Vitamin D Repletion in Patients with Primary Hyperparathyroidism and Coexistent Vitamin D Insufficiency

0021-972X/05/$15.00/0 Printed in U.S.A. The Journal of Clinical Endocrinology & Metabolism 90(4):2122–2126 Copyright © 2005 by The Endocrine Society doi: 10.1210/jc.2004-1772 BRIEF REPORT Vitamin D Repletion in Patients with Primary Hyperparathyroidism and Coexistent Vitamin D Insufficiency Department of Medicine (A.G., J.L., A.H., G.G., I.R.R.), University of Auckland, 92019 Auckland, New Zealand; and Department of Chemical Pathology (J.S.D.), Labplus, Auckland City Hospital, Auckland, New Zealand Vitamin D insufficiency is common in patients with primary hyperparathyroidism (PHPT) and may be associated with more severe and progressive disease. Uncertainty exists, however, as to whether repletion of vitamin D should be undertaken in patients with PHPT. Here we report the effects of vitamin D repletion on biochemical outcomes over 1 yr in a group of 21 patients with mild PHPT [serum calcium <12 mg/dl (3 mmol/liter)] and coexistent vitamin D insufficiency [serum 25 hydroxyvitamin D [25(OH)D] <20 ␮g/liter (50 nmol/liter)]. In response to vitamin D repletion to a serum 25(OH)D level greater than 20 ␮g/liter (50 nmol/liter), mean levels of serum calcium and phosphate did not change, and serum calcium did not exceed 12 mg/dl (3 mmol/liter) in any patient. Levels of intact PTH fell by 24% at 6 months (P < 0.01) and 26% at 12 P RIMARY HYPERPARATHYROIDISM (PHPT) is a common endocrine condition, particularly in postmenopausal women (1). Frequently PHPT is asymptomatic, and there is uncertainty as to the optimal management of this form of the disease. A considerable body of evidence, however, suggests a low incidence of disease progression and/or disease complications in patients managed by observation alone (2–9). Vitamin D deficiency [serum 25 hydroxyvitamin D [25(OH)D] ⬍ 20 ␮g/liter (50 nmol/liter)] is increasingly common worldwide, principally as a consequence of sunlight deprivation consequent on both increased public awareness of the risk of skin malignancies associated with exposure to UV radiation and increasing numbers of frail elderly people (10, 11). Patients with PHPT may be at higher risk than eucalcemic individuals of vitamin D deficiency because of accelerated catabolism of 25(OH)D induced by the increased levels of 1,25 dihydroxyvitamin D3 [1,25(OH)2D] that are characteristic of the disorder (12, 13). In eucalcemic subjects, treatment of vitamin D deficiency is recommended to correct First Published Online January 11, 2005 Abbreviations: ALP, Alkaline phosphatase; 1,25(OH)2D, 1,25 dihydroxyvitamin D3; 25(OH)D, 25 hydroxyvitamin D; PHPT, primary hyperparathyroidism. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community. months (P < 0.01). There was an inverse relationship between the change in serum 25(OH)D and that in intact PTH (r ⴝ ⴚ0.43, P ⴝ 0.056). At 12 months, total serum alkaline phosphatase was significantly lower, and urine N-telopeptides tended to be lower than baseline values (P ⴝ 0.02 and 0.13, respectively). In two patients, 24-h urinary calcium excretion rose to exceed 400 mg/d, but the group mean 24-h urinary calcium excretion did not change. These preliminary data suggest that vitamin D repletion in patients with PHPT does not exacerbate hypercalcemia and may decrease levels of PTH and bone turnover. Some patients with PHPT may experience an increase in urinary calcium excretion after vitamin D repletion. (J Clin Endocrinol Metab 90: 2122–2126, 2005) secondary hyperparathyroidism, normalize bone turnover, and reduce the risks of fractures and falls (14, 15). Epidemiological studies suggest that vitamin D-deficient patients with PHPT have higher levels of PTH and markers of bone turnover, larger parathyroid adenomas, and more frequent fractures than vitamin D-replete patients (16 –19). These studies suggest that vitamin D deficiency may exacerbate the biochemical phenotype of PHPT by promoting more marked parathyroid cell proliferation and imply that maintenance or restoration of vitamin D sufficiency might prevent or reverse this phenomenon. However, only very limited published data are available that address the effects of correction of vitamin D deficiency in PHPT (20 –22), in part because of concerns that such therapy might exacerbate the hypercalcemia and/or hypercalciuria that are features of PHPT (18, 23). In our unit, it has been standard practice to maintain vitamin D sufficiency in patients with PHPT. In this paper, we report the results of a prospective audit of the effects of vitamin D repletion [to a serum level of 25(OH)D ⬎ 20 ␮g/liter (50 nmol/liter)] on biochemical indices of calcium metabolism in a cohort of patients with mild PHPT and vitamin D insufficiency. Our results suggest that repletion of vitamin D in patients with PHPT modestly reduces levels of PTH and markers of bone turnover, without exacerbating hypercalcemia. Although the mean level of urinary calcium excretion did not change within the 2122 Andrew Grey, Jenny Lucas, Anne Horne, Greg Gamble, James S. Davidson, and Ian R. Reid Grey et al. • Vitamin D Repletion in Primary Hyperparathyroidism group, two patients experienced an increase in urinary calcium excretion. Patients and Methods Patients Vitamin D replacement Vitamin D repletion was undertaken using cholecalciferol 1.25 mg (50,000 IU) tablets (PSM Healthcare, Auckland, New Zealand). Patients were prescribed one tablet per week for 1 month and thereafter one tablet per month for 12 months. Calcium supplements were not prescribed. Measurements All measurements were performed on samples collected after overnight fasting. Serum calcium was measured 1 wk after the initial dose of cholecalciferol and monthly thereafter for the duration of the observation period. Serum 25(OH)D was measured monthly. Intact PTH, total alkaline phosphatase (ALP), urinary excretion of N-telopeptides, and 24-h urinary calcium excretion were measured at baseline and after 6 and 12 months of vitamin D supplementation. Serum 1,25(OH)2D was measured at baseline and after 6 months of vitamin D supplementation in 10 patients. Total serum calcium, phosphate, albumin, and creatinine were measured using a modular autoanalyzer (Roche, Stockholm, Sweden). An albumin-adjusted serum calcium was calculated using the formula sCaadj ⫽ total sCa ⫺ 0.02 (sAlbumin [grams per liter] ⫺ 40). Serum 25(OH)D was measured by a competitive RIA (Diasorin, Stillwater, MN); serum 1,25(OH)2D by RIA (IDS, Boldon, UK); intact PTH by either an electrochemiluminescence immunoassay [E170, Roche, normal range 19 – 81 pg/ml (1.7–7.3 pmol/liter)] or a two-site immunoradiometric assay [Nichols Institute Diagnostics, San Clemente, CA; normal range 11–55 pg/ml (1–5 pmol/liter)]. In each subject, all the PTH measurements were performed using the same assay. Urine N-telopeptides of type 1 collagen were measured by an enzyme-linked immunoassay (Ostex International Inc., Seattl (...truncated)