods and disease definitions. CONCLUSION: Current evidence suggests that lower 2D:4D ratios are associated with OA-related outcomes, particularly in knee and hand OA, with several studies indicating stronger associations in women. These findings suggest that variation in 2D:4D may reflect developmental and sex-dependent patterns of musculoskeletal health rather than a causal relationship. However, evidence regarding OP remains insufficient to draw definitive conclusions. Further large-scale prospective studies using standardized assessment methods are needed to clarify these associations and their underlying biological mechanisms.