Critical Considerations in the Interpretation of Bone Turnover Marker Data in Hormonal Contraceptive Users. Comment on Tassi et al. Hormonal Contraception and Bone Metabolism: Emerging Evidence from a Systematic Review and Meta-Analysis of Studies on Post-Pubertal and Reproductive-Age Women. Pharmaceuticals 2025, 18, 61.

In response to the recent meta-analysis by Tassi et al. on hormonal contraception and bone metabolism, we raise critical concerns regarding the interpretation of bone turnover markers as surrogates for bone mineral density (BMD). While bone turnover markers can offer early insights into bone remodeling, they do not directly predict long-term BMD changes, which require 12-24 months to detect. The assumption that equivalent percentage changes in bone formation and resorption markers reflect stable BMD is not supported by current evidence. Bone metabolism varies significantly across life stages, particularly during adolescence and early adulthood, when peak bone mass is still accruing-underscoring the need for age-specific analyses. Additionally, biomarker interpretation is limited by assay variability, inconsistent sampling protocols, and uncertain clinical implications, especially for formation markers. Mechanistically, estrogen supports bone integrity by inhibiting resorption and promoting formation; thus, combined hormonal contraceptives (CHCs) containing estrogen may help preserve bone health. In contrast, progestin-only methods can suppress endogenous estrogen production, potentially compromising skeletal development. We advocate for longitudinal studies incorporating both BMD and turnover markers, stratified by age and contraceptive formulation, to guide safer and more informed contraceptive choices that protect long-term bone health.