Overt hyperthyroidism is associated with changes in bone metabolism, whereas the effect of levothyroxine (L-T4) load in patients with differentiated thyroid carcinoma (DTC) is controversial. The aim of our study was to evaluate osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappaB ligand (RANK-L) in patients with DTC with suppressed endogenous thyrotropin due to L-T4 regimen. A cohort of 80 subjects with DTC (68 women and 12 men; age range, 27-81 years) was studied. A cohort of 55 subjects with a history of partial or total surgery for nonmalignant thyroid pathology served as a control group. Groups were matched for sex, age, and body mass index. Per-week dosage of L-T4 was significantly higher in patients with DTC than in controls (P < .001). More elevated free T(4) concentrations (P < .001) and more suppressed thyrotropin and thyroglobulin levels (P < .001) were found in subjects with DTC than in controls. No difference in serum or urinary parameters related to bone metabolism or dual-energy x-ray absorptiometry was noted between the groups. Overall, OPG levels were similar in both groups but were significantly (P = .03) lower in postmenopausal women with DTC than in postmenopausal control women. Only control women showed lower OPG levels in premenopausal than in postmenopausal (P = .002) conditions. Overall, RANK-L levels were significantly higher (P = .03) in subjects with DTC than in controls. In both groups, OPG and RANK-L levels were unrelated to each other. A significant positive correlation was seen between OPG levels and age in both subjects with DTC (P < .001) and controls (P < .001). Serum RANK-L correlated negatively with age in subjects with DTC (P = .05). Although there were several differences in L-T4 dosages, OPG and RANK-L levels were similar in patients with a history of DTC and those with a history of nonmalignant thyroid diseases. The correlation between circulating OPG and RANK-L levels was not significant. The increase in OPG with age indicates its protective role in bone loss. The cause of bone loss after long-term L-T4 load will be more extensively studied.