Male osteoporosis is an important disease, with 25-30% of all hip fractures occurring in men. In a recent randomized, placebo-controlled study of osteoporotic males, alendronate 10 mg daily for 2 yr led to significant increments in bone mineral density (BMD), of a similar magnitude to those observed in postmenopausal women. In this study, specimens collected at intervals during the recent trial of alendronate in male osteoporosis, from 197 of the original 241 participants, were assayed for testosterone, estradiol, IGF-I, IGF binding protein 3 (IGFBP-3), bone-specific alkaline phosphatase [BSAP (serum)], and N-telopeptide of type I collagen corrected for creatinine [NTx (urine)]. Together with fracture and densitometry data from the original study, relationships were examined between BMD and serum IGF-I, IGFBP-3, testosterone, estradiol, BSAP, and urine NTx, both at baseline and during treatment with alendronate, to gain possible insights into the pathogenesis of male osteoporosis. Statistically significant (P <or= 0.05) associations were documented, at baseline, between the presence of vertebral fracture and each of serum IGF-I, serum IGFBP-3, serum free testosterone, total spine BMD, and total body BMD. No statistically significant correlations were observed between any of the baseline variables (IGF-I, IGFBP-3, estradiol, testosterone, and presence of vertebral fracture) and the BMD response to alendronate at any site. In a multivariate analysis, used to identify possible combinations of factors capable of predicting baseline BMD or response to alendronate, statistically significant (P <or= 0.01) relationships were seen, at baseline, between BMD and body mass index, age, and prior fracture. However, no statistically significant relationships were seen between any of the baseline variables (age, body mass index, testosterone, estradiol, IGF-I, IGFBP-3, and prior fracture) and change in BMD at any site. These data suggest that among men with osteoporosis it is not possible to identify patients who would be particularly good candidates for therapy with alendronate on the basis of biochemical or hormonal markers. Alendronate therapy appears to benefit osteoporotic males equally, irrespective of baseline serum testosterone, estradiol, IGF-I, or markers of bone turnover.