Context: Subjects with complete androgen insensitivity (CAI) and 5α-reductase-2 deficiency (5αRD-2) are natural human models to study the direct effect of androgens on bone mineral density (BMD).

Objective: The objective of this study was to test the hypothesis that androgens have a direct effect on BMD in men.

Design: This was a prospective, observational study (1989–1999) using dual energy x-ray absorptiometry.

Setting: The study was set in an outpatient specialty referral center.

Patients or Other Participants: All known subjects with these conditions (12 CAI and 16 5αRD-2) from diverse sociodemographic backgrounds were recruited for the study.

Interventions: There were no interventions.

Main Outcome Measure: Mean Z score and weight-matched Z score at lumbar spine and femoral neck for CAI and 5αRD-2 subjects were determined.

Results: Twelve CAI subjects had mean Z score at L2–L4 of −2.84 (±0.97, P < 0.001) and a mean weight-matched Z score of −2.52 (±0.94, P < 0.001). The mean Z score at the femoral neck was −1.33 (±0.91, P < 0.001) and the mean weight-matched Z score was −1.10 (±0.82, P = 0.001). Sixteen 5αRD-2 subjects had a mean Z score at L2–L4 of −0.84 (±1.29, P = 0.02) and a mean weight-matched Z score for 15 of 16 patients of −0.44 (±1.08, P = 0.14). The mean Z score at the femoral neck was 0.14 (±1.02, P = 0.58) and the mean weight-matched Z score for 15 of 16 patients was 0.49 (±0.94, P = 0.06). Therefore, in CAI subjects, BMD was significantly decreased in the spine and hip. 5αRD-2 subjects had normal BMD values.

Conclusions: 1) Androgens are of direct importance in the development and/or maintenance of BMD; and 2) testosterone and/or low levels of dihydrotestosterone appear to be sufficient for BMD development and/or maintenance.