A Rat Model of Thyroid Hormone-Induced Bone Loss: Effect of Antiresorptive Agents on Regional Bone Density and Osteocalcin Gene Expression

Abstract

Thyroid hormone has been shown to stimulate bone resorption. Both endogenous hyperthyroidism and exogenous thyroxine suppressive therapy have been associated with reduction in bone mineral density (BMD), but the patholophysiology of thyroxine-induced bone loss is not well understood. First we studied the effect of L-T4 (0.1-0.3 microgram/g body weight ip/day) on bone turnover in rats by measuring regional BMDs and osteocalcin mRNA. Next we determined whether antiresorptive agents (calcitonin 1 microU/gip/day or sodium etidronate given cyclically at 10 micrograms/g po for 3 consecutive days out of every week) could prevent bone loss. Groups of 10 male Sprague-Dawley rats each weighing 320-350 g were studied before and after 3 weeks of treatment. L-T4 treatment resulted in reduction in BMDs in the lumbar spine, tail, and femur as measured by dual energy X-ray absorptiometry, but there was no correlation with the dosage of L-T4 or the serum T4 level. Treatment with sodium etidronate or calcitonin alone did not alter the regional BMD. Cyclical sodium etidronate, but not calcitonin, was able to prevent the bone loss induced by L-T4 treatment. L-T4 caused a dose-dependent increase in femur osteocalcin mRNA concentration. Treatment with calcitonin resulted in 50% reduction of osteocalcin mRNA, but sodium etidronate had no effect. In conclusion, cyclical sodium etidronate prevents bone loss induced by exogenous L-T4 in rats and may be useful in preventing osteoporosis in patients given long term TSH-suppressive doses of thyroxine therapy.

Thyroid hormone stimulation of osteocalcin gene expression in ROS 17/2.8 cells is mediated by transcriptional and post-transcriptional mechanisms

“…Hypothyroid patients have reduced levels of serum OC, which are rapidly normalized after T 4 treatment. Rats treated with excessive levels of thyroid hormone have a dose-dependent increase in the levels of OC mRNA in the femur (Ross & Graichen 1991, Kung & Ng 1994. In situ hybridization experiments document that T 4 treatment increases expression of OC mRNA in femoral osteoblasts, but not in vertebral osteoblasts (Kung & Ng 1994), pointing towards a differential response of vertebral and femoral osteoblasts to thyroid hormone.…”

“…Rats treated with excessive levels of thyroid hormone have a dose-dependent increase in the levels of OC mRNA in the femur (Ross & Graichen 1991, Kung & Ng 1994. In situ hybridization experiments document that T 4 treatment increases expression of OC mRNA in femoral osteoblasts, but not in vertebral osteoblasts (Kung & Ng 1994), pointing towards a differential response of vertebral and femoral osteoblasts to thyroid hormone. Rats treated with high dose T 4 for 28 days have reduced bone mineral density in the femur but not in the spine, corresponding to the regions of thyroid hormoneinduced OC mRNA expression (Gouveia et al 1997).…”

Effects of concomitant diabetes mellitus and hyperthyroidism on testicular and epididymal histoarchitecture and steroidogenesis in male animals

“…Mice with random blood glucose level >17 mmol/L (normal: random 7.1-8.2 mmol/L) were considered diabetic. The mice of the DH and H groups were intraperitoneally injected with LT4 (0.3 mg/kg body weight) (Kung and Ng, 1994;Chandra et al, 2010;Kim et al, 2012) on a daily basis till the end of the experiment. The experimental mice were kept without any type of reversal treatment such as insulin or methimazole, throughout the study period.…”

Rapid Inhibition of Thyroxine-Induced Bone Resorption in the Rat by an Orally Active Vitronectin Receptor Antagonist

“…Studies in the rat have supported this hypothesis (Eriksen et al, 1985;Yamamoto et al, 1993b). Biochemical markers of bone turnover have also been shown to be increased in the rat (Harvey et al, 1991;Kung and Ng, 1994;Taimela et al, 1994;Ishihara et al, 1997). Taken together, these results suggest that patients with hyperthyroidism could potentially benefit from therapy that prevents the increased bone turnover and bone loss.…”

“…Previous reports (Ongphiphadhanakul et al, 1993;Kung and Ng, 1994;Ishihara et al, 1997) have shown that excess thyroid hormone in rats causes increased levels of the bone formation markers, osteocalcin and alkaline phosphatase, and the resorption markers, tartrate-resistant acid phospha- tase, pyridinoline, and Dpd. Ongphiphadhanakul et al (1993) have shown that after 3 weeks of treatment in male hyperthyroid rats with a bisphosphonate, femoral mRNA levels of tartrate-resistant acid phosphatase and alkaline phosphatase were reduced compared with T4 controls.…”