This study used a randomized, 2 x 2 factorial design to evaluate over 2 years the effect of intranasal salmon calcitonin and intramuscular nandrolone decanoate on bone mass in elderly women with established osteoporosis. The study was double masked in relation to calcitonin and open in relation to nandrolone decanoate. One hundred and twenty-three women aged 60-88 years who had sustained a previous osteoporotic fracture, or had osteopenia, were recruited through an outpatient clinic. Women were assigned to one of four groups: (1) daily placebo nasal spray, (2) 400 IU intranasal calcitonin daily, (3) 20 intramuscular injections of 50 mg nandrolone decanoate (given as two courses of 10 injections) plus placebo nasal spray, or (4) 20 injections of 50 mg nandrolone decanoate plus 400 IU intranasal calcitonin daily. All subjects received 1000 mg calcium supplementation daily. Outcomes measured included changes in bone mineral density (BMD) at the lumbar spine, as measured by dual-energy quantitative computed tomography (DEQCT), in BMD of the proximal femur, and BMD and bone mineral content (BMC) of the lumbar spine and forearm, as measured by dual-energy X-ray absorptiometry (DXA). Significant positive changes from baseline in DXA BMC at the lumbar spine were observed over 2 years in the calcitonin group (5.0 +/- 1.9%, mean +/- SE) and in the nandrolone deconate group (4.7 +/- 1.9%) but not in the placebo group (1.1 +/- 2.2%) or the combined therapy group (0.7 +/- 1.8%). Modelling based on the 2 x 2 factorial design revealed that nandrolone decanoate was associated with a 3.8 +/- 1.8% (p < 0.05) gain in DXA BMD at the proximal femur. Modelling also revealed that calcitonin treatment was associated with a loss of 11.5 +/- 4.7% in DEQCT BMD at the lumbar spine and a loss of 3.7 +/- 1.8% in DXA BMD at the proximal femur (p < 0.05). There was in vivo antagonism between the two medications of 7.9 +/- 3.9% for DXA BMC at the lumbar spine. Both agents caused positive changes from baseline in lumbar spine BMC. Nandrolone decanoate had beneficial effects on BMD at the proximal femur. This dose of intranasal calcitonin was associated with deleterious effects on trabecular BMD at the lumbar spine and total BMD at the proximal femur. There may be significant clinical antagonism between these two medications.