Bone Markers Are Diminished in Offspring of Long-Lived Families Compared With Matched Controls, but Respond Equally to T3 and rhTSH

Objective: We explored the effects of T3 and rhTSH administration on bone turnover in subjects of the Leiden Longevity Study. Design: Twenty-six subjects (13 offspring and 13 matched controls), mean age 68 y, underwent a rhTSH (0.1 mg i.m) and a T3 challenge (100 µg orally) with an interval of at least 3 m. Bone markers were measured at baseline and hereafter once daily for 3–4 days. Outcome Measures: Bone markers and changes after T3 and rhTSH. The influence of sex, group and time, and relations with incremental changes in TSH, fT4 and T3. Results: CTX (bone resorption) was lower in offspring than controls (mean ± SEM), 0.324±0.026 vs 0.443±0.036 ng/mL, P= 0.02. P1NP (bone formation) was also lower in offspring than in controls (40.3±2.2 vs 59.0± 4.7 ng/mL, P=0.004). No sex differences were found. In offspring, CTX but not P1NP was positively related to TSH and fT4 (R=0.48, P=0.001 and R=0.55, P=0.005). In controls, CTX was negatively related to TSH (R=-0.50, P=0.009), while P1NP was positively related with fT4 (R=0.52, P=0.006). TSH administration increased bone resorption and formation (P<0.0001 and 0.005, respectively). CTX was maximal at 48 h, increasing from 0.415±0.032 to 0.470 ±0.037 ng/mL, P=0.001. P1NP increased from 51.1±4.09 to a maximum of 56.2±3.9 ng/mL at 24 h (P=0.005). T3 also increased bone resorption (P=0.049) and formation (P=0.001). CTX increased from 0.386±0.034 to 0.410± 0.041 ng/mL, P=0.05, and P1NP from 48.9± 4.3 to 55.5±4.2 ng/mL, P=0.007), with maximal values at 48 h. Offspring and controls had similar responses and sex had generally no statistical impact. Significant linear regressions were found between the incremental changes of CTX and TSH at 24 h (R=0.44, P=0.003), but not later. Here, significant linear relation were found for the incremental fT4 and CTX (R=0.60, P=0.001 at 48 h, and R=0.49, P=0.013 at 72 h). For P1NP such relations were not present (R values between from 0.002 to 0.14). T3 changes did not correlate with bone markers at any time point. Conclusion: This study demonstrates that bone turnover is diminished in members of long-lived families where bone resorption was positively related to serum TSH and fT4. Nevertheless, the responses to TSH (and fT4) and T3 were similar in offspring and controls. Interestingly, the maximal effect of TSH increment on bone resorption preceded that of fT4, suggesting that TSH may have an independent stimulatory effect on bone resorption. At physiological TSH concentrations such stimulatory effect on bone resorption may be postulated in offspring, along with many other factors, e.g PTH, vitamin D, GH, sex hormones and cytokines.