help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-1772
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Grey, A.
Right arrow Articles by Reid, I. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Grey, A.
Right arrow Articles by Reid, I. R.
Related Collections
Right arrow Calcium and Bone Metabolism
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 4 2122-2126
Copyright © 2005 by The Endocrine Society

BRIEF REPORT

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

Andrew Grey, Jenny Lucas, Anne Horne, Greg Gamble, James S. Davidson and Ian R. Reid

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

Address all correspondence and requests for reprints to: Associate Professor Andrew Grey, Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: a.grey{at}auckland.ac.nz; or James S. Davidson, Department of Chemical Pathology, Labplus, Auckland City Hospital, Private Bag 92-024, Auckland, New Zealand.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
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 µg/liter (50 nmol/liter)].

In response to vitamin D repletion to a serum 25(OH)D level greater than 20 µg/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 months (P < 0.01). There was an inverse relationship between the change in serum 25(OH)D and that in intact PTH (r = –0.43, P = 0.056). At 12 months, total serum alkaline phosphatase was significantly lower, and urine N-telopeptides tended to be lower than baseline values (P = 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.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
PRIMARY 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, 3, 4, 5, 6, 7, 8, 9).

Vitamin D deficiency [serum 25 hydroxyvitamin D [25(OH)D] < 20 µg/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 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, 17, 18, 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, 21, 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 µg/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 group, two patients experienced an increase in urinary calcium excretion.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Twenty-five hypercalcemic patients (23 women, two men) referred to the Endocrinology Department at Auckland City Hospital were found to have PHPT and coexistent vitamin D insufficiency [25(OH)D < 20 µg/liter (50 nmol/liter)]. All patients had serum calcium less than 12 mg/dl (3 mmol/liter) and were considered by their attending physician to be suitable for conservative (nonoperative) management. Four of the female patients were taking antiresorptive agents before commencing vitamin D replacement (three estrogen, one estrogen and etidronate). No alteration was made to these treatments during the 12 months of observation.

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., Seattle, WA).

Bone densities of the lumbar spine (L1–L4) and femoral neck were measured in 13 and 12 patients, respectively, at baseline and after 12 months of vitamin D therapy, using a DPX-L densitometer (Lunar, Madison, WI).

Statistical analysis

All analyses were performed using the procedures of SAS (version 9.1; SAS Institute, Cary, NC). The Student’s t test for paired samples was used to test whether biochemical or bone density variables changed over 6 and 12 months. These comparisons were prespecified, so a difference was considered statistically significant if P < 0.05 for a two-tailed test. Confirmatory analyses using a standard mixed-models approach to repeated measures produced the same conclusions. Relationships between biochemical variables, and their changes over time, were assessed using Pearson’s correlation coefficient.

The current report represents an audit of an established clinical practice in our unit, for which our institutional ethics committee does not require that written informed consent be obtained. Patients consented to the treatment and investigations described as part of their normal medical care.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Table 1Go shows the baseline demographic and biochemical characteristics of the patients. There was the expected predominance of women, and the biochemical measurements were typical of patients with mild PHPT. All patients had baseline serum calcium less than 12 mg/dl (3 mmol/liter). The mean baseline serum 25(OH)D level was 11 µg/liter (28 nmol/liter, range 3.2–21). Of the 25 subjects who commenced vitamin D replacement, evaluable data were available for 21. Three women discontinued the vitamin D supplement within the first month. Of these, one developed nonspecific arthralgia, one felt generally unwell, and one did not wish to continue taking a monthly tablet. A fourth patient underwent parathyroid surgery at her request after 3 months of vitamin D repletion. During that time, her serum 25(OH)D level increased from 4.4 µg/liter (11 nmol/liter) to 33 µg/liter (83 nmol/liter) and serum calcium declined from 11.4 mg/dl (2.86 mmol/liter) to 10.9 mg/dl (2.73 mmol/liter). Two other women underwent parathyroid surgery during the year of observation; one during an admission for cholecystectomy, the other electively. For each of these patients, biochemical data after 6 months of vitamin D supplementation were available, and they were included in the analysis.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Baseline characteristics of patients with primary hyperparathyroidism

 
After initiation of cholecalciferol therapy, the serum 25(OH)D increased such that the level in each individual patient exceeded 20 µg/liter (50 nmol/liter) (Fig. 1Go). The mean (range) increment in serum 25(OH)D at 6 months was 19 (6–37) µg/liter [47 (16–92) nmol/liter]; the mean (± SD) levels of serum 25(OH)D at 6 and 12 months after commencing vitamin D replacement were 30 ± 7 µg/liter (76 ± 17 nmol/liter) and 31 ± 6 µg/liter (77 ± 14 nmol/liter), respectively (P = ns for comparison of 6- and 12-month values). Thus, there was no evidence of a progressive increase in serum 25(OH)D levels over time. Levels of 1,25(OH)2D did not change significantly after either 6 months [change from baseline, 12 ± 33 pg/ml (30 ± 83 pmol/liter), P = 0.28, n = 10] or 12 months [change from baseline, 24 ± 32 pg/ml (60 ± 81 pmol/liter), P = 0.13, n = 6] of vitamin D repletion.



View larger version (36K):
[in this window]
[in a new window]
  		FIG. 1. Levels of serum 25(OH)D in patients with PHPT and vitamin D insufficiency treated with cholecalciferol for 1 yr. Values for individual patients are connected by the solid lines. The dotted line represents the level of serum 25(OH)D above which the World Health Organization defines vitamin D sufficiency. To convert serum 25(OH)D values to nanomoles per liter, multiply by 2.5.

 
Serum calcium did not change after vitamin D repletion (Fig. 2AGo). The mean changes in serum calcium after 6 and 12 months of vitamin D repletion were 0.005 ± 0.03 mg/dl (0.02 ± 0.12 mmol/liter) (P = 0.51) and –0.008 ± 0.02 mg/dl (–0.03 ± 0.09 mmol/liter) (P = 0.12), respectively. No patient experienced a rise in serum calcium to greater than 12 mg/dl (3 mmol/liter). Ionized calcium did not change over 12 months of vitamin D repletion [change from baseline, 0.04 ± 0.36 mg/dl (0.01 ± 0.09 mmol/liter), n = 11, P = 0.61]. In one patient, the serum calcium ostensibly rose by 1.4 mg/dl (0.35 mmol/liter), from 10.5 to 11.9 mg/dl (2.62 to 2.97 mmol/liter) between the baseline and 6-month assessments (Fig. 2AGo). She did not develop symptoms of hypercalcemia, and a review of her monthly serum calcium data revealed that the level of 11.9 mg/dl (2.97 mmol/liter) was clearly an outlying value [mean (range) of four other measurements 10.9 (10.6–11.4) mg/dl [2.72 (2.64–2.84) mmol/liter]. She underwent elective parathyroid surgery 7 months after commencing vitamin D replacement during an admission to the hospital for cholecystectomy.



View larger version (14K):
[in this window]
[in a new window]
  		FIG. 2. Serum calcium (A) and PTH (B) values in patients with PHPT and vitamin D insufficiency treated with cholecalciferol for 1 yr. Each data point represents the change from baseline value in an individual patient at the indicated time point. The horizontal bars represent group mean ± SD. **, P < 0.01 vs. baseline. To convert serum calcium values to millimoles per liter, divide by 4. To convert PTH values to picomoles per liter, divide by 11.1

 
Levels of intact PTH declined by 25% during vitamin D repletion (Fig. 2BGo). The average change in PTH was similar in magnitude at 6 and 12 months [change at 6 months, –33 ± 49 pg/ml (–3.0 ± 4.4 pmol/liter), P = 0.007; change at 12 months, –36 ± 44 pg/ml (–3.2 ± 4.0 pmol/liter), P = 0.004] (Fig. 2BGo). The change in the serum 25(OH)D level was inversely correlated with the change in the level of PTH at 6 months (r = –0.43, P = 0.056), consistent with a causal relationship between the two variables. There was no correlation between change in serum 1,25(OH)2D and change in PTH after 6 months of vitamin D repletion (r = –0.02, P = 0.96).

The decline in PTH levels was accompanied by a significant fall in total ALP (Fig. 3Go). One patient with a serum {gamma}-glutamyltransferase greater than 100 U/liter was excluded from this analysis. Total ALP fell by 13.6 ± 28 U/liter from baseline to 6 months (n = 14, P = 0.10) and 18.9 ± 26 U/liter from baseline to 12 months (n = 14, P = 0.02). Urine N-telopeptide excretion tended to decline at 12 months (change from baseline values, –14.5 ± 33 nmol bone collagen equivalent per millimole creatinine, n = 14, P = 0.13).



View larger version (14K):
[in this window]
[in a new window]
  		FIG. 3. Plot of changes in total ALP (dark bars) and urine N-telopeptides of type 1 collagen (open bars) in patients with PHPT and vitamin D insufficiency treated with cholecalciferol for 1 yr. *, P < 0.05 vs. baseline. BCE, Bone collagen equivalent; creat, creatinine.

 
Overall, 24-h urinary excretion of calcium did not change during the 12-month observation period. There was a small, nonsignificant increase observed at 6 months [60 ± 112 mg/d (1.5 ± 2.8 mmol/d); P = 0.08], but by 12 months the mean urine calcium excretion was comparable with that at baseline [change from baseline, –0.4 ± 116 mg/d (–0.01 ± 2.9 mmol/d), P = 0.99]. In three patients the 24-h urinary calcium excretion rose to exceed 400 mg/d (10 mmol/d) after 6 months of vitamin D replacement. In one of these, urinary calcium excretion fell subsequently, such that the 12-month value was below that recorded at baseline. No patient developed symptomatic urolithiasis during the observation period.

There was no change in bone mineral density at either the lumbar spine (change from baseline, 0.00 ± 0.05 g/cm2, P = 0.98, n = 13) or femoral neck (change from baseline, 0.01 ± 0.07 g/cm2, P = 0.71, n = 12) after 12 months of vitamin D repletion.

Reanalysis of the data set after excluding the patients who were receiving antiresorptive therapy or the male patients did not alter the results.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our findings suggest that vitamin D repletion in patients with mild PHPT does not promote an increase in serum calcium and may modestly decrease levels of PTH and bone turnover. There may be a small early (<6 month) increase in urinary calcium excretion, the clinical significance of which is uncertain. These data are consistent with the suggestion from epidemiological studies that hypovitaminosis D in PHPT is associated with a more severe biochemical phenotype (17, 18, 24) and suggest that maintenance of vitamin D sufficiency may restrain the progression of PHPT.

Vitamin D insufficiency [serum 25(OH)D < 20 µg/liter (50 nmol/liter)] is a common finding in eucalcemic populations (10). Vitamin D deficiency may be more common in patients with PHPT than in eucalcemic patients because of accelerated catabolism of 25(OH)D induced by the elevated levels of 1,25(OH)2D that are characteristic of the disorder (12, 13, 25). Silverberg et al. (18) reported that 53% of a cohort of patients with PHPT manifested vitamin D insufficiency, and Carnevale et al. (26) found serum 25(OH) levels less than 12 µg/liter (30 nmol/liter) in 27% of their cohort. Some authorities advocate surgical intervention for patients with PHPT and hypovitaminosis D (18, 23), and others caution against vitamin D supplementation (27) because of concerns that repletion of vitamin D might exacerbate hypercalcemia and hypercalciuria, but there are virtually no published data that address the biochemical effects of vitamin D repletion in PHPT. Kantorovich et al. (22) described three patients with PHPT and vitamin D insufficiency, in two of whom PTH fell, and serum calcium remained stable, after vitamin D repletion. Our data provide evidence that vitamin D repletion in patients with PHPT may be reasonable and safe and argue against the need to refer patients with PHPT and vitamin D insufficiency for parathyroid surgery in the absence of other indications.

The mechanism by which vitamin D repletion leads to a decline in PTH levels in PHPT is unclear. Our finding that the magnitude of the increment in 25(OH)D level was correlated with the degree of decline in PTH is suggestive of a vitamin D-dependent mechanism. An attractive hypothesis is that, in the presence of a PTH-induced increase in 1{alpha}-hydroxylase activity (28), vitamin D repletion in PHPT might lead to increased levels of circulating 1,25(OH)2D, which is a known inhibitor of PTH gene transcription, PTH protein production and parathyroid gland proliferation (29, 30). The limited data available from our study do not support this notion because there was no association between change in 1,25(OH)2D and change in PTH. Furthermore, administration of active vitamin D metabolites to patients with PHPT does not decrease PTH levels (31), and levels of 1,25(OH)2D are not related to those of 25(OH)D in cross-sectional studies of PHPT (16, 18). It is possible, however, that parathyroid-derived 1,25(OH)2D (32, 33) might act in an intracrine fashion to reduce PTH levels, independent of the circulating 1,25(OH)2D level. Alternative explanations include non-1,25(OH)2D-mediated effects of 25(OH)D or other vitamin D metabolites on PTH production or stimulation by vitamin D repletion of expression in parathyroid tissue of the vitamin D receptor, diminution of which in parathyroid adenomas (34, 35) may promote tumor growth and greater PTH production.

The reductions we observed in markers of bone turnover presumably reflect the lowering of PTH levels. Although the reduction in the bone resorption marker urine N-telopeptide was not statistically significant, this is likely the result of the small sample size and the large biological variation in the measurement of this variable. Our findings are consistent with those of a cross-sectional study that reported inverse associations between serum 25(OH)D and both PTH and ALP in 124 patients with PHPT (18). Chronic PTH excess stimulates bone turnover and promotes bone loss, at least at skeletal sites enriched for cortical bone (36, 37); conversely, surgical correction of PHPT decreases markers of bone turnover and increases bone mineral density (37, 38). Limited observational data suggest that hypovitaminosis D and the degree of PTH elevation are independently associated with fracture risk in PHPT (19). Thus, the reduction in PTH levels and bone turnover that accompany vitamin D repletion in patients with PHPT might be predicted to lead to increased BMD and reduced fracture risk. That our data did not demonstrate any effect of vitamin D repletion on bone mineral density might reflect the short follow-up and/or the small sample size.

The significance of the increase in urinary calcium excretion that we observed in two of our patients after vitamin D repletion is uncertain. Although relative hypercalciuria is a feature of PHPT and urolithiasis occurs in 10–20% of patients with PHPT (39), urinary calcium excretion is a poor predictor of stone formation, such that regular monitoring of urinary calcium excretion is no longer recommended in patients with PHPT (40). A previous episode of urolithiasis is the most powerful predictor of subsequent stone formation in PHPT, and long-term follow-up of patients who have not had renal tract stones suggests that the risk of a first event is low (9). Nonetheless, until more safety data are available, it is important to monitor urine calcium excretion in patients with PHPT after vitamin D repletion.

In summary, the current data provide preliminary evidence that judicious replacement of vitamin D, to a serum value of 25(OH)D above the level regarded by the World Health Organization as sufficient for skeletal health in eucalcemic individuals, may be safe in patients with PHPT and coexistent vitamin D insufficiency. The observation that vitamin D repletion reduces levels of PTH and bone turnover in PHPT suggests that maintenance of vitamin D sufficiency in patients with PHPT may restrain disease progression and severity. Larger studies of vitamin D repletion in PHPT, with longer follow-up, are both justified and necessary to assess the safety and efficacy of this treatment.


   Footnotes
 
This work was supported by the Health Research Council of New Zealand.

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.

Received September 7, 2004.

Accepted January 5, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Adami S, Marcocci C, Gatti D 2002 Epidemiology of primary hyperparathyroidism in Europe. J Bone Miner Res 17:N18–N23
  2. Rubinoff H, McCarthy N, Hiatt RA 1983 Hypercalcemia: long-term follow-up with matched controls. J Chronic Dis 36:859–868[CrossRef][Medline]
  3. Posen S, Clifton-Bligh P, Reeve TS, Wagstaffe C, Wilkinson M 1985 Is parathyroidectomy of benefit in primary hyperparathyroidism? Q J Med 54:241–251
  4. Rao DS, Wilson RJ, Kleerekoper M, Parfitt AM 1988 Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: evidence for biphasic disease course. J Clin Endocrinol Metab 67:1294–1298[Abstract/Free Full Text]
  5. Sampson MJ, van’t Hoff W, Bicknell EJ 1987 The conservative management of primary hyperparathyroidism. Q J Med 65:1009–1014[Medline]
  6. Wermers RA, Khosla S, Atkinson EJ, Hodgson SF, O’Fallon WM, Melton 3rd LJ 1997 The rise and fall of primary hyperparathyroidism: a population-based study in Rochester, Minnesota, 1965–1992. Ann Intern Med 126:433–440[Abstract/Free Full Text]
  7. Davies M, Fraser WD, Hosking DJ 2002 The management of primary hyperparathyroidism. Clin Endocrinol (Oxf) 57:145–155[CrossRef][Medline]
  8. Miedlich S, Krohn K, Paschke R 2003 Update on genetic and clinical aspects of primary hyperparathyroidism. Clin Endocrinol (Oxf) 59:539–554[CrossRef][Medline]
  9. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP 1999 A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med [Erratum (2000) 342:144] 341:1249–1255
  10. Lips P, Duong T, Oleksik A, Black D, Cummings S, Cox D, Nickelsen T 2001 A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab 86:1212–1221[Abstract/Free Full Text]
  11. Holick MF 2001 Sunlight "D"ilemma: risk of skin cancer or bone disease and muscle weakness. Lancet 357:4–6[CrossRef][Medline]
  12. Clements MR, Davies M, Hayes ME, Hickey CD, Lumb GA, Mawer EB, Adams PH 1992 The role of 1,25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency. Clin Endocrinol (Oxf) 37:17–27[Medline]
  13. Clements MR, Davies M, Fraser DR, Lumb GA, Mawer EB, Adams PH 1987 Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism. Clin Sci 73:659–664[Medline]
  14. Chapuy MC, Arlot ME, Delmas PD, Meunier PJ 1994 Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. BMJ 308:1081–1082[Free Full Text]
  15. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY, Wong JB 2004 Effect of vitamin D on falls: a meta-analysis. JAMA 291:1999–2006[Abstract/Free Full Text]
  16. Rao DS, Honasoge M, Divine GW, Phillips ER, Lee MW, Ansari MR, Talpos GB, Parfitt AM 2000 Effect of vitamin D nutrition on parathyroid adenoma weight: pathogenetic and clinical implications. J Clin Endocrinol Metab 85:1054–1058[Abstract/Free Full Text]
  17. Rao DS, Agarwal G, Talpos GB, Phillips ER, Bandeira F, Mishra SK, Mithal A 2002 Role of vitamin D and calcium nutrition in disease expression and parathyroid tumor growth in primary hyperparathyroidism: a global perspective. J Bone Miner Res 17:N75–N80
  18. Silverberg SJ, Shane E, Dempster DW, Bilezikian JP 1999 The effects of vitamin D insufficiency in patients with primary hyperparathyroidism. Am J Med 107:561–567[CrossRef][Medline]
  19. Nordenstrom E, Westerdahl J, Lindergard B, Lindblom P, Bergenfelz A 2002 Multifactorial risk profile for bone fractures in primary hyperparathyroidism. World J Surg 26:1463–1467[CrossRef][Medline]
  20. Lumb GA, Stanbury SW 1974 Parathyroid function in human vitamin D deficiency and vitamin D deficiency in primary hyperparathyroidism. Am J Med 56:833–839[CrossRef][Medline]
  21. Woodhouse NJ, Tun Chot S, Bordier P, Sigurdsson G, Joplin GF 1973 Vitamin D administration in primary hyperparathyroidism. Clin Sci 44:3P (passim)
  22. Kantorovich V, Gacad MA, Seeger LL, Adams JS 2000 Bone mineral density increases with vitamin D repletion in patients with coexistent vitamin D insufficiency and primary hyperparathyroidism. J Clin Endocrinol Metab 85:3541–3543[Abstract/Free Full Text]
  23. Bilezikian JP 2000 Primary hyperparathyroidism. When to observe and when to operate. Endocrinol Metab Clin North Am 29:465–478[CrossRef][Medline]
  24. Bandeira F, Caldas G, Freese E, Griz L, Faria M, Bandeira C 2002 Relationship between serum vitamin D status and clinical manifestations of primary hyperparathyroidism. Endocr Pract 8:266–270[Medline]
  25. Davies M, Heys SE, Selby PL, Berry JL, Mawer EB 1997 Increased catabolism of 25-hydroxyvitamin D in patients with partial gastrectomy and elevated 1,25-dihydroxyvitamin D levels. Implications for metabolic bone disease. J Clin Endocrinol Metab 82:209–212[Abstract/Free Full Text]
  26. Carnevale V, Manfredi G, Romagnoli E, De Geronimo S, Paglia F, Pepe J, Scillitani A, D’Erasmo E, Minisola S 2004 Vitamin D status in female patients with primary hyperparathyroidism: does it play a role in skeletal damage? Clin Endocrinol (Oxf) 0:81–86
  27. al Zahrani A, Levine MA 1997 Primary hyperparathyroidism. Lancet 349:1233–1238[CrossRef][Medline]
  28. Feldman D 1999 Vitamin D, parathyroid hormone, and calcium: a complex regulatory network. Am J Med 107:637–639[CrossRef][Medline]
  29. Miura R, Furukawa Y, Yumita S, Sohn HE, Mizunashi K, Yoshinaga K 1987 25-Hydroxyvitamin D3 loading test in primary hyperparathyroidism, hypoparathyroidism and pseudohypoparathyroidism. Endocrinol Jpn 34:97–104[Medline]
  30. Beckerman P, Silver J 1999 Vitamin D and the parathyroid. Am J Med Sci 317:363–369[CrossRef][Medline]
  31. Lind L, Wengle B, Sorensen OH, Wide L, Akerstrom G, Ljunghall S 1989 Treatment with active vitamin D (alphacalcidol) in patients with mild primary hyperparathyroidism. Acta Endocrinol 120:250–256
  32. Correa P, Segersten U, Hellman P, Akerstrom G, Westin G 2002 Increased 25-hydroxyvitamin D3 1{alpha}-hydroxylase and reduced 25-hydroxyvitamin D3 24-hydroxylase expression in parathyroid tumors—new prospects for treatment of hyperparathyroidism with vitamin D. J Clin Endocrinol Metab 87:5826–5829[Abstract]
  33. Segersten U, Correa P, Hewison M, Hellman P, Dralle H, Carling T, Akerstrom G, Westin G 2002 25-Hydroxyvitamin D(3)-1{alpha}-hydroxylase expression in normal and pathological parathyroid glands. J Clin Endocrinol Metab 87:2967–2972[Abstract/Free Full Text]
  34. Carling T, Rastad J, Szabo E, Westin G, Akerstrom G 2000 Reduced parathyroid vitamin D receptor messenger ribonucleic acid levels in primary and secondary hyperparathyroidism. J Clin Endocrinol Metab 85:2000–2003[Abstract/Free Full Text]
  35. Sudhaker Rao D, Han ZH, Phillips ER, Palnitkar S, Parfitt AM 2000 Reduced vitamin D receptor expression in parathyroid adenomas: implications for pathogenesis. Clin Endocrinol (Oxf) 53:373–381[CrossRef][Medline]
  36. Grey AB, Stapleton JP, Evans MC, Reid IR 1996 Accelerated bone loss in post-menopausal women with mild primary hyperparathyroidism. Clin Endocrinol (Oxf) 44:697–702[Medline]
  37. Guo CY, Thomas WE, al-Dehaimi AW, Assiri AM, Eastell R 1996 Longitudinal changes in bone mineral density and bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 81:3487–3491[Abstract]
  38. Silverberg SJ, Gartenberg F, Jacobs TP, Shane E, Siris E, Staron RB, McMahon DJ, Bilezikian JP 1995 Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism. J Clin Endocrinol Metab 80:729–734[Abstract]
  39. Silverberg SJ 2000 Natural history of primary hyperparathyroidism. Endocrinol Metab Clin North Am 29:451–464[CrossRef][Medline]
  40. Bilezikian JP, Potts Jr JT, Fuleihan Gel H, Kleerekoper M, Neer R, Peacock M, Rastad J, Silverberg SJ, Udelsman R, Wells SA 2002 Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab 87:5353–5361[Free Full Text]



This article has been cited by other articles:


Home page
 Eur J EndocrinolHome page
J R Tucci
Vitamin D therapy in patients with primary hyperparathyroidism and hypovitaminosis D
Eur. J. Endocrinol., July 1, 2009; 161(1): 189 - 193.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
R. Eastell, A. Arnold, M. L. Brandi, E. M. Brown, P. D'Amour, D. A. Hanley, D. S. Rao, M. R. Rubin, D. Goltzman, S. J. Silverberg, et al.
Diagnosis of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Third International Workshop
J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 340 - 350.
[Abstract] [Full Text] [PDF]

Home page
 Postgrad. Med. J.Home page
P Iglesias and J J Diez
Current treatments in the management of patients with primary hyperparathyroidism
Postgrad. Med. J., January 1, 2009; 85(999): 15 - 23.
[Abstract] [Full Text] [PDF]

Home page
 JAMAHome page
N. Farag, T. Delbanco, and G. J. Strewler
Update: A 64-Year-Old Woman With Primary Hyperparathyroidism
JAMA, November 5, 2008; 300(17): 2044 - 2045.
[Full Text] [PDF]

Home page
 NEJMHome page
M. F. Holick
Vitamin D Deficiency
N. Engl. J. Med., July 19, 2007; 357(3): 266 - 281.
[Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
K. Zajickova, J. Vrbikova, L. Canaff, P. D. Pawelek, D. Goltzman, and G. N. Hendy
Identification and Functional Characterization of a Novel Mutation in the Calcium-Sensing Receptor Gene in Familial Hypocalciuric Hypercalcemia: Modulation of Clinical Severity by Vitamin D Status
J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2616 - 2623.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
B Moosgaard, P Vestergaard, L Heickendorff, F Melsen, P Christiansen, and L Mosekilde
Plasma 25-hydroxyvitamin D and not 1,25-dihydroxyvitamin D is associated with parathyroid adenoma secretion in primary hyperparathyroidism: a cross-sectional study.
Eur. J. Endocrinol., August 1, 2006; 155(2): 237 - 244.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
R. Vieth
Critique of the Considerations for Establishing the Tolerable Upper Intake Level for Vitamin D: Critical Need for Revision Upwards
J. Nutr., April 1, 2006; 136(4): 1117 - 1122.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
Y. Kinoshita, M. Taguchi, A. Takeshita, D. Miura, S. Tomikawa, and Y. Takeuchi
1,25-Dihydroxyvitamin D Suppresses Circulating Levels of Parathyroid Hormone in a Patient with Primary Hyperparathyroidism and Coexistent Sarcoidosis
J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6727 - 6731.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Grey, A.
Right arrow Articles by Reid, I. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Grey, A.
Right arrow Articles by Reid, I. R.
Related Collections
Right arrow Calcium and Bone Metabolism

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals