*4.2.1. Mineral metabolism in hyperthyroidism*

Hyperthyroidism is associated with impaired mineral metabolism. Increased serum calcium levels have been reported in up to 27% of hyperthyroid patients (Begic-Karup et al, 2001), but severe and symptomatic hypercalcemia is rare. Concentrations of serum alkaline phosphatase and osteocalcin are also frequently elevated. These findings are reminiscent of those in primary hyperparathyroidism, however, serum parathyroid hormone is mostly low-normal (Iqbal et al, 2003). True primary hyperparathyroidism and thyrotoxicosis may coexist (Beus & Stack, 2004; Wagner et al, 1999). Decreased plasma 25 hydroxycholecalciferol levels observed in hyperthyroidism could participate to the lower intestinal absorption of calcium and osteopenia in these patients (Mohan et al, 2004). Bone resorption markers, urinary pyridinoline and deoxypyridinoline, are increased 7-8 times more than in age and sex matched controls (Kraenzlin et al, 2008). Furthermore, hyperthyroid patients display a greater increase in urinary pyridinoline cross-links than that in serum markers of bone formation (osteocalcin, bone-specific alkaline phosphatase) (Akalin et al, 2002; Kisakol et al, 2003). Altogether, an increased bone turnover in these patients is in favor of osteoclastic bone resorption.

After initiation of anti-thyroid treatment, biochemical markers of bone resorption, such as urinary hydroxyproline, serum pyridinoline, serum deoxypiridinoline cross-links, have been found to fall, with a subsequent rise of the bone formation markers (Mosekilde et al 1990; Siddiqi et al, 1997; Garnero et al, 1994). Elevation of serum PTH has been reported in some patients with severe thyrotoxicosis under anti-thyroid treatment (Pantazi et al, 2000). This rise in PTH was suggested to play a role in inducing some temporal changes in mineral metabolism and participate to the reversal of the catabolic bone status of hyperthyroidism to anabolic. Furthermore, another study found that in hyperthyroidism, despite normal or high IGF-I levels, IGF-I bioactivity is reduced, probably because of high levels of IGF-binding protein-1 (Miell et al, 1993). Treatment of thyrotoxicosis reverses this abnormality. The rise in IGF-I bioactivity may therefore have a positive effect on the bone metabolism.

### *4.2.2. Overt hyperthyroidism and skeletal changes*

258 Thyroid Hormone

2005).

**4.2. Hyperthyroidism** 

as a continuous variable had no effect on BMD.

hypothyroidism affects bone structure (Nagata et al, 2007).

discussed and compared with the data in healthy population.

*4.2.1. Mineral metabolism in hyperthyroidism* 

patients is in favor of osteoclastic bone resorption.

normal range. However, there was no association between TSH and BMD, and serum TSH

Bone quality was studied by Nagata et al. using quantitative ultrasound in postmenopausal women with subclinical hypothyroidism. The results demonstrated that calcaneo osteo sono assessment indices of right feet measured by ultrasound bone densitometer decreased according to the increase in TSH concentration. The authors have suggested that

Hyperthyroid patients present with an increased bone turnover and a risk for osteoporosis. The activity of osteoblasts and osteoclasts are increased, the latter predominates favoring resorption, negative balance of calcium, and bone loss (Melsen & Mosekilde, 1977; Mosekilde et al, 1990). Thyrotoxicosis in adults is a recognized cause of high-bone-turnover osteoporosis. Reduced bone mineral density was noted in hyperthyroid patients with an increased susceptibility to fragility fracture (Mosekilde et al, 1990; Vestergaard et al, 2002,

In both, clinical and subclinical hyperthyroidism, elevation of markers of bone turnover and decreased BMD have been reported (Kumeda et al, 2000; Heemstra et al, 2006; Lee et al, 2006). Previous studies that investigated impact of thyroid dysfunction on BMD and fracture risk did not provide conclusive results. Recently published population studies indicate association of endogenous subclinical hyperthyroidism with an increased fracture risk (Bauer et al, 2001; Jamal et al, 2005; Vadiveloo et al, 2011). Consequences of the hyperthyroid status (overt and subclinical) on bone turnover, BMD and fracture risk will be

Hyperthyroidism is associated with impaired mineral metabolism. Increased serum calcium levels have been reported in up to 27% of hyperthyroid patients (Begic-Karup et al, 2001), but severe and symptomatic hypercalcemia is rare. Concentrations of serum alkaline phosphatase and osteocalcin are also frequently elevated. These findings are reminiscent of those in primary hyperparathyroidism, however, serum parathyroid hormone is mostly low-normal (Iqbal et al, 2003). True primary hyperparathyroidism and thyrotoxicosis may coexist (Beus & Stack, 2004; Wagner et al, 1999). Decreased plasma 25 hydroxycholecalciferol levels observed in hyperthyroidism could participate to the lower intestinal absorption of calcium and osteopenia in these patients (Mohan et al, 2004). Bone resorption markers, urinary pyridinoline and deoxypyridinoline, are increased 7-8 times more than in age and sex matched controls (Kraenzlin et al, 2008). Furthermore, hyperthyroid patients display a greater increase in urinary pyridinoline cross-links than that in serum markers of bone formation (osteocalcin, bone-specific alkaline phosphatase) (Akalin et al, 2002; Kisakol et al, 2003). Altogether, an increased bone turnover in these Pathological skeletal changes, including osteopenia and osteoporosis, with higher incidence of fracture rates have been reported in hyperthyroid patients. Accordingly, hyperthyroidism was found 2.5-fold more often in postmenopausal women presenting with hip fracture than in controls. Among postmenopausal women, risk of hip fracture was significantly higher in patients with overt untreated hyperthyroidism and a history of past hyperthyroidism (Wejda et al, 1995). These findings were confirmed by a prospective follow-up study realized in 9516 Caucasian women, 65 years of age or older (Cummings et al, 1995). The authors demonstrated a higher risk of hip fracture among women who had previous hyperthyroidism. Another study reported that the prevalence of all types of fractures in patients with a history of thyroid disease was not different from that of control subjects.

However, women with a history of hyperthyroidism or thyroid cancer appeared to have their first fracture earlier than women without thyroid disease (Solomon et al, 1993). Median lumbar BMD in patients with thyrotoxicosis was shown to be 12.6% lower than that of normal individuals before the initiation of treatment (Krolner et al, 1983). Decreased BMD in hyperthyroid patients was demonstrated particularly in areas consisting of cortical bone. The risk of hip fracture increased significantly with age at diagnosis of hyperthyroidism (Campos-Pastor et al, 1993; Udayakmar et al, 2006; Vestergaard et al, 2002, 2005). The etiology of hyperthyroidism is not believed to play a role in the severity of hyperthyroid bone disease (Jodar et al, 1997).

A recent meta-analysis (Vestergaard et al, 2005) evaluated data regarding BMD and fracture risk in 20 (962 patients) and 5 publications, respectively (62 830 patients and controls). The results showed that patients with hyperthyroidism have a significantly decreased BMD. These values were lower in untreated patients compared to those under treatment, particularly for the lumbar spine (-0.83 vs. -0.27 Z-score) and the femoral site (-0.75 vs. -0.15 Z-score). The risk of hip fracture at the moment of diagnosis of hyperthyroidism was 1.6 (95% CI 0.7 to 3.4), and the value of BMD alone was associated with a risk of hip fracture corresponding to 1.2 (95% CI 0.9-1.5).

Decreased bone density in hyperthyroid patients tended to normalize under treatment (Wejda et al, 1995, Jodar et al, 1997). The improvement of BMD was noted even though no other specific anti-osteoporotic measures were introduced. The type of treatment of hyperthyroidism, iodine 131 or anti-thyroid drugs was not shown to alter the fracture risk (Vestergaard et al, 2005).

Thyroid Disorders and Bone Mineral Homeostasis 261

osteoporosis, but there is no evidence to support this theory, and studies have shown no

Previously, the effects of thyroid hormone treatment upon lumbar spine BMD were studied in a consecutive series of patients with myxedema. Patients with myxoedema did not differ from normal individuals as regards initial lumbar BMD, but levothyroxine-treatment caused a significant reduction in this variable. The median decrease in lumbar BMC after 1 year was 8.9% (95% confidence limits 1.5-15.4%, P less than 0.05). This loss of bone might be attributed to an inappropriate increase in bone turnover in the euthyroid status (Krolner et al, 1983). Accelerated bone turnover was shown to occur in women with subclinical hypothyroidism during replacement L-T4 treatment and normal TSH levels (Meier et al, 2004; Tarraga Lopez et al, 2011). In these women, bone loss was attributed to an adaptive mechanism on decreased bone turnover in pre-existent hypothyroidism. Finally, a long-term L-T4 treatment in children and adolescents with congenital hypothyroidism, diffuse goiter or with chronic lymphocytic thyroiditis did not affect BMD nor had a negative effect on the attainment of peak bone mass (Kooh et al, 1996; Saggese et al, 1996; Tumer et al, 1999). These results suggest that careful regulation of thyroid replacement is critical. Significant effects of prolonged L-T4-replacement therapy on bone tissue in patients with congenital hypothyroidism can be avoided by careful monitoring of serum TSH and adjustment of

Treatment with thyroid hormones with the objective to suppress TSH levels is used for example after surgery and radioiodine in differentiated thyroid carcinomas. The patients are maintained in subclinical hyperthyroidism, a condition associated with increased bone

Previous studies indicated that adults receiving high doses of L-T4-replacement therapy may be at risk of excessive bone loss. Reduction in BMD was observed after exogenous administration of high L-T4 doses used to fully suppress TSH in cases of thyroid cancer, goiters or nodules. Further, a review of cross-sectional and prospective studies examining the effect of thyroid hormone suppression on skeletal integrity in adults showed neither significant negative effect nor a decrease in BMD (Greenspan et al, 1990). Conflicting results were reported also in children. A significant reduction in peripheral BMD was found in children and adolescents receiving suppressive doses of L-T4 treatment for endemic goiter,

More recently, suppression of TSH in hyperthyroidism or after thyroid hormone treatment has been shown to result in decrease in BMD and increase in fracture risk in postmenopausal women (Vestergaard et al, 2000; Bauer et al, 2001; Jamal et al, 2005; Kim et al, 2006). Similar results have been demonstrated in premenopausal women and men by Karner et al (2005). Recently realized systematic reviews analyzing effects of subclinical hyperthyroidism showed that postmenopausal women with subclinical hyperthyroidism may present an increased risk, whereas no increased risk has been demonstrated in men and

difference in bone density or fracture risk in patients undergoing treatment.

doses of L-T4 (Salerno et al, 2004).

turnover.

**5.2. Thyroid hormone suppressive therapy** 

Hashimoto's thyroiditis or thyroid cancer (Radetti et al, 1993).
