SummaryOBJECTIVE-Testosterone therapy for osteoporosis has not been studied extensively in women because of its potential to cause virilization. Female-to-male transsexuals are genetic females who suffer from gender dysphoria and thus take supra-physiologic doses of testosterone to change from the female to male phenotype. The aim of this study is to examine the effects of testosterone treatment on the genetic female skeleton.PATIENTS AND DESIGN-A group of 15 female-to-male transsexuals was prospectively enrolled for observation over a 2-year period. The subjects had a mean age of 37·0 ± 3·0 years. All of the subjects self-administered testosterone esters intramuscularly at a mean dose of 70·7 ± 4·5 mg weekly. MEASUREMENTS-The subjects had measurements of bone mineral density (BMD) by dual X-ray absorptiometry (DXA) of the femoral neck and spine (L2-L4) at 12-month intervals. They had determinations of serum oestradiol, testosterone, soluble RANKL (sRANKL), osteoprotegerin (OPG) and urine N-telopeptide (NTX) at the date of enrolment and at the end of 2 years.RESULTS-There was a significant positive increase in mean BMD of 7·8% at the femoral neck and a nonsignificant increase in mean BMD of 3·1% at the spine over 2 years. The levels of testosterone reached the upper normal range for males and the levels of oestradiol declined to near the postmenopausal range. sRANKL levels decreased significantly in female-to-male transsexuals who newly initiated testosterone therapy. There was no significant change in urine NTX or serum OPG during the study.CONCLUSIONS-We conclude that supra-physiologic testosterone therapy increases BMD at the hip while maintaining BMD at the spine in female-to-male transsexuals. The effects of testosterone may be the result of testosterone hormone directly acting on the bone or indirectly through aromatization to oestradiol. Lower RANKL levels coupled with unchanged OPG levels results in an increased OPG/RANKL ratio, which may be beneficial to the bone by inhibiting osteoclastogenesis. Oestrogen is regarded as the dominant sex steroid hormone in maintaining bone mineral density (BMD) in males and females. Oestrogen therapy in postmenopausal women prevents bone loss (Wells et al., 2002), increases BMD (Lindsay & Thome, 1990) and prevents fractures (Women's Health Initiative, 2002). Oestradiol rather than testosterone in men correlates more strongly with BMD (Greendale et al., 1997;Khosla et al., 1998;Amin et al., 2000;Szulc et al., 2003) and is a stronger determinant of peak bone mass (Khosla et al., 2001). Men who have either defective aromatase (Bilezikian et al., 1998) or oestrogen receptor (Smith et al., 1994) develop severe osteoporosis, which further supports the notion that oestradiol is the more dominant sex steroid in preserving bone density.Previously, testosterone was considered the more dominant sex steroid in men. With ageing, men experience declining levels of testosterone (Morley et al., 1997) and decreasing BMD (Meier et al., 1984;Jones et al., 1994;Fatayerji et al., 1999;Melto...