Bone Mass Effects of Cross-Sex Hormone Therapy in Transgender People

Updated Systematic Review and Meta-Analysis

Tayane Muniz Fighera; Patrícia Klarmann Ziegelmann; Thaís Rasia da Silva; Poli Mara Spritzer


J Endo Soc. 2019;3(5):943-964. 

In This Article

Abstract and Introduction


Context: The impact of long-term cross-sex hormone therapy (CSHT) in transgender men and women is still uncertain.

Objective: To perform a systematic review and meta-analysis and update the evidence regarding the effects of CSHT on bone mineral density (BMD) in transgender men and women.

Data Sources: Medline, Cochrane Central Register of Controlled Trials, and Embase were searched for studies published until August 2018.

Study Selection: Of 10,849 studies, 19 were selected for systematic review. All included patients were aged >16 years and received CSHT with BMD assessment by dual-energy X-ray absorptiometry (DXA).

Data Extraction: Data on BMD, CSHT, and clinical factors affecting bone mass were collected. A National Institutes of Health scale was used to assess the quality of studies.

Data Synthesis: Nineteen studies were meta-analyzed (487 trans men and 812 trans women). In trans men, mean BMD difference compared with natal women was not significant in any site in either cross-sectional or before-after studies. In trans women, mean BMD difference was not significant compared with natal men at the femoral neck, total femur, and lumbar spine in cross-sectional studies; before-after studies reported a slight but significant increase in lumbar spine BMD after 12 and ≥24 months of treatment.

Conclusions: Long-term CSHT had a neutral effect on BMD in transgender men. In transgender women, only lumbar spine BMD seemed to be affected after CSHT. This evidence is of low to moderate quality as a result of the observational design of studies, small sample sizes, and variations in hormone therapy protocols.


Transgender people experience a deep and persistent sense of incongruence between their gender of identity and the sex attributed to them at birth, with distress lasting for ≥6 months.[1–3] Hormone therapy and gender-affirming surgery (GAS) are the main therapeutic strategies for gender transition. Cross-sex hormone therapy (CSHT) suppresses gonadal hormones and secondary sex characteristics of the biological sex while inducing body characteristics of the gender of identity.[4] Although gender transition has been associated with improvement in mental health and other areas of functioning,[4–6] the full long-term effects of CSHT are still uncertain.

Sex steroids are major determinants of bone homeostasis. In boys, during puberty, testosterone stimulates periosteal apposition, leading to increased bone width and size compared with girls, despite the similar cortical thickness.[7] In turn, estrogen plays a main regulatory role in bone metabolism in both women and men, acting on bone remodeling and keeping it within physiological limits. Estradiol acts on the lifespan of osteoblasts, decreasing apoptosis and increasing the functional capacity of individual osteoblasts. In osteoclasts, estradiol induces apoptosis and decreases cellular differentiation.[8] Estrogen deficiency is associated with an imbalance between bone resorption and bone formation that is linked to osteoblast apoptosis, oxidative stress, and osteoblastic NF-κB (RANKL) activity.

Not much is known about the effects of CSHT on bone mass in transgender individuals.[9] Recent data from transgender men (female to male) and women (male to female) receiving hormone therapy have shown an increase in bone mineral density (BMD) after 12 months of treatment.[10] Another study on long-term testosterone therapy reported larger cortical bone size in trans men compared with natal females.[11] Conversely, trans women receiving estrogen therapy may lose lean mass in association with androgen deprivation, which over time can lead to smaller bones[12] and higher prevalence of low bone mass.[13,14]

To date, few studies evaluating the impact of CSHT on bone mass have been published, and a definitive conclusion has not been reached. A previous meta-analysis including 13 studies has assessed the relationship between hormone therapy and BMD. The results suggested that BMD was not significantly different in trans men and that lumbar spine BMD was increased in transwomen with CSHT.[15] Since then, however, new evidence has become available. Therefore, the aim of the present systematic review and meta-analysis was to update the available evidence regarding the effect of CSHT on BMD in transgender men and women.