THE 20TH CENTURY witnessed major advances in several

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1 JOURNAL OF BONE AND MINERAL RESEARCH Volume 22, Supplement 2, 2007 doi: /JBMR.07S American Society for Bone and Mineral Research Vitamin D Deficiency and Primary Hyperparathyroidism Shonni J Silverberg ABSTRACT: Temporally associated with the improvement in vitamin D nutrition in many Western countries in the mid-20th century, there was a change in many characteristics of primary hyperparathyroidism. Osteitis fibrosa cystica became a rare manifestation of what is now frequently an asymptomatic disease. At the same time, in patients with the disease, levels of PTH and parathyroid adenoma weights have fallen dramatically. In view of these observations and others, an association between vitamin D deficiency and severity of primary hyperparathyroidism has been proposed. Data support an association on two distinct levels. First, regardless of the clinical severity of primary hyperparathyroidism, the disease seems to be more severe in those with concomitant vitamin D deficiency. Second, vitamin D deficiency and insufficiency seem to be more prevalent in patients with primary hyperparathyroidism than in geographically matched populations. The association between vitamin D deficiency and primary hyperparathyroidism has clear implications. Co-existing vitamin D deficiency may cause the serum calcium level to fall into the normal range, which can lead to diagnostic uncertainty. With regard to management, preliminary data on vitamin D repletion in patients with mild primary hyperparathyroidism suggest that, in some cases, correction of vitamin D deficiency may be accomplished without worsening the underlying hypercalcemia. Vitamin D deficient patients undergoing parathyroidectomy are also at increased risk of postoperative hypocalcemia and hungry bone syndrome, which underscores the importance of preoperative assessment of vitamin D status in all patients with primary hyperparathyroidism. J Bone Miner Res 2007;22:S2;V100 V104. doi: /JBMR.07S202 Key Words: primary hyperparathyroidism, vitamin D deficiency, parathyroidectomy INTRODUCTION THE 20TH CENTURY witnessed major advances in several areas affecting skeletal metabolism. In the 1930s, the fortification of milk led to improved vitamin D nutrition in the United States and some Western European countries. This, in turn, led to a marked reduction in the incidence of rickets. Several decades later, with the introduction of the multichannel autoanalyzer, a new clinical phenotype of primary hyperparathyroidism was recognized. (1 3) Asymptomatic primary hyperparathyroidism (PHPT) quickly emerged as the most common presentation of this disorder in the United States and some other Western countries. As the clinical profile of PHPT evolved, the hallmark skeletal abnormality of this disorder, osteitis fibrosa cystica, became a rarity in the United States, although this manifestation of classical PHPT is still commonplace in some parts of the world. Symptomatic and severe PHPT persists, in particular, in regions where vitamin D deficiency remains endemic. In view of these observations, and supported by recent epidemiological data from around the world, some have proposed an association between vitamin D deficiency and the severity of PHPT. This review will summarize the data on the association of vitamin D nutrition and PHPT and point to areas where future study is needed. The author states that she has no conflicts of interest. A GLOBAL VIEW: MORE SEVERE DISEASE As the clinical phenotype of primary hyperparathyroidism has altered from a highly symptomatic to a largely asymptomatic disease, levels of PTH in the disease and parathyroid adenoma weights have fallen dramatically. Global geographic differences remain, however, in the biochemical and clinical features of PHPT. Both clinical and laboratory features of PHPT are more severe in those regions where vitamin D deficiency is endemic. (4 10) Rao et al. (4) surveyed data from PHPT patients from varied geographic locales and found an inverse association between the extent of elevation of serum PTH in affected patients and 25-hydroxyvitamin D [25(OH)D] levels (Fig. 1). Data from countries where vitamin D deficiency is widespread (such as India, Turkey, and Saudi Arabia) also suggest an inverse relationship between serum 25(OH)D levels and parathyroid adenoma weight. (4,6,10) However, it is clear that this relationship is more complex than these simple correlations might suggest. Indeed, adenoma weights were far greater in Indian than American patients with similar degrees of vitamin D deficiency, and adenoma weights were similar among in Indian patients with and without vitamin D deficiency. (4,11) Our group had the opportunity to compare two modern cohorts of patients with PHPT, one in New York City and the other in Beijing, China. (7) Although <20% of the Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA. V100

2 VITAMIN D DEFICIENCY AND PRIMARY HYPERPARATHYROIDISM V101 FIG. 1. A global view of the association of PTH and 25(OH)D levels in studies of patients with primary hyperparathyroidism. PTH levels represent elevations above the upper limit of the assay normal range. Countries or cities on the x-axis represent the geographic locations where patients with primary hyperparathyroidism have been studied. To convert serum 25(OH)D values to nanomoles per liter, multiply by 2.5. Adapted from Rao et al. (4) American cohort were symptomatic (all with nephrolithiasis), 94% of Chinese patients had symptoms of PHPT. Fracture and osteitis fibrosa cystica were common. Biochemical evaluation showed several distinguishing features, among them profound vitamin D deficiency. The Chinese patients had marked hypercalcemia (serum calcium, 12.4 versus 10.7 mg/dl), dramatic elevations in PTH (21 versus 1.5 times the upper limit of normal), and severely depressed levels of 25(OH)D (8 versus 21 ng/ml; for conversion to nm, multiply by 2.5). In Brazil, examination of patients with severe PHPT confirmed that those with osteitis fibrosa cystica had significantly lower levels of 25(OH)D and significantly higher levels of PTH than did those without bone disease. (9) In addition to data supporting more severe clinical manifestations of PHPT in patients with vitamin D deficiency, there is accumulating evidence that low levels of vitamin D are more frequent among patients with PHPT than in non- PHPT control subjects. Boudou et al. (12) recently reported on 145 patients who underwent parathyroidectomy in France. In this group, serum 25(OH)D was reported to be low (<20 ng/ml) in 93% of patients compared with geographic norms in the French population, which estimate prevalence of vitamin D insufficiency at 38%. MILD PRIMARY HYPERPARATHYROIDISM FIG. 2. PTH levels differ by tertile of 25(OH)D in 124 patients with mild primary hyperparathyroidism (*ANOVA, p < ). Range of 25(OH)D levels (ng/ml) for each tertile are shown in text boxes within the bars. Adapted from Silverberg et al. (14) In the United States and other Western nations, PHPT today is generally a disorder characterized by mild hypercalcemia and few overt symptoms. However, there are clearly consequences when even mild PHPT exists with concomitant vitamin D insufficiency or deficiency. First, the co-existence of these findings may have diagnostic implications. Insufficient or frankly low vitamin D stores tend to oppose the effect of PHPT to increase serum and urinary calcium levels. This can lead to a reduction of these indices into the normal range, which may in turn lead to diagnostic confusion. Indeed, vitamin D deficiency may well be the most common explanation for the biochemical constellation seen in what may be thought to be normocalcemic PHPT. In fact, it is more appropriate to reserve the term normocalcemic PHPT for those patients who have no cause for secondary hyperparathyroidism. Ironically, some have suggested that the high prevalence of vitamin D insufficiency in such areas as Southern Europe may lead to an underestimation of the prevalence of PHPT, because the dearth of vitamin D causes elevated levels of serum calcium to decline into the normal range. (13) In such patients, PTH levels would not be measured, and the diagnosis of PHPT would not be pursued. As has been reported in more severe PHPT, there are data supporting an increased prevalence of vitamin D insufficiency in patients with disease characterized by mild hypercalcemia as well. In 124 patients with mild PHPT [mean values: serum calcium, 10.7 mg/dl; PTH, 121 pg/ml; 25(OH)D, 21 ng/ml], we found only 7% of patients to have levels of 25(OH)D that were below the assay normal limit (9 52 ng/ml). (14) However, over one half had 25(OH)D levels <20 ng/ml and fully 84% had 25(OH)D levels <30 ng/ml. Furthermore, we found that PTH levels were inversely associated with 25(OH)D concentrations, with those patients with the lowest levels of vitamin D having the most elevated PTH concentrations (Fig. 2). Consistent with the effect of excess PTH in this group, those with lowest vitamin D levels also had highest levels of alkaline phosphatase, lowest BMD at the distal one-third radius site, and highest mineralizing surface (% MS/BS) and extent of osteoid (% OS/ BS) on histomorphometric examination of transiliac crest bone biopsies. We found no association of 25(OH)D levels with the concentration of 1,25-dihydroxyvitamin D, which speaks against a role for enhanced conversion to the active moiety as an explanation for the low levels of 25(OH)D in PHPT. These data were extended by Moosegaard et al., (15) who also reported an increased prevalence of vitamin D deficiency in mild PHPT (N 289; mean serum calcium, 11.0 mg/dl; Fig. 3). Although they found no association of 25(OH)D levels with adenoma weight, they did report that low levels of this form of vitamin D were associated with evidence of increased disease severity. When controlled for age, sex, BMI, serum creatinine, and season, their data confirmed that low 25(OH)D concentrations were associated with increased PTH and alkaline phosphatase levels and also with lower BMD at both the femoral neck and radius. This group has also reported that parathyroid secretory activity in PHPT is related to circulating levels of 25(OH)D and not 1,25-dihydroxyvitamin D. (16) Although most current data on mild PHPT are suggestive, not all reports confirm an association of vitamin D

3 V102 SILVERBERG FIG. 3. Prevalence of vitamin D insufficiency and deficiency in mild primary hyperparathyroidism in comparison with agematched osteoporotic control subjects (Control) or healthy blood donors (Normal). *Difference from primary hyperparathyroid FIG. 4. Vitamin D repletion in primary hyperparathyroidism. group at p < Adapted from Moosegaard et al. (15) Effect of 12 mo of cholecalciferol on 25(OH)D and PTH levels in 21 patients. *Difference in PTH levels from pretreatment baseline. Adapted from Grey et al. (24) levels with skeletal indices. In a study of patients with somewhat more severe hypercalcemia [mean serum calcium: 11.4 mg/dl; mean 25(OH)D: 19 nm], Carnevale et al. (17) used a progressively restricted multivariate model to assess effects on BMD. They found that PTH concentration, age, and BMI had the predominant effects on bone mass, whereas 25(OH)D levels had no independent effect on BMD at any site. While confirming that 25(OH)D levels in the insufficiency and deficiency range were common in Japanese patients with mild PHPT (mean serum calcium, 10.8 mg/dl), Yamashita et al. (18) also found no differences in biochemical characteristics or bone densitometry according to vitamin D levels. One additional clinical feature of mild PHPT is worth mentioning with respect to vitamin D deficiency. Recent reports have suggested that 25(OH)D deficiency may be associated with worse cognition and lower mood in older adults. (19 21) It remains unclear whether the frequent finding of low levels of 25(OH)D might account for the neuropsychological complaints so common in patients with mild PHPT. MANAGEMENT Data have long been available suggesting that parathyroid function is responsive to the usual stimuli in PHPT. Over 20 yr ago, Insogna et al. (22) reported that, in PHPT, a calcium intake of 1000 mg/d was associated with a suppression of levels of both PTH and 1,25-dihydroxyvitamin D. To date, there are no data to support draconian restrictions of calcium and/or vitamin D intake in this disease. Indeed, further increases in PTH levels and perhaps further increase in parathyroid gland size could result from such an approach. Data on the repletion of vitamin D in deficient patients with PHPT are limited. Kantorovich et al. (23) found increased BMD at the spine and hip in five patients who had simultaneous low 25(OH)D and elevated PTH levels after therapy with vitamin D. This study was limited by its very small sample size. In addition, the presumptive diagnosis of PHPT is questionable in several patients. These subjects had serum calcium levels in the lower end of the normal range even after vitamin D repletion, raising the possibility that they had secondary rather than primary hyperparathyroidism. The more promising study of Grey et al. (24) did find benefits of vitamin D repletion in patients with typical mild PHPT (mean serum calcium, 10.8 mg/dl). This study treated a small cohort (N 21) of such patients with cholecalciferol, 50,000 units/wk for 4 wk, followed by 50,000 units monthly for the balance of a year. In association with the rise in 25(OH)D levels, PTH levels declined by 25%, without a concomitant increase in serum or urinary calcium in the group as whole (Fig. 4). It is important to note that one patient did have a significant rise in serum calcium, whereas three had markedly increased urinary calcium excretion (>400 mg/d) at some point during the study, highlighting the importance of careful monitoring of any patients with PHPT who are treated with vitamin D. These data suggest a potential benefit of vitamin D repletion in selected patients who are not planning to undergo parathyroidectomy and clearly call for confirmation and extension in larger clinical trials. In those patients undergoing surgery for PHPT, the presence of vitamin D deficiency/insufficiency has other implications. In the presence of vitamin D deficiency, there must be heightened concern about postparathyroidectomy hypocalcemia as a result of hungry bones. Whereas hungry bone syndrome was commonplace in classical PHPT, recent data are mixed on the association of preoperative D deficiency with postoperative hypocalcemia. (12,25) However, the repercussions in terms of postparathyroidectomy hyperparathyroidism are clear. Postoperative elevations in PTH levels are consistently associated with lower levels of vitamin D, whether measured before surgery (26,27) or immediately after surgical cure. (28) Rigorous trials of postoperative repletion of vitamin D in patients with concomitant vitamin D deficiency and PHPT have not been done. SUMMARY AND FUTURE DIRECTIONS The association of vitamin D deficiency and PHPT is evident on two distinct levels. First, in those with PHPT, the

4 VITAMIN D DEFICIENCY AND PRIMARY HYPERPARATHYROIDISM V103 disease seems to be more severe in those with concomitant vitamin D deficiency. PHPT is frequently symptomatic in areas where vitamin D deficiency is endemic, and osteitis fibrosa cystica remains a common feature of the disease. There are also data supporting increased severity of hyperparathyroidism in those patients with mild PHPT and concomitant vitamin D deficiency or insufficiency. Second, vitamin D deficiency and insufficiency seems to be more prevalent in patients with PHPT than in geographically matched populations. This is the case even in populations of patients with mild, asymptomatic PHPT that are more common in the United States today. However, because current data are all cross-sectional, it is not possible to determine causality of the association between vitamin D deficiency and PHPT. There have been many possible explanations put forth for this association, the details of which are beyond the scope of this report. (29 37) Chronic vitamin D deficiency has been proposed to lead to autonomous parathyroid gland stimulation with subsequent hyperplasia and eventual adenoma growth. Alternatively, chronic vitamin D deficiency could accelerate the growth of a preexisting adenoma. The increased levels of 1,25-dihydroxyvitamin D in PHPT have also been proposed to influence overall vitamin D status. Possible mechanisms might include an inhibition of the production of vitamin D 3 in skin, an inhibition of the production of 25-hydroxyvitamin D in the liver, or increased renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. There are also data suggesting that the half-life of 25-hydroxyvitamin D is significantly shortened in PHPT, with increased metabolic clearance caused by enhanced hepatic inactivation. Finally, others point to decreased bioavailability of vitamin D in PHPT patients because of increased body weight. Although the cause, or more likely causes, of the association between vitamin D deficiency and PHPT remain obscure, the observation has clear management implications. Available data support the need for randomized trials of vitamin D repletion in patients with co-existing vitamin D deficiency and PHPT. These trials must assess possible benefits of such intervention (including any improvements in hip and forearm BMD and reduced fracture risk) against the potential risks of hypercalcemia, hypercalciuria, and kidney stones. Looking to the future, it is interesting to speculate on the potential consequences of shifts in the prevalence of these two conditions. It is unclear whether the increasing global prevalence of vitamin D insufficiency/deficiency will have an impact on the clinical picture of PHPT. At the same time, shifts in the use of multichannel biochemical screening may decrease the recognition of the truly asymptomatic patient with PHPT. Whether these shifts will be associated with a return to a clinically more severe phenotype of PHPT remains to be seen. ACKNOWLEDGMENTS SJS is supported by NIH Grants DK074457, K24 DK074457, and DK REFERENCES 1. Albright F, Reifenstein EC 1948 The Parathyroids Glands and Metabolic Bone disease. Williams and Wilkins, Baltimore, MD, USA. 2. Heath H, Hodgson SF, Kennedy MA 1980 Primary hyperparathyroidism incidence, morbidity and potential economic impact in a community. N Engl J Med 302: Silverberg SJ, Bilezikian JP 2001Clinical presentation of primary hyperparathyroidism in the United States. In: Bilezikian JP, Marcus R, Levine MA (eds.) The Parathyroids. 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