Key Findings of the Meta-Analysis
A meta-analysis examining the effects of puberty blockers and gender-affirming hormone therapy (GAHT) on bone density in transgender and gender-diverse adolescents found that pubertal suppression temporarily slowed bone accrual but was followed by partial recovery after GAHT initiation. The study, which analyzed 10 longitudinal studies involving 751 adolescents, reported that absolute bone mineral density (BMD) remained stable during gonadotropin-releasing hormone agonist (GnRHa) therapy, with mean durations up to 38.4 months. However, lumbar spine BMD z-scores dropped significantly compared to sex-assigned-at-birth normative references. After starting GAHT, z-scores showed partial recovery, though they remained numerically lower than baseline for both assigned female at birth (AFAB) and assigned male at birth (AMAB) groups. Absolute BMD increased modestly with GAHT, indicating ongoing bone accrual despite residual z-score differences. The authors noted that while z-scores did not fully return to baseline, they were generally not statistically different across most skeletal sites, suggesting a modest and uncertain shortfall in catch-up rather than a persistent deficit.
Mechanisms and Context of Skeletal Vulnerability
The study attributes skeletal vulnerability during pubertal suppression to GnRHa-induced changes in body composition, including reduced lean mass and increased fat mass, which may impair the muscle-bone unit critical for skeletal development. Lower baseline BMD has also been observed in some transgender and gender-diverse adolescents, particularly those assigned male at birth, potentially increasing their vulnerability to treatment-related bone changes. The authors emphasized that adolescence is the primary window for acquiring lifelong bone mass, underscoring the importance of monitoring bone health throughout gender-affirming care. They highlighted that while bone accrual slowed during puberty blockers, it resumed after GAHT, with consistent recovery patterns across different cohorts and healthcare settings. However, they noted that z-scores often remained below baseline during follow-up, indicating an ongoing gap in the evidence regarding long-term outcomes.
Clinical Implications and Recommendations
Researchers advised clinicians to prioritize bone health monitoring as part of routine gender-affirming care, emphasizing a dynamic approach rather than focusing on single treatment phases. They recommended addressing modifiable lifestyle factors, including adequate calcium and vitamin D intake, regular weight-bearing exercise, and structured dual-energy X-ray absorptiometry (DXA) surveillance. The study also highlighted the importance of tailoring treatment timing and duration to individual patient needs. Anatomical site-specific analyses revealed that the lumbar spine was most responsive to hormonal changes, while total hip and femoral neck trajectories showed more modest and heterogeneous patterns. Meta-regressions indicated that higher body mass index, shorter GnRHa duration, longer GAHT exposure, and older age at GnRHa initiation were associated with more favorable bone density outcomes. Baseline vitamin D insufficiency was common, prompting recommendations for routine supplementation of approximately 600 IU/day of cholecalciferol alongside balanced nutrition and physical activity.
Limitations and Future Research Needs
The study acknowledged several limitations, including relatively short follow-up periods, lack of parallel cisgender comparator groups, inconsistent adjustment for key confounders, and sparse reporting of bone turnover markers or fracture rates. The authors emphasized that peak bone mass is typically achieved in early adulthood, necessitating longer-term studies to determine whether bone mineral density continues to recover into adulthood. They also noted the need for standardized protocols to address gaps in data collection, such as fracture incidence and biomarkers of bone turnover. While the meta-analysis provided insights into the trajectory of bone density during puberty suppression and GAHT, the authors stressed that further research is required to fully understand the long-term implications of these interventions on skeletal health.
Conclusion
The findings highlight the temporary impact of puberty blockers on bone density in transgender and gender-diverse adolescents, with partial recovery observed after initiating gender-affirming hormone therapy. The study underscores the importance of integrating bone health monitoring into comprehensive gender-affirming care, emphasizing the need for ongoing evaluation rather than a focus on isolated treatment phases. While absolute BMD increased modestly with GAHT, residual z-score differences suggest that skeletal development remains a dynamic process requiring sustained attention. The authors called for continued research to address gaps in understanding long-term outcomes, particularly regarding the potential for full recovery of bone density into adulthood. Their recommendations for lifestyle modifications and tailored treatment approaches aim to mitigate risks associated with skeletal vulnerability during this critical period of development.