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Disturbances of Calcium Homeostasis Consistent with Mild Primary Hyperparathyroidism in Premenopausal Women and Associated Morbidity

Department of Surgery (H.S., E.L.) and Endocrine Unit, Department of Medicine (Ö.L.), University Hospital, S-751 85 Uppsala, Sweden; and Endocrine Surgery (J.R.), AstraZeneca R&D, S-151 85 Södertälje, Sweden

Address all correspondence and requests for reprints to: Helene Siilin, Department of Surgery, University Hospital, S-751 85 Uppsala, Sweden. E-mail: helene.siilin{at}bredband.net.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Primary hyperparathyroidism (PHPT) and associated morbidity are comprehensively assessed in elderly females; however, less is known of the disease in younger women.

Objectives: Our objectives were to estimate the prevalence of mild disturbances in calcium homeostasis, which could be analogous with early PHPT, in a premenopausal population, and determine the potential presence of associated morbidity.

Design: Initial results from this longitudinal study are from 2002–2004.

Setting: We conducted a population-based screening of serum (s)-calcium in conjunction with routine mammography.

Participants: Participants included premenopausal women, 40–50 yr of age (n = 1900). Cases fulfilling previously evaluated biochemical criteria for PHPT (n=214) were matched to controls (n = 214).

Main Outcome Measurements: All participants underwent investigation, including screening of parameters of calcium homeostasis, dual x-ray absorptiometry, and body mass index assessment, and filled out extensive health and quality of life (SF-36) questionnaires. Participants were divided into four groups depending on the relation between s-calcium/intact PTH. Statistical comparisons between cases and controls as well as among the four groups were performed to evaluate morbidity.

Results: The prevalence of assumed mild PHPT, i.e. inappropriate intact PTH value in relation to total s-calcium, was estimated to be 5.1% (n = 96). Women with mild disturbances in calcium homeostasis had statistically significant lower bone mineral density in the proximal femur and femoral neck, higher body mass index, and lower scores for vitality and general health in the analysis of SF-36.

Conclusions: Mild disturbances in calcium homeostasis in premenopausal women were more prevalent than previously thought and were associated with obesity, lower bone mineral density, and decreased quality of life.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Primary hyperparathyroidism (PHPT) is a common endocrine disease, existing in both genders and in all age groups (1, 2, 3, 4, 5). The disease is nearly three times more common in women than in men (6), and women around menopause appear to be at particular risk (7, 8). The incidence of patients with PHPT appears to increase (2, 4), although one study (6) reports decreasing incidence. The etiology of PHPT is not fully understood, and in a majority of cases, an underlying cause cannot be identified.

Before the introduction of automated measurement of serum (s)-calcium in the early 1970s, the disease had often developed into an advanced stage before diagnosis and was characterized by marked hypercalcemia. At present in Western societies, most cases of PHPT are incidentally diagnosed in connection with blood screening for other reasons, and the clinical picture of the disease is incompletely defined. The majority of patients with PHPT are asymptomatic or have vague symptoms (9). At diagnosis, the s-calcium level is usually mildly to moderately elevated or within normal reference range, in combination with an inappropriately elevated intact PTH (iPTH) (10, 11, 12). Nevertheless, mild PHPT is associated with cardiovascular complications, psychiatric instability, and increased risk of different malignant diseases (1, 13, 14, 15, 16). Moreover, concomitant metabolic abnormalities in patients with mild PHPT have also been determined, i.e. glucose intolerance and dyslipidemia (17, 18, 19). Obesity in Western societies is an increasing metabolic problem (20, 21), and association with PHPT has recently come to attention (22, 23).

The morbidity of the disease has been comprehensively assessed in menopausal females (17, 24, 25), but the prevalence and impact of PHPT on younger females have not been explored to the same extent. The estrogen deficiency occurring at or after menopause is thought to be one explanation of why PHPT is more prevalent in postmenopausal females. However, the progress of the disease is slow, and subtle disturbances in calcium homeostasis probably exist before onset of menopause.

The primary aims of this study were to estimate the prevalence of mild disturbances in calcium homeostasis presumably analogous with early PHPT in premenopausal females, to report on baseline data in the cases, and to determine the potential presence of associated metabolic disturbances. Measurements of impact on quality of life and general health are also included in this first report on morbidity in the cohort.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Design

Premenopausal women between 40 and 50 yr of age were invited to participate in this study in connection with routine mammography health screening. Women taking hormonal replacement treatment or contraceptives containing estrogen were excluded. The subjects included had to be clinically premenopausal at the time of inclusion and were asked about menstrual flow during the last 6 months, and if in doubt, FSH was determined. The mammography center is sited at the University Hospital of Uppsala, Sweden. The local ethics committee approved the study, and the initial inclusion period was from March 1, 2002, until February 28, 2003.

Main study

After informed consent, a nonfasting venous blood sample was collected from all participants (n = 1900, Fig. 1A). At the University Hospital’s biochemical laboratory, the blood samples were analyzed for s-calcium and s-albumin, from which total s-calcium (albumin-adjusted s-calcium) was calculated according to a formula (see Biochemistry below). All women with total s-calcium of at least 2.50 mmol/liter (n = 540) were asked to continue in the trial (Fig. 1B).

View larger version (24K): [in this window] [in a new window]   FIG. 1. Flowchart of participants in the study.

The diagnostic criteria used to define the 232 women (Fig. 1C) were the same criteria previously established for surgically verified PHPT in postmenopausal women (7), except that the initial screening threshold for s-calcium was lowered for the present study from at or above 2.55 mmol/liter (7) to 2.50 mmol/liter. Additionally, as in the previous study (7), one of the following conditions had to be fulfilled at subsequent testing: fasting total s-calcium less than 2.50 mmol/liter and iPTH at least 55 ng/liter, fasting total s-calcium 2.50–2.60 mmol/liter and iPTH at least 35 ng/liter, and fasting total s-calcium more than 2.60 mmol/liter and iPTH at least 25 ng/liter.

The rationale for including women with lower screening s-calcium (value at or above 2.50 mmol/liter) was based on revised data presented several years after the initial study of postmenopausal women (8).

At the third sampling occasion (between March 2003 and November 2004), controls (n = 214) were chosen from women with total s-calcium less than 2.50 mmol/liter at first screening. The cases (n = 214) were matched with controls with respect to age and date of initial investigation (Fig. 1, D and E).

Fasting blood samples were analyzed for cases (n = 214) and controls (n = 214) and included hemoglobin, leukocytes, blood platelets, s-calcium, iPTH, s-phosphate, s-albumin, s-creatinine, s-potassium, s- sodium, blood glucose, and 25-hydroxyvitamin D [25(OH)D] as well as urinary calcium (see Biochemistry below).

In conjunction with this third occasion, the participants were examined by dual x-ray absorptiometry (DXA), and body mass index (BMI) was determined. Eventually, extensive health and quality of life (SF-36) questionnaires were completed (26).

Subjects with suspected vitamin D deficiency (values < 20 µg/liter) indicating possible secondary PHPT were excluded (n = 62; 41 cases and 21 controls).

Subgroups study

All participants, cases and controls, were considered as one cohort (n = 366) for further methodical investigation of the impact of minor disturbances in calcium homeostasis on metabolic morbidity, bone mineralization, and physical and mental health.

Median total s-calcium and median iPTH were calculated from all participants. The median value for total s-calcium was 2.41 mmol/liter and was set as the first cutoff value. Median iPTH value was 49 ng/liter and set as the second cutoff value.

The subjects included were then divided into four different groups depending on the combination of total s-calcium and iPTH value, as follows (Fig. 1F): group A (low-low), with s-calcium at or below 2.41 mmol/liter and iPTH at or below 49 ng/liter (n = 90); group B (low-high), with s-calcium at or below 2.41 mmol/liter and iPTH more than 49 ng/liter (n = 93); group C (high-low), with s-calcium at or above 2.41 mmol/liter and iPTH at or below 49 ng/liter (n = 98); and group D (high-high): s-calcium at or above 2.41 mmol/liter and iPTH more than 49 ng/liter (n = 85). Group D (high-high) consisted of women with the most abnormal biochemical pattern, i.e. inappropriately elevated iPHT in relation to total s-calcium.

Biochemistry

Total s-calcium (normal range, 2.20–2.60 mmol/liter) was measured by automatic immunoanalyzer (ADVIA 1650; Bayer Diagnostic, Gothenburg, Sweden). Plasma iPTH (iPTH normal range, 12–65 ng/liter) was measured with the ADVIA Centaur two-site immuno-chemiluminometric assay (ADVIA Centaur; Bayer Diagnostic) with an interassay coefficient of variation of less than 8.1%. Serum creatinine (normal range, 64–106 µmol/liter) was analyzed on Bayer ADVIA 1650 with reagents from Synermed. Nichols Advantage Specialty System was used for measurements of 25-hydroxyvitamin D (normal range, 10–70 µg/liter). Blood chemistry including fasting blood glucose, hemoglobin, leukocytes, blood platelets, s-phosphate, s-potassium, s-sodium, and urinary calcium were analyzed by the Uppsala University Hospitals’ clinical routine analysis. To calculate total s-calcium, the s-calcium measured was adjusted for s-albumin with the following formula: albumin-adjusted s-calcium = analyzed s-calcium – (analyzed s-albumin – 46) x 0.02 (27).

DXA

Bone mineral density (BMD) of the lumbar spine and femoral neck was measured with DXA (Lunar Prodigy DXA; GE Lunar Corp., Madison, WI) The coefficients of variation for the BMD measurements ranged from 0.5–3%, depending on application.

Health questionnaire and SF-36 (Health Related Quality of Life questionnaire)

All participants answered questions on their previous and present health problems. The questions included prevalence of diabetes mellitus, hypertension, cardiac complications, fractures, thyroid or parathyroid diseases, nephrolithiasis, and malignancies. They also reported the number of children they had given birth to, for how long they had breastfed them, and smoking and exercise habits. SF-36 was used to evaluate quality of life (26).

Statistics

For all statistical analysis, StatSoft’s statistical software program STATISTICA (release 7) was used. Comparisons were made between cases and controls as well as between the four different groups.

Normal distribution was controlled, and skewed variables were logarithmically transformed [plasma-iPTH, s-FSH, s-phosphate, 25(OH)D, and BMD for left and right hips and mean), or if not appropriate, suitable nonparametric tests were performed (glucose). For continuous variables, ANOVA and Student’s unpaired t test were used. Mann-Whitney U test and Kruskal-Wallis ANOVA were used for analyzing SF-36 and ² test and Fisher’s exact test for frequency distribution regarding answers (categorical variables) in the health questionnaires. Analysis of covariance was used for adjusting for covariates, i.e. weight and 25(OH)D for BMD. Statistical data are shown as mean and SD in addition to confidence intervals and P values in illustrations. P value < 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Main study

After the initial screening of 1900 subjects with 34 subjects dropping out, there remained 1866 subjects in the survey (Fig. 1). Dropouts included 33 cases who had had hysterectomies, which resulted in problems in clinically establishing whether they were premenopausal or not, and one subject’s blood sample was lost. Mean total s-calcium for the entire screening cohort (n = 1866) was 2.45 ± 0.10 mmol/liter (2.08–2.89 mmol/liter). In the subgroup of 540 (29%) individuals, consisting of those with total s-calcium of at least 2.50 mmol/liter at screening and who were asked to continue in the trial, the mean total s-calcium was 2.57 ± 0.07 mmol/liter (2.50–2.89 mmol/liter). From that group, there were five additional dropouts, one case because of malignancy (lymphoma), one case declared lack of interest, and three individuals did not respond to repeated invitations (Fig. 1B).

At the second evaluation (fasting blood sample), the remaining 535 women had a mean total s-calcium of 2.48 ± 0.09 mmol/liter (2.22–2.79 mmol/liter) and mean iPTH of 46 ± 23.1 ng/liter (<10–164 ng/liter). At the subsequent examination, 232 subjects had screening total s-calcium of at least 2.50 mmol/liter in combination with one of the preset biochemical criteria for PHPT. These were asked to return for 25(OH)D measurements, and 18 individuals then declined further testing. The mean value of 25(OH)D in the remaining 214 subjects was 28 ± 9.7 µg/liter (7–54 µg/liter). Overall, 19.5% (n = 41 cases) had 25(OH)D values less than 20 µg/liter; these were consequently excluded.

None was excluded due to elevated s-creatinine, and only one subject had slightly elevated value (119 µmol/liter). Urinary calcium below 1 mmol/liter was detected in 13 of the cases, of which none had total s-calcium above 2.60 mmol/liter; therefore, familial hypocalciuric hypercalcemia could be dismissed.

According to the diagnostic criteria stipulated (with screening s-calcium value 2.55 mmol/liter) (7), the prevalence of assumed mild primary hyperparathyroidism, i.e. inappropriate iPTH value in relation to total s-calcium, was estimated to be 5.1% (n = 96) (Table 1, column 1).

View larger version (12K): [in this window] [in a new window]   FIG. 2. A, BMD femoral neck (g/cm3), adjusted for vitamin D and weight, in cases and controls (P = 0.022); B, the four groups (P < 0.01) of different s-calcium and plasma-iPTH relations. Vertical bars denote 95% confidence interval (see Statistics).

Subgroups study

In the four groups of calcium in relation to iPTH, significant differences were determined for BMD in L2–L4, total body, proximal femur, and femoral neck (Fig. 2B) as well as for body weight and BMI. Group A (low-low) had significantly higher BMD in all locations, and group D (high-high) had higher mean body weight and hence mean BMI (Table 3). 25(OH)D was also significantly decreased in Group D (high-high) (Table 3). The significant differences in BMD remained after adjusting for covariates, 25(OH)D, and weight (Fig. 2B). No differences between the four groups were highlighted in the analysis of SF-36.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The main findings in this screening study of calcium disturbances in premenopausal women were that early PHPT might be more prevalent in this age group than previously thought, although the diagnostic criteria are yet to be surgically verified. Nevertheless, it was evident that mild disturbances in calcium homeostasis were associated with impaired bone mineralization, obesity, and decreased quality of life.

Prevalence

The estimated figures for prevalence of PHPT were based on the same criteria as in the population-based screening study of PHPT in postmenopausal women (7), in which the authors surgically and histopathologically verified the diagnosis of PHPT.

The biochemical recognition of the disease generally also includes normocalcemic patients with an inappropriately elevated iPTH (1, 2, 8, 11) as well as iPTH within the normal range (11, 12, 28). By lowering the inclusion total s-calcium to 2.50 mmol/liter, subjects with minor disturbances in calcium homeostasis could be included to attempt to identify potential PHPT early in the development of the disease (8).

The prevalence data reported before PTH assays were available were lower than in studies including measurements of iPTH (5). In a health screening study from Stockholm, Sweden (5). the prevalence ranges from 0.36–1.3%, and the figures are based on moderate hypercalcemia at or above 2.78 mmol/liter at inclusion. In different study populations, including both genders and all age groups, prevalence outcome for PHPT (0.17–13.9%) are reported (2, 4, 5, 8), and even minor changes in the cutoff limit of s-calcium for defining PHPT have great impact on the results (2, 5, 8). The prevalence of assumed PHPT varied depending on which biochemical criteria were used to identify the imbalance between s-calcium and iPTH. Even though the cutoff limit for inclusion in this study (total s-calcium 2.50 mmol/liter) was set in the upper normal range, prevalence in the range of 0.7–9.3% was unexpected, when all three of the preset criteria groups were included, as seen, for example, in Table 1 (column 2).

However, comparison of diagnostic criteria fulfillment at the two different fasting examinations revealed only 2.7% of the cases fulfilled the same or another criterion. This highlighted the importance of long-term evaluation in this cohort.

Vitamin D

Based on the assumption that vitamin D deficiency could exist and thus might cause secondary PHPT, 19% of the women in this study were excluded. These findings could be indicative of masked PHPT; however, a bias in this respect should increase the prevalence of early PHPT. The women were included because of an inappropriate high level of iPTH and therefore did not reflect the true prevalence of vitamin D insufficiency in this cohort. In a Danish survey of healthy perimenopausal women (29), only 2.8% had vitamin D levels above 20 µg/liter associated with PTH levels above normal range. There is evidence that PTH does not decrease if vitamin D supplement is given for values over 20 µg/liter (30), yet the discussion of defining vitamin D insufficiency continues.

Obesity is considered responsible for reducing vitamin D levels (31), and in this study, 27% of the subjects in group D (high-high) were obese (Table 3). This group had significantly lower mean 25(OH)D than the other groups, which in turn might have influenced iPTH values (32). Additionally, a weak negative correlation was identified between 25(OH)D and iPTH in the whole population (P < 0.05; r = –0.15).

Obesity

The prevalence of obesity has increased remarkably since 1970, and this trend is obvious in many Western countries (20, 21, 33). In Sweden, approximately 20% of the general population is overweight, and 10% of the adult population is obese (www.scb.se).

In this study, noticeable differences in body weight and, accordingly, BMI were detected between cases and controls. The results were reliable even when comparing women with most atypical biochemical patterns of s-calcium and iPTH levels and those with more normal s-calcium and iPTH distribution (i.e. the four groups). The association between mild PHPT and obesity was consistent with previously published articles, and increased body weight appears to be a risk factor preceding calcium/iPTH disturbances (22, 23, 34). However, whether increased body weight induces calcium disorders or vice versa is still unclear. In this study, there was a positive correlation between iPTH and body weight of premenopausal females; this correlation has previously been established for postmenopausal women (23).

An association between obesity and calcium disturbance was detected, and the high prevalence of assumed early PHPT in premenopausal women might be a direct consequence of the epidemic increase of obesity in the Western world today.

BMD

Mild PHPT is often (subjectively) asymptomatic; objectively, there is associated morbidity such as renal impairment, increased risk of fragility fractures due to loss of bone mass, increased risk for cardiovascular events, and psychiatric problems (13, 15, 35, 36, 37).

In the analysis of DXA measurements between cases and controls as well as among the four groups, the significant differences of mean BMD for proximal femur and femoral neck were still present after adjustment for weight and 25(OH)D levels (Fig. 2, A and B).

The results implied that exceedingly mild disturbances in calcium homeostasis, analogous with early PHPT, can have a negative impact on bone mineralization. However, the differences measured may not have any clinical implications because the mean BMD values for both cases and controls were within normal reference range. Even so, parathyroidectomy is independently associated with decreased fracture risk regardless of age or chemical imbalance between calcium and iPTH (38).

Quality of life

Psychiatric disturbances are one of the complications in PHPT. The symptoms experienced by patients are often vaguely described, but a majority have disturbances of depressive character (35). In this cohort, demonstrable differences in life quality between cases and controls with reference to vitality and general health were evident, even after adjustment for obesity. There is some evidence that psychiatric symptoms regress after successful parathyroidectomy (35); however, according to a recent longitudinal study (39), this is unconfirmed.

Limitations

The applied diagnostic criteria used in this present study (i.e. recognition of the disease) were based on biochemical criteria surgically validated for postmenopausal women, and the criteria need to be clinically verified for younger females. Clinical examinations and follow-up of the cases in this cohort will be important for the ultimate diagnosis. In 2007, all individuals will have taken the first 3-yr follow-up.

In addition, when describing the morbidity, several variables were analyzed, and chance might have influenced the statistical analysis for some variables.

In conclusion, mild disturbances in calcium homeostasis (i.e. biochemical signs that could be indicative of early PHPT) in premenopausal women were more prevalent than previously thought and were associated with obesity. Furthermore, associations between calcium disturbances and impaired BMD as well as decreased quality of life were detected. This cohort will be investigated intermittently in the future to evaluate associated morbidity and changes in calcium homeostasis during menopause.

	Acknowledgments

 
Eva Strandqvist, R.N., is thanked for taking care of the participants in a most skillful and professional way. Eva Ribom, Ph.D., is appreciated for valuable statistical advice. Marja Gustafsson, Ann Charlotte Adolfsson, and Inger Abrahamsson are thanked for their professional help with DXA measurements.

	Footnotes

 
Disclosure Statement: H.S. and E.L. have nothing to declare. Ö.L. has received consulting and lecture fees from different companies (AstraZeneca, MSD, Lilly, Nycomed Servier, and Amgen). J.S. is a full-time employee and has equity shares in AstraZeneca, which has no marketed or development compounds in the area of calcium homeostasis.

First Published Online November 27, 2007

Abbreviations: BMD, Bone mineral density; BMI, body mass index; DXA, dual x-ray absorptiometry; iPTH, intact PTH; 25(OH)D, 25-hydroxyvitamin D; PHPT, primary hyperparathyroidism; s, serum.

Received March 15, 2007.

Accepted October 25, 2007.

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