Recombinant Human TSH Modulates In Vivo C-Telopeptides of Type-1 Collagen and Bone Alkaline Phosphatase, but Not Osteoprotegerin Production in Postmenopausal Women Monitored for Differentiated Thyroid Carcinoma

Abstract

In women monitored for thyroid carcinoma, short-term stimulation with rhTSH induced an acute decrease in serum C-telopeptides of type-1 collagen and an increase in serum BALP levels without any effect on OPG production. The inhibitory effect of TSH on bone resorption occurred only in postmenopausal women who showed low BMD and a high bone turnover rate as an effect of L-thyroxine suppressive therapy.Introduction: It has been recently shown that thyrotropin (TSH) has an inhibitory activity on skeletal remodeling in in vitro conditions. Here, we have aimed at evaluating whether TSH has similar effects in vivo. For this purpose, we have evaluated the sequential profile of serum bone metabolism markers during acute stimulation with recombinant human TSH (rhTSH) in thyroidectomized women monitored for thyroid carcinoma. Materials and Methods:The study group included 66 thyroidectomized patients, of whom 38 were premenopausal and 28 postmenopausal, who underwent routine rhTSH-assisted whole body radioactive iodine scanning for differentiated thyroid carcinoma. The patients were sequentially evaluated for TSH, free triiodothyronine (FT3), free thyroxine (FT4), bone alkaline phosphatase (BALP), C-telopeptides of type-1 collagen (CrossLaps), and osteoprotegerin (OPG) levels during rhTSH stimulation. The samples were drawn just before and 2 and 7 days after the first administration of rhTSH. BMD was evaluated by ultrasonography at baseline. Seventy-one healthy women (41 premenopausal and 30 postmenopausal) acted as a control group. Results and Conclusions: At study entry, all patients had subclinical thyrotoxicosis as effect of L-thyroxine (L-T4) treatment. The patients had higher serum CrossLaps and OPG levels and lower BMD than healthy subjects. Postmenopausal patients showed comparable serum FT4 and FT3 concentrations with those found in premenopausal patients. However, postmenopausal patients showed higher serum CrossLaps (p < 0.001), OPG (p ‫ס‬ 0.03), and BALP (p < 0.001) levels and lower BMD (p < 0.001) than those measured in premenopausal patients. Two days after the first administration of rhTSH, all patients had serum TSH values >100 mUI/liter. At this time, serum CrossLaps levels decreased significantly (p < 0.001) and BALP values increased (p ‫ס‬ 0.001) with respect to the baseline values in postmenopausal but not in premenopausal patients. rhTSH did not induce any significant change in serum OPG values either in premenopausal or in postmenopausal patients. One week after the first rhTSH administration, serum CrossLaps values decreased again to values comparable with those measured at baseline, whereas serum BALP values remained high. This study shows that subclinical thyrotoxicosis is accompanied by high bone turnover rate with an increase in serum OPG levels compared with euthyroid healthy subjects. Acute increase in serum TSH levels is accompanied by a reversible inhibition of bone resorption. This effect is characterized by a decrease in serum CrossLaps and an increase in BALP levels without any e...

Pituitary-bone connection in skeletal regulation

“…In contrast, the over-expression of constitutively activated TSHR in osteoclast precursor cells [64] or transgenically, in mouse precursors [73] inhibited osteoclastogenesis. In post-menopausal women, a single subcutaneous injection of TSH drastically lowered serum C-telopeptide to premenopausal levels within 2 days, with recovery at day 7 [71]. In none of the studies with TSH replacement did thyroid hormones increase, exemplifying again that the pituitary-bone axis is more primitive than the pituitary-thyroid axis.…”

“…At least 20 clinical studies have since documented tight and highly reproducible correlations between low TSH levels, bone loss, bone geometry, and fracture risk in patient cohorts across the globe . Evidence also shows that TSH protects the skeleton by exerting anti-resorptive and anabolic actions in rodent models and in people [37,[62][63][64][65][66][67][68][69][70][71].…”

Short-term hypothyroidism after Levothyroxine-withdrawal in patients with differentiated thyroid cancer: clinical and quality of life consequences

“…On this basis, rhTSH administration is clinically safe and may have beneficial effects on the vascular system by reducing arterial blood pressure and increasing circulating nitric oxide (55). Moreover, in postmenopausal, but not in premenopausal women, monitored for DTC, rhTSH administration acutely decreases the serum C-telopeptides of type-1 collagen and increases serum bone alkaline phosphatase levels, but does not affect osteoprotegerin production (56). Thus, an acute increase in serum TSH concentration leads to a marked inhibition of bone resorption.…”

The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density

“…In the context of conflicting data on a functional role for TSH in skeletal development, our data, which were corrected for serum TSH levels, outline the importance of local T 3 for bone metabolism. (13)(14)(15)(16)(17)(35)(36)(37)(38) Two recent papers by Bassett and colleagues, (18,19) who studied mice with complete or haploinsufficiency of TRa and -b, concluded that TRa regulates both skeletal development and adult bone maintenance.…”