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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-1891
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1525-1530
Copyright © 2005 by The Endocrine Society

Association between Primary Hyperparathyroidism and Increased Body Weight: A Meta-Analysis

Mark J. Bolland, Andrew B. Grey, Greg D. Gamble and Ian R. Reid

Department of Medicine, University of Auckland, Auckland 1020, New Zealand

Address all correspondence and requests for reprints to: Dr. Mark Bolland, Osteoporosis Research Group, Department of Medicine, University of Auckland, Private Bag 92 019, Auckland 1020, New Zealand. E-mail: m.bolland{at}auckland.ac.nz.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Although primary hyperparathyroidism is frequently asymptomatic, it has been associated with an increased prevalence of hypertension, insulin resistance, dyslipidemia, cardiovascular mortality, and cancer. Previously we reported that patients with primary hyperparathyroidism are heavier than age-matched controls. Increased body weight could contribute to the association between primary hyperparathyroidism and these extraskeletal complications. We searched MEDLINE for English language studies published between 1975 and 2003 that reported body weight or body mass index in subjects with primary hyperparathyroidism and a healthy age- and sex-comparable eucalcemic control group. Seventeen eligible studies were identified. Subjects with primary hyperparathyroidism were 3.34 kg (95% confidence interval, 1.97–4.71; P < 0.00001) heavier than controls in 13 studies reporting body weight. In four studies reporting body mass index, subjects with primary hyperparathyroidism had an increased body mass index of 1.13 kg/m2 (–0.29 to 2.55; P = 0.12) compared with controls. Standard mean difference analysis showed that subjects with primary hyperparathyroidism had an increased weight or body mass index of 0.3 SD (0.19–0.40; P < 0.00001) compared with controls. We conclude that patients with primary hyperparathyroidism are heavier than their eucalcemic peers, and that increased body weight may contribute to the reported associations between primary hyperparathyroidism and some extraskeletal complications.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PRIMARY HYPERPARATHYROIDISM IS one of the most common endocrine conditions, particularly in postmenopausal women. The prevalence of primary hyperparathyroidism has been estimated at three in 1000 in the general population and as high as 21 in 1000 in postmenopausal women (1). The incidence in Rochester, Minnesota, is estimated to be 20/100,000/yr (2). Frequently, it appears to be asymptomatic, and there is uncertainty as to the optimal management of this form of the disease. Most longitudinal studies indicate that the hypercalcemia is not progressive, and that renal function remains stable (3, 4, 5). Such data suggest that it is reasonable to leave asymptomatic individuals untreated (5). However, there is epidemiological evidence, primarily from European studies, that suggests that primary hyperparathyroidism is associated with increased incidences of hypertension, insulin resistance, dyslipidemia, cardiovascular disease, and malignancy (6, 7, 8, 9, 10, 11, 12, 13, 14). These considerations would argue in favor of intervention, even in asymptomatic individuals, with the hope of reducing morbidity from these conditions. Although the recent NIH consensus conference guidelines (15) do not support such an approach, a number of editorials have argued that parathyroidectomy should be performed for almost all patients (16, 17, 18).

In 1994, we reported that body weight was increased in a cohort of postmenopausal women with asymptomatic primary hyperparathyroidism (19). Subsequently, we reported that the increase in body weight appeared to antedate the development of hypercalcemia (20). This suggests that the increase in weight is not secondary to primary hyperparathyroidism and therefore is unlikely to be affected by parathyroid surgery. Because increased body weight is known to be associated with hypertension, insulin resistance, dyslipidemia, and cardiovascular disease (21), it is possible that increased body weight accounts for these other associations of primary hyperparathyroidism. If this is the case, surgical correction of the parathyroid abnormality is unlikely to impact on the frequency of these other conditions. Indeed, the available data suggest that parathyroidectomy does not influence hypertension, dyslipidemia, or the incidence of cardiovascular disease (8, 9, 10, 11, 22, 23, 24, 25).

Clearly, the possible association of increased body weight with primary hyperparathyroidism is central to an understanding not only of the etiology of this condition, but also of its morbidity and optimal treatment. Because this question does not appear to have been specifically revisited since the time of our earlier publications, we have meta-analyzed all the published studies that report body weight in subjects with primary hyperparathyroidism and in age- and sex-comparable healthy controls. This analysis confirms our earlier report, suggesting there is need for a reappraisal of many aspects of this common condition.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study selection

MEDLINE was searched from 1975–2003 using the term "primary hyperparathyroidism." To be eligible for consideration, a study must have been published in English, have had a control group, and have presented data on body weight or body mass index for both groups. Fifty-nine studies meeting these criteria were identified. Additional specific exclusion criteria were: 1) groups not comparable for mean age (within 7 yr) or gender (male/female ratio within 15%); 2) groups matched for weight, body mass index, or body size; 3) groups matched for other variables that are likely to be related to body weight (blood pressure and glucose tolerance); 4) studies of subjects postparathyroidectomy; and 5) studies in which the control group was selected from a population with comorbidities likely to significantly impact on body weight (such as diabetes mellitus, osteoporosis, vascular disease, and malignancy). Where the same cohort was described in more than one publication, only the largest study conforming to the inclusion and exclusion criteria was included. Each of the 59 studies identified was independently assessed by three of the authors (M.B., A.G., and I.R.), and a consensus was reached regarding the suitability of each study without knowledge of the body weight data.

Statistics

Data were analyzed using Review Manager (RevMan, 2003) version 4.2.3 for Windows (The Cochrane Collaboration, Oxford, UK). Weighted mean differences in weight and body mass index were calculated for all eligible studies using a fixed effects model. A global analysis was performed using the standardized mean differences for body weight and body mass index. In the presence of significant heterogeneity (P < 0.10), a random effects model was also run in an attempt to incorporate the differences between studies into the analysis. Funnel plots for each model were inspected. All tests were two-tailed; P < 0.05 was considered statistically significant, and 95% confidence intervals are presented.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Of the 59 studies identified, 15 were excluded because of previous or subsequent publication of the study group; nine because of matching for weight, body mass index, or body size; eight because the control groups were not comparable in age or gender distribution; four because of control group comorbidities; three because of matching for blood pressure; and two because they were carried out after parathyroid surgery. Thus, 18 studies were eligible for inclusion in the review: 14 studies (Table 1GoGo) presenting body weight (6, 19, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37) and four studies (Table 2Go) presenting body mass index (38, 39, 40, 41). Dalberg et al. (30) presented data as the median ± range. These data were not included in the final analysis because of the lack of statistical compatibility with the other data. Grey (31) presented one group of premenopausal and a separate group of postmenopausal subjects, each with a matched control group. These two groups were analyzed separately. Hagag et al. (41) published data on two groups of patients with primary hyperparathyroidism. These data were pooled and compared with the solitary control group. Thus, the final analysis contained 17 studies that collectively reported data on 617 patients with primary hyperparathyroidism and 1248 controls.


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  		TABLE 1. Studies of primary hyperparathyroidism and eucalcemic controls presenting data on body weight

 

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  		TABLE 1A.
 

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  		TABLE 2. Studies of primary hyperparathyroidism and eucalcemic controls presenting data on body mass index

 
Subjects with primary hyperparathyroidism were, on the average, 3.34 kg (95% confidence interval, 1.97–4.71; P < 0.00001) heavier than controls in the 13 studies presenting body weight (Fig. 1Go). In the study excluded because it reported group weights as the median ± range, the median weight in subjects with primary hyperparathyroidism was 7 kg greater than that in controls, consistent with the results of the other studies. In three of the four studies presenting body mass index, subjects with primary hyperparathyroidism had an increased body mass index compared with controls. However when analyzed using a random effects model (necessitated by significant heterogeneity, P = 0.04, between studies), the difference in body mass index between groups was 1.13 kg/m2, a result that fails to reach statistical significance (P = 0.12; 95% confidence interval, –0.29 to 2.55). Although body mass index is related to weight, it cannot be converted to weight without knowledge of the height of the individual subjects. A measure of overall effect, however, can be obtained by pooling data from the studies reporting weight and body mass index and applying a standard mean difference analysis. This analysis demonstrated that body weight or body mass index was, on the average, 0.3 SD (95% confidence interval, 0.19–0.40; P < 0.00001) higher in the subjects with primary hyperparathyroidism than in controls. This is equivalent to 3.1 kg in terms of weight and 1.1 kg/m2 in terms of body mass index.



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  		FIG. 1. Weighted mean difference in body weight in studies of primary hyperparathyroidism (PHPT) and eucalcemic controls that present data on body weight. P = 0.13 for heterogeneity between trials. The lines show 95% confidence intervals (CI) for each study, and the diamond shows 95% CI for the pooled analysis. P < 0.00001 for weighted mean difference.

 
The finding of increased body weight in association with primary hyperparathyroidism was consistent across the studies. Only three studies did not report higher body weight or body mass index in the subjects with primary hyperparathyroidism. These three studies had features suggesting that their subjects were not representative of patients with asymptomatic primary hyperparathyroidism and mild hypercalcemia. In all three studies the means for serum calcium were higher than in the remainder of the studies [11.70–12.2 mg/dl (2.93–3.05 mmol/liter) compared with 10.24–11.36 mg/dl (2.6–2.83 mmol/liter)]. In one of the studies, all subjects had osteitis fibrosa cystica or renal stones (26). Two of the studies were in patients preparing for parathyroid surgery (29, 40), and two were smaller (15 and 10 subjects, respectively) and had younger subjects (mean age, 46.3 and 44 yr) than the remainder (26, 29).

The degree of hypercalcemia appeared to have an important influence on body weight. In the three studies in which the mean serum calcium was at least 11.70 mg/dl (2.93 mmol/liter), the groups with primary hyperparathyroidism weighed less than the control groups. In the remaining studies in which the mean serum calcium was less than 11.36 mg/dl (2.83 mmol/liter), the groups with primary hyperparathyroidism were heavier than the controls, and the difference in body weight between groups did not correlate with mean serum calcium.

There was a predominance of females in the study groups (563 of 617 participants), reflecting the well known difference in prevalence of primary hyperparathyroidism between genders. Where menopausal status was given, 313 of 351 women were recorded as postmenopausal; however, in 212 women, the menopausal status was not recorded. When subjects were analyzed by categories (postmenopausal, premenopausal, menopausal status not recorded, or male), subjects with primary hyperparathyroidism were consistently heavier than controls across all groups by amounts similar to the overall pooled result (data not shown).

Only two studies reported data on body composition (19, 32). In both studies the majority of the weight difference (7.2 of 9.2 kg, and 2.6 of 4.5 kg, respectively) was attributable to increased fat mass.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This meta-analysis confirms our previous findings that subjects with primary hyperparathyroidism are heavier than eucalcemic controls. Most of the individual studies were small, with only a modest weight difference, and in 10 studies the between-group difference in body weight did not reach statistical significance. This explains why the observation that body weight is increased in primary hyperparathyroidism has not been generally recognized. However, the results are consistent across 13 studies reporting body weight and four studies reporting body mass index. The differences between the results of the three studies that did not report higher body weight or body mass index in the group with primary hyperparathyroidism and the remainder raise the possibility that the anorectic effects of more severe hypercalcemia (42) might negate the weight differences observed in mild primary hyperparathyroidism. Alternatively, the pathogenesis of primary hyperparathyroidism in young adults might be different from that in older subjects, paralleling the marked differences in the epidemiology of the condition between these groups (43, 44).

The increases in weight and body mass index observed here in subjects with primary hyperparathyroidism are probably of clinical significance. Large prospective studies have shown that increased body weight is associated with a number of diseases (45, 46, 47). Using data from these studies, an increased body mass index of 1.1 kg/m2 would increase the risk of diabetes mellitus by 155%, of gallstones by 20%, of hypertension by 15–25%, of heart disease by 6–11% (46, 47), and all-cause mortality by 6% in women and 10% in men (45). Data from the INTERSALT trial (48) predict that a 3.1-kg weight difference would be associated with an increase in blood pressure of 0.9/0.7 mm Hg.

A number of longitudinal studies of subjects with primary hyperparathyroidism have reported an increased risk of cardiovascular disease and/or mortality (3, 9, 10, 11, 12, 14, 22, 23, 25, 49, 50, 51), although not all studies have confirmed this (52, 53). None of these studies reported or adjusted for body weight. Reported standardized mortality rates in subjects with primary hyperparathyroidism range from 1.2–1.7, whereas relative risks for cardiovascular disease range from 1.7–2.5. Increased body weight may contribute to the increased risk of cardiovascular disease in primary hyperparathyroidism, although it may not entirely account for the reported increase in risk. We have previously published data showing that increased body weight antedates the diagnosis of primary hyperparathyroidism (20) and was, in fact, present at all ages throughout the adult lives of patients with primary hyperparathyroidism. The longer lifetime exposure to increased body weight in patients with primary hyperparathyroidism may exacerbate the risks of complications of obesity compared with those participants in epidemiological studies in which the average duration of follow-up was only 10 yr.

Increased body weight is associated with an increased risk of several important vascular risk factors. Hypertension (8, 9, 54, 55, 56); hyperlipidemia in some (57), but not all, studies (24, 58, 59, 60); and glucose intolerance (7, 24, 26, 61, 62, 63, 64, 65) have also been associated with primary hyperparathyroidism, providing a potential explanation for the increased risk of vascular disease in primary hyperparathyroidism. Other researchers have suggested that the increased cardiovascular risk in primary hyperparathyroidism may be contributed to by vascular and cardiac calcification resulting directly from the hypercalcemia, but the evidence for this is not compelling (66). Increased body weight has also been associated with gallstone disease (46) and an increased risk of death from a variety of cancers, including those of the gastrointestinal tract, kidney, breast, and female reproductive tract (67). Cholelithiasis (68, 69) and increased cancer occurrence (13, 14) and mortality from cancer (12) have also been reported in association with primary hyperparathyroidism. Thus, increased body weight may contribute to the reported associations between primary hyperparathyroidism and these seemingly unrelated conditions.

A key question that arises from this study is the mechanism of the association between body weight and primary hyperparathyroidism. The cause and effect relationship could operate in either direction. For instance, there is evidence that increased intracellular calcium concentrations in adipocytes cause insulin resistance and inhibit lipolysis (70), and PTH elevates intracellular calcium in many cell types (71). It is also possible that PTH influences adipocyte differentiation, because adipocytes and osteoblasts share common precursor cells (72), and PTH acts directly on osteoblasts (73). These observations imply that increased fat mass is the main contributor to the increased body weight, is a consequence of primary hyperparathyroidism, and therefore is likely to be corrected by parathyroidectomy. To our knowledge, there are no published studies on the effects of surgical correction of primary hyperparathyroidism on fat mass or body weight. An alternative explanation for our findings is that increased body weight predisposes to the development of primary hyperparathyroidism. A positive association between PTH concentrations and body weight has also been found in eucalcemic populations (74, 75, 76, 77). In all cases, 25-hydroxyvitamin D levels were inversely correlated with body weight, probably because vitamin D is fat soluble and is sequestered by adipose tissue. Thus, increased body weight may promote vitamin D deficiency, resulting in secondary hyperparathyroidism (78). Secondary hyperparathyroidism appears to increase the risk of developing parathyroid adenomata, a phenomenon that is well documented in the contexts of either renal failure (79) or long-term oral phosphate supplementation (80). This hypothesis is supported by our earlier observation that increased body weight usually antedates the development of hypercalcemia in primary hyperparathyroidism (20).

There are limitations to our findings. Despite the high prevalence of primary hyperparathyroidism, data from only 617 cases could be included in this meta-analysis. It is possible that selection bias may have influenced the results. Eight studies were carried out using patients referred for (or who subsequently had) parathyroid surgery. Three studies involved population screening. In two studies it was not clear how the patients were recruited. In the remaining studies, patients were attending endocrinology clinics. Subjects with more severe disease may therefore be overrepresented in this review. However, we believe, as discussed previously, that this would tend to minimize any increase in body weight because of the potential for anorexia associated with symptomatic disease. Ascertainment bias is also a possibility, if people who are overweight were more likely to have serum calcium measured and as a consequence be found to have primary hyperparathyroidism. We think this is an unlikely explanation for our findings given the consistency of the observation and the fact that three of the studies were population-based screening studies.

In conclusion, this analysis of a substantial, existing body of published data confirms that increased body weight is consistently present in cohorts of subjects with primary hyperparathyroidism and suggests that the association is real. This observation raises important questions regarding the mechanism of the association, and provides a potential explanation for the increased prevalence of several cardiovascular risk factors and of increased cardiovascular mortality in patients with primary hyperparathyroidism. Ultimately, these findings mandate a reexamination of the indications for parathyroidectomy in patients with asymptomatic disease, because although the updated NIH consensus conference guidelines (15) do not include these conditions as indications for parathyroidectomy, a number of editorialists do (16, 17, 18).


   Footnotes
 
M.J.B. is the recipient of an Australian and New Zealand Bone and Mineral Society Postgraduate Research Scholarship.

First Published Online December 21, 2004

Received October 1, 2004.

Accepted December 10, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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