Although controversies exist on the possible adverse effect of T4 on bone mass, most studies reported bone loss in estrogen-deprived postmenopausal women taking suppressive doses of T4. We prospectively studied 46 postmenopausal women with carcinoma of thyroid for 2 yr to evaluate the rate of bone loss and assess whether calcium supplementation with or without intranasal calcitonin was able to decrease the rate of bone loss. All patients were receiving a stable dose of L-T4 (170 +/- 60 micrograms/day or 3.0 +/- 1.4 micrograms/kg.day) for more than 1 yr. All had TSH levels of 0.03 mIU/L or less and an elevated free T4 (FT4) index, but normal T3 levels. The calcium intake was low and averaged 507 +/- 384 g/day as assessed by dietary recall. The subjects were randomized into three groups: 1) intranasal calcitonin (200 IU daily) for 5 days/week plus 1000 mg calcium daily, 2) calcium alone, or 3) placebo. Total body and regional bone mineral density were measured by a dual energy x-ray absorptiometry bone densitometer at 6-month intervals. The results showed that both groups 1 and 2 had stable bone mass, whereas patients in groups 3 showed significant bone loss at the end of 2 yr (lumbar spine, 5.0%, hip, 6.7%, trochanter, 4.7%; Ward's triangle, 8.8%; P < 0.05), with bone mineral densities at all four regions lower than those in the other two groups (P < 0.05). There were no differences between groups 1 and 2. All three groups had elevated osteocalcin levels compared with age-matched reference controls. At 1 yr, the osteocalcin level decreased in groups 1 and 2, but remained significantly raised in group 3. No significant changes were detected in the bone-specific alkaline phosphatase levels. Urinary hydroxyproline excretion increased in group 3 at the end of 2 yr, but remained the same in groups 1 and 2. In conclusion, T4-suppressive therapy was associated with bone loss in postmenopausal women, which could be prevented by either calcium supplementation or intranasal calcitonin, although the latter did not provide additional benefit compared to calcium alone. However, careful titration of T4 dosage to maintain biochemical euthyroidism is a better way to avoid the adverse effect of T4 on bone.