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To study the influence of glucocorticoid replacement therapy on bone mineral density.Cross-sectional.University hospital in the Netherlands.91 patients with Addison disease who had been receiving glucocorticoid replacement therapy for a mean of 10.6 years (range, 0.5 to 36.5 years).Bone mineral density of the lumbar spine and both femoral necks using a dual-energy x-ray absorptiometer and basal serum concentrations of adrenocorticotropin, gonadal hormones, and adrenal androgens.Decreased bone mineral density (less than 2 standard deviations (SD) of the mean value of an age-matched reference population) was found in 10 of 31 men (32%; 95% CI, 17% to 51%) and in 4 of 60 women (7%; CI, 2% to 16%). No statistically significant differences were found between men and women with regard to age, duration of glucocorticoid substitution, or glucocorticoid dose, either in absolute quantities or when expressed per kilogram of body weight. However, in men with decreased bone mineral density, the daily hydrocortisone dose per kilogram of body weight (0.43 +/-0.08 mg/kg; mean +/-SD) was significantly (P = 0.032) higher than in men with normal bone mineral density (0.35 +/-0.10 mg/kg). After correction for possible confounding variables, a significant linear correlation was found between hydrocortisone dose per kilogram of body weight and bone mineral density of the lumbar spine in the men (regression coefficient, -0.86; CI, -1.60 to -0.13; P = 0.029) but not in the women.Long-term treatment with standard replacement doses of glucocorticoids may induce bone loss in men with Addison disease. Adjustment of glucocorticoid therapy to the lowest acceptable dose is mandatory in Addison disease, and regular measurement of bone mineral density may be helpful in identifying men at risk for the development of osteoporosis.