Changes in Parameters of Bone and Mineral Metabolism during Therapy for Hyperthyroidism

Abstract

Hyperthyroid patients have high bone turnover and negative calcium and phosphorus balance often associated with mild osteopenia. Early during antithyroid treatment bone turnover decreases, the mineral balance is converted to positive, and sometimes hypocalcemia occurs. The aim of this investigation was to study the mechanisms of the changes in some parameters of bone and mineral metabolism after treatment of thyrotoxicosis. Thirteen newly diagnosed patients with Graves’ disease (seven postmenopausal women, four premenopausal women, and two men) were studied longitudinally, every 6 weeks, for 1 yr after commencing antithyroid treatment with methimazole. Mean serum calcium and phosphorus were both slightly above the normal mean at week 0 and decreased significantly (by 10% and 24%, respectively) during treatment. Fasting urinary calcium was 236 ± 4 (mean ± sem) mg/g creatinine, and the fractional excretion of Ca was 2.0 ± 0.33% before treatment; both fell significantly to minimums of 61 ± 20 mg/g and 0.6 ± 0.16%, respectively. Urinary phosphorus was 282 ± 60 mg/g creatinine, and the fractional excretion of phosphorus was 3.3 ± 0.6% before treatment; both increased significantly to 452 ± 40 mg/g and 8.4 ± 1.0%, respectively, during treatment. The z-scores were calculated from the mean and sd of the respective control groups. The z-score of urinary N-telopeptides of type I collagen (U.NTx) was 9.3 ± 1.3 at week 0 and declined exponentially, but failed to normalize after 1 yr of antithyroid treatment. The serum alkaline phosphatase (ALP) z-score was initially 2.2 ± 0.2, increased to 6.0 ± 1.0 at week 6, and declined slowly there after to 1.0 ± 1.1 at week 54. The serum osteocalcin (OC) z-score showed a temporal pattern similar to that of ALP. It was initially 2.2 ± 0.2, increased to 4.0 ± 0.6 at week 6, and later declined slowly to 0.7 ± 0.5 at week 54. The failure of the markers of bone turnover to normalize after 1 yr of therapy indicates an on-going high rate of bone turnover despite the attained euthyroidism. The uncoupling index (UI = z-score of U.NTx minus z-score of OC) was 7.1 ± 1.2 before treatment, indicating unbalanced bone turnover in favor of bone resorption, and fell close to zero at week 30 of treatment. Pretreatment plasma PTH was suppressed slightly to 2.17 ± 0.47 pmol/L and rose significantly during treatment, reaching a plateau of 5.27 ± 0.78 at week 12. In all postmenopausal women PTH increased above the upper limit of normal (6.84 pmol/L). Pretreatment serum 25-hydroxyvitamin D was normal and remained unchanged during treatment, whereas 1,25-dihydroxyvitamin D was initially subnormal and rose to normal level after treatment. There was a significant positive linear correlation between PTH and U.NTx after week 12. PTH was also significantly correlated with ALP, but not with OC. ALP and OC were significantly correlated. A significant positive correlation was found between T3 and U.NTx, and a negative correlation was found between T3 and each of the formation markers (ALP and OC) over the 0- to 12-week interval. The latter correlations and the very high pretreatment UI indicate some inhibitory effect of the high thyroid hormone levels on the osteoblasts. The marked and sustained elevation of PTH, more pronounced in the postmenopausal women, during the first year of treatment of hyperthyroidism seems to play a pivotal role in maintaining a relatively high rate of bone turnover despite euthyroidism, and in the conservation of calcium by reducing renal calcium excretion and increasing calcium absorption (via 1,25-dihydroxyvitamin D). It may also account in part for the additional rise of the bone formation markers by an anabolic effect on the osteoblasts. Endogenous PTH may be important in the restoration of bone mineral density of treated hyperthyroid patients.