Abstract
Context:
Normocalcemic primary hyperparathyroidism is typically identified after referral to a specialty clinic. At diagnosis, patients demonstrate features seen in hypercalcemic primary hyperparathyroidism. Normocalcemic hypoparathyroidism has been discovered after hypocalcemia unmasked after bisphosphonate administration.
Objective:
We hypothesized that screening unselected, nonreferral populations, such as The Osteoporotic Fractures in Men (MrOS) study and Dallas Heart Study (DHS), would identify asymptomatic subjects with normocalcemic hyperparathyroidism and hypoparathyroidism.
Methods:
Normocalcemic hyperparathyroidism was defined as serum PTH greater than the upper reference range with normal albumin-adjusted serum calcium, excluding common secondary causes (renal failure [estimated glomerular filtration rate <60 mL/min], 25-hydroxyvitamin D <20 ng/mL, and thiazide use), and normocalcemic hypoparathyroidism as PTH below the reference range with normocalcemia. Cross-sectional data were obtained from MrOS, and longitudinal data (baseline and 8 years) from DHS.
Results:
In 2364 men from MrOS, we identified 9 with normocalcemic hyperparathyroidism (prevalence 0.4%) and 26 with normocalcemic hypoparathyroidism (1.1%). In 3450 men and women from DHS, we identified 108 with normocalcemic hyperparathyroidism (3.1%) and 68 with normocalcemic hypoparathyroidism (1.9%). Of the 108 normocalcemic hyperparathyroid subjects, 64 had follow-up data. Hypercalcemic primary hyperparathyroidism developed in 1 subject whereas 13 (0.6% of the follow-up cohort) showed persistently elevated PTH levels with normocalcemia. Of the 26 normocalcemic hypoparathyroid subjects with follow-up data, none developed overt hypoparathyroidism and 2 (0.09%) had persistent evidence of normocalcemic hypoparathyroidism.
Conclusions:
This study documents normocalcemic primary hyperparathyroidism and hypoparathyroidism identified among community-dwelling individuals. Larger studies are needed to determine the true prevalence and natural history of these parathyroid disorders.
Primary hyperparathyroidism, a common endocrine disorder, is traditionally defined by hypercalcemia and an elevated or inappropriately normal PTH concentration. A newer presentation of primary hyperparathyroidism has been described in which serum calcium is normal and PTH is elevated in the absence of secondary causes of hyperparathyroidism, such as renal disease or vitamin D deficiency (1–6). Recognition of this phenotype of primary hyperparathyroidism, normocalcemic primary hyperparathyroidism, supports a biphasic chronological time course, in which PTH levels are first elevated but serum calcium is normal, followed by the development, in some, of frank hypercalcemia. Although normocalcemic primary hyperparathyroidism was recognized by the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism in 2008 (7), little is known about its epidemiology or natural history. The descriptions of normocalcemic primary hyperparathyroidism are confounded among the various studies published to date by differing methods to exclude secondary hyperparathyroidism (8–11). Moreover, reports of normocalcemic primary hyperparathyroidism have come largely from referral centers in which subjects were seen for a suspected metabolic bone disease (12–15). For example, among 37 individuals who were referred to a metabolic bone disease unit and subsequently diagnosed with normocalcemic primary hyperparathyroidism, 57% had osteoporosis by bone mineral density (BMD) T-scores <−2.5, 11% had documented fragility fractures, and 14% had nephrolithiasis (10). These individuals were thus more symptomatic than the typical cohort of patients with hypercalcemic primary hyperparathyroidism (16). These studies, although defining a new phenotype of primary hyperparathyroidism, could not give insight into how frequently community-dwelling individuals would be identified if not part of a referral population.
In contrast to primary hyperparathyroidism, hypoparathyroidism is a disease characterized by hypocalcemia and abnormally low or absent PTH levels. Hypoparathyroidism occurs primarily as an autoimmune disorder or after neck surgery. Permanent postoperative hypoparathyroidism has been reported in 2% to 13% of patients after total thyroidectomy (17). Progressive loss of parathyroid function may occur over months to years (18). In the context of previous surgical damage or autoimmune destruction of the parathyroid glands, it follows that there may be a first phase of the disease in which the serum calcium level is maintained but that the PTH levels are low, forming a pathophysiological counterpart to normocalcemic primary hyperparathyroidism. This phase is not likely to be recognized because PTH levels are rarely measured when the serum calcium concentration is normal. Up to now, the discovery of normocalcemic or subclinical hypoparathyroidism has been primarily in the context of hypocalcemia, sometimes life-threatening, after bisphosphonate administration to patients not previously recognized to have inadequate parathyroid gland reserves (19–22). To our knowledge, there has never been a formal investigation of the prevalence of normocalcemic hypoparathyroidism. In particular, no study has focused upon a community-dwelling population that is not suspected of an underlying metabolic bone disease.
We hypothesized that screening unselected, nonreferral community-dwelling populations, such as The Osteoporotic Fractures in Men (MrOS) study and Dallas Heart Study (DHS), would identify asymptomatic subjects with normocalcemic primary hyperparathyroidism and normocalcemic hypoparathyroidism. Recognizing these 2 populations with subclinical hyper- or hypoparathyroidism would significantly advance our understanding of the spectrum and development of parathyroid disease.
Materials and Methods
Study populations
The MrOS study is an unselected community-based study investigating risk factors for fracture in older men (23, 24). Ambulatory, community-dwelling men aged 65 years or older without bilateral hip replacements were included. In brief, 5994 men were recruited from 6 U.S. clinical centers (Birmingham, Alabama; Minneapolis, Minnesota; Palo Alto, California; the Monongahela Valley near Pittsburgh, Pennsylvania; Portland, Oregon; and San Diego, California) for a baseline visit between March 2000 and April 2002. Participants were not recruited with regard to their bone health. We evaluated a random subset of 2503 men (42% of the entire cohort). All participants provided written informed consent. The study was approved by institutional review boards at all institutions.
The DHS is a population-based cohort study designed to study cardiovascular disease among different race/ethnic groups (25). In brief, a probability sample of 6101 male and female residents of Dallas County aged 18 to 65 years were recruited from July 2000 to January 2002. The DHS (DHS1) became a longitudinal study when laboratory and other data were collected approximately 8 years later (DHS2) (NCT00344903). We evaluated the 3557 subjects, aged 18 to 65 years, from DHS1 who completed the phlebotomy visit (58% of the entire cohort). Follow-up data were available in 2122 of these subjects 8 years later. All participants provided written informed consent. The study was approved by institutional review board at the University of Texas Southwestern.
Assessment of serum calcium, PTH, and 25-hydroxyvitamin D
MrOS study
PTH was measured at the Columbia University Medical Center Bone Marker laboratory using immunoradiometric assay (total intact PTH [second generation]; Scantibodies Laboratory Inc, Santee, California) as previously described (26). The normal range of the assay is 14 to 66 pg/mL. Interassay and intra-assay coefficients of variation (CV) are 8.4% and 5.6%, respectively. Serum calcium was measured by automated techniques, with a normal range of 8.4–10.4 mg/dL. 25-Hydroxyvitamin D was measured by liquid chromatography/mass spectrometry at the Mayo Clinic (Rochester, MN) using mass spectrometry as previously described (27), with a sensitivity of 4 ng/mL for 25-hydroxyvitamin D2 and 2 ng/mL for 25-hydroxyvitamin D3 and an interassay and intra-assay CV of 4.4% and 4.9%, respectively.
The DHS
PTH was measured at the Columbia University Medical Center Bone Marker laboratory using chemiluminescence immunoassay [Intact PTH (second generation); Immunodiagnostic Systems, Scottsdale, Arizona]. The normal range of the assay is 14.3 to 55.0 pg/mL. Interassay and intra-assay CVs are <7% and <5%, respectively. Serum calcium was measured by automated techniques, with a normal range of 8.4 to 10.2 mg/dL. 25-Hydroxyvitamin D was measured by ELISA (Immunodiagnostic Systems), with a sensitivity of 2 ng/mL and interassay and intra-assay CVs of <10% and <8%, respectively.
Other measures
For both studies, demographic characteristics were self-reported. Body mass index (BMI) was calculated based on measured height and weight using standard equipment. The Modification of Diet in Renal Disease (MDRD) study equation was used to estimate glomerular filtration rate by the following formula: 186 × serum creatinine−1.154 × age−0.203 × (1.212 if black) × (0.742 if female) (28). Serum calcium was adjusted for hypoalbuminemia by the following formula: [0.8 × (4.0 − patient's albumin) + serum calcium]. 25-Hydroxyvitamin D deficiency was defined as a level ≤20 ng/mL, consistent with the most recent definition of vitamin D deficiency by the Institute of Medicine (29).
MrOS study
Medication use was assessed on the baseline questionnaire and verified by review of medication bottles by trained staff. Calcium and vitamin D intake/supplement use was captured at baseline using a modified Block Food Frequency Questionnaire. All additional measures have been previously reported. Available bone turnover markers included procollagen I N-terminal propeptide (Roche Diagnostics, Mannheim, Germany) with interassay and intra-assay CVs of <4.4%, C-terminal telopeptide (Roche Diagnostics) with interassay and intra-assay CVs of <4.2%, and tartrate-resistant acid phosphatase (SBA-Sciences, Turku, Finland) with interassay and intra-assay CVs of <7% and <4.2%, respectively (30). Sex hormone measures included testosterone and estradiol, measured with gas chromatography/liquid chromatography/mass spectrometry, with mean CVs of 3.2% and 3.5%, respectively (31), and SHBG (Diagnostic Products Corp, Los Angeles, California) with CV of 7.1% (31). Free fractions of testosterone and estradiol were calculated by the method of Södergård and colleagues (31, 32).
BMD was measured at the lumbar spine and proximal femur using dual-energy x-ray absorptiometry (DXA) (23) and central quantitative computed tomography (CT) (cQCT) (33) at baseline. Each clinical site used DXA machines of the same model and manufacturer (QDR 4500; Hologic, Inc, Waltham, Massachusetts). The intraclinic CV for spine phantoms was 0.34% to 0.42% and for hip phantoms was 0.37% to 0.58%. The interclinic CV for the spine was 0.6% spine and for the hip was 0.9%, with the maximum difference between means 1.4% for the spine and 2.2% for the hip. Although different CT machines were used at each site, the same type of calibration phantom (Image Analysis, Columbia, Kentucky) with known hydroxyapatite concentrations (0, 75, and 150 mg/cm3) was included in every scan. Images were obtained using a standardized protocol in which the lumbar region was scanned from 5 mm above the L1 superior endplate to 5 mm below the L2 inferior endplate.
The DHS
Previously measured bone turnover markers included osteoprotegerin (R&D Systems, Minneapolis, Minnesota) with interassay and intra-assay CVs of 10.6% and 3.6%, respectively (34) and C-terminal telopeptide (Roche Diagnostics) with interassay and intra-assay CVs of <4.2%.
Statistical analysis
Hypercalcemic primary hyperparathyroidism was defined as an albumin-adjusted serum calcium above the assay reference range (MrOS normal range, 8.4–10.4 mg/dL; DHS normal range, 8.4–10.2 mg/dL) with serum PTH greater than the upper limit of the assay (MrOS normal range, 14–66 pg/mL, DHS normal range, 14.3–55.0 pg/mL) or inappropriately normal (≥ 25 pg/mL) (35). Normocalcemic primary hyperparathyroidism was defined as serum PTH greater than the upper limit of the assay with normal albumin-adjusted serum calcium, and excluding disorders associated with secondary hyperparathyroidism, including renal insufficiency (creatinine clearance <60 mL/min), vitamin D deficiency (25-hydroxyvitmamin D ≤20 ng/mL), and thiazide diuretic use (available for both MrOS and DHS) and/or lithium use (available only in DHS).
Overt hypoparathyroidism was defined as serum PTH below the reference range of the assay along with an albumin-adjusted serum calcium concentration below the assay reference range. Normocalcemic hypoparathyroidism was defined as serum PTH below the reference range of the assay along with a normal albumin-adjusted serum calcium concentration.
Characteristics of the subjects were summarized with descriptive statistics, using frequencies and percentages for categorical variables. For continuous variables, mean and SD were calculated, and these characteristics were compared across groups by Wilcoxon rank sum test. For discrete variables, characteristics were compared between groups by χ2. Data are reported as means and SDs. The α-level set at 0.05 was adjusted with a Bonferroni correction to account for multiple comparisons.
Results
MrOS: epidemiology
Of the randomly selected 2503 subjects, 139 did not have serum calcium values and were excluded, leaving 2364 men for this analysis. We identified 27 men with abnormal albumin-adjusted serum calcium, including 17 men with hypercalcemic primary hyperparathyroidism (excluded from further analysis). We identified 87 men with elevated PTH and normal albumin-adjusted serum calcium. We excluded all common secondary causes of hyperparathyroidism: renal insufficiency (52 excluded), vitamin D deficiency (24 excluded), and thiazide diuretic use (2 excluded). Nine men remained in whom the presence of normocalcemic primary hyperparathyroidism was established as defined (prevalence 0.4%). There were no significant differences between subjects provisionally identified with normocalcemic primary hyperparathyroidism and those with normal PTH in terms of age, height, weight, BMI, phosphorus, bone turnover markers, testosterone, estradiol, SHBG, or lumbar spine or femoral neck BMD by DXA or cQCT (Table 1).
Table 1.
MrOS: Characteristics of Subjects With Normocalcemic Primary Hyperparathyroidism vs Normal PTHa
| Parameter | Normocalcemic Primary Hyperparathyroidism (n = 9) | Normal PTH (n = 2224) | P Value |
|---|---|---|---|
| Age, y | 70.0 ± 6 | 73.5 ± 6 | .04 |
| Height, cm | 176.1 ± 11 | 174.3 ± 7 | .90 |
| Weight, kg | 88.6 ± 20 | 83.4 ± 13 | .50 |
| BMI, kg/m2 | 28.3 ± 3 | 27.4 ± 4 | .49 |
| White, % | 8 (88.9) | 2031 (91.3) | .56 |
| Serum calcium adjusted for albumin, mg/dL | 9.4 ± 0.6 | 9.3 ± 0.3 | .75 |
| Intact PTH, pg/mLb | 77.5 ± 13 | 32.5 ± 11 | <.0001 |
| Serum phosphorus, mg/dL | 3.0 ± 0.5 | 3.2 ± 0.4 | .35 |
| 25-Hydroxyvitamin D, ng/mLc | 25.2 ± 5 | 26.8 ± 9 | .48 |
| Creatinine, mg/dL | 1.0 ± 0.1 | 1.0 ± 0.2 | .76 |
| Procollagen I N-terminal propeptide, ng/mL | 31.6 ± 6 | 38.3 ± 25 | .72 |
| C-terminal telopeptide, ng/mL | 0.4 ± 0.2 | 0.4 ± 0.2 | .74 |
| Tartrate-resistant acid phosphatase 5b, U/L | 3.4 ± 0.6 | 3.2 ± 1.0 | .48 |
| SHBG, nmol/L | 55.9 ± 22 | 49.2 ± 20 | .42 |
| Testosterone, ng/mL | 526.8 ± 302 | 406.2 ± 171 | .47 |
| Free testosterone, ng/mL | 9.4 ± 4 | 7.9 ± 3 | .58 |
| Estrogen, pg/mL | 24.7 ± 11 | 22.5 ± 9 | .92 |
| Free Estrogen, pg/mL | 0.5 ± 0.2 | 0.5 ± 0.2 | .91 |
| Lumbar spine BMD, g/cm2 | 1.1 ± 0.1 | 1.2 ± 0.3 | .99 |
| Femoral neck BMD, g/cm2 | 0.8 ± 0.1 | 0.8 ± 0.1 | .97 |
| Single-slice integral BMD, average L1L2, g/mL | 0.24 ± 0.03 | 0.21 ± 0.04 | .02 |
| Single-slice trabecular BMD, average L1L2, g/mL | 0.13 ± 0.02 | 0.11 ± 0.04 | .08 |
| Femoral neck, integral BMD, g/mL | 0.28 ± 0.05 | 0.29 ± 0.06 | .75 |
| Femoral neck, trabecular BMD, g/mL | 0.09 ± 0.05 | 0.07 ± 0.05 | .46 |
Results are shown as mean ± SD. Values in bold remain significant with Bonferroni correction.
By definition, PTH was >66 pg/mL in the subjects with normocalcemic primary hyperparathyroidism.
By definition, 25-hydroxyvitamin D was >20 pg/mL in the subjects with normocalcemic primary hyperparathyroidism.
We did not identify any men with overt hypoparathyroidism but identified 26 subjects with normal serum calcium but a low PTH value (prevalence 1.1%). The men with a provisional diagnosis of subclinical normocalcemic hypoparathyroidism had higher phosphorus levels (3.5 ± 0.4 vs 3.2 ± 0.4 mg/dL; P = .0001) than the subjects in the cohort with normal PTH (Table 2). Most men with normocalcemic hypoparathyroidism were taking ≥1000 mg calcium per day (54% vs 23%; P = .0006). There were no significant differences between subjects provisionally diagnosed with normocalcemic hypoparathyroidism and those with normal PTH in terms of age, height, weight, BMI, bone turnover markers, testosterone, estradiol, SHBG, or lumbar spine or femoral neck BMD by DXA or cQCT.
Table 2.
MrOS: Characteristics of subjects with normocalcemic hypoparathyroidism vs normal PTHa
| Parameter | Normocalcemic Hypoparathyroidism (n = 26) | Normal PTH (n = 2224) | P Value |
|---|---|---|---|
| Age, y | 73.4 ± 6 | 73.5 ± 6 | .95 |
| Height, cm | 174.5 ± 7 | 174.3 ± 7 | .69 |
| Weight, kg | 85.7 ± 12 | 83.4 ± 13 | .31 |
| BMI, kg/m2 | 28.2 ± 4 | 27.4 ± 4 | .43 |
| White, % | 23 (88.5) | 2031 (91.3) | .49 |
| Daily calcium supplementation, mg | 632 ± 520 | 344 ± 440 | .02 |
| Daily calcium supplementation >1000 mg, % | 14 (53.9) | 508 (22.8) | .0006 |
| Daily vitamin D supplementation, IU | 264 ± 230 | 227 ± 200 | .36 |
| Serum calcium adjusted for albumin, mg/dL | 9.5 ± 0.4 | 9.3 ± 0.3 | .003 |
| Intact PTH, pg/mLb | 12.2 ± 2 | 32.5 ± 11 | <.0001 |
| Serum phosphorus, mg/dL | 3.5 ± 0.4 | 3.2 ± 0.4 | .0001 |
| 25-Hydroxyvitamin D, ng/mL | 28.8 ± 8 | 26.8 ± 9 | .21 |
| Procollagen I N-terminal propeptide, ng/mL | 29.8 ± 11 | 38.4 ± 25 | .15 |
| C-terminal telopeptide, ng/mL | 0.3 ± 0.2 | 0.4 ± 0.2 | .25 |
| Tartrate-resistant acid phosphatase 5b, U/L | 3.1 ± 0.9 | 3.2 ± 1.0 | .77 |
| SHBG, nmol/L | 50.2 ± 19 | 49.4 ± 20 | .67 |
| Testosterone, ng/mL | 395.0 ± 172 | 406.2 ± 171 | .92 |
| Free testosterone, ng/mL | 7.5 ± 3 | 7.9 ± 3 | .55 |
| Estrogen, pg/mL | 19.9 ± 12 | 22.5 ± 9 | .09 |
| Free estrogen, pg/mL | 0.5 ± 0.2 | 0.5 ± 0.2 | .32 |
| Lumbar spine BMD, g/cm2 | 1.2 ± 0.12 | 1.2 ± 0.3 | .94 |
| Femoral neck BMD, g/cm2 | 0.8 ± 0.1 | 0.8 ± 0.1 | .51 |
| Single-slice integral BMD, average L1L2, g/mL | 0.21 ± 0.03 | 0.21 ± 0.04 | .48 |
| Single-slice trabecular BMD, average L1L2, g/mL | 0.11 ± 0.04 | 0.11 ± 0.04 | .89 |
| Femoral neck, integral BMD, g/mL | 0.29 ± 0.05 | 0.29 ± 0.06 | .93 |
| Femoral neck, trabecular BMD, g/mL | 0.08 ± 0.04 | 0.07 ± 0.05 | .41 |
Results are shown as mean ± SD. Values in bold remain significant with Bonferroni correction.
By definition, PTH was <14 pg/mL in the subjects with normocalcemic hypoparathyroidism.
DHS: epidemiology and natural history
Of 3557 subjects, 107 were excluded due to missing PTH or 25-hydroxyvitamin D values. Of the 3450 subjects remaining for this analysis, 50 subjects had abnormal albumin-adjusted serum calcium, including 20 with hypercalcemic primary hyperparathyroidism (excluded from further analysis). We identified 673 subjects with elevated PTH and normal albumin-adjusted serum calcium. We excluded all common secondary causes of hyperparathyroidism: renal insufficiency (56 excluded), vitamin D deficiency (499 excluded), and thiazide diuretic or lithium use (10 excluded). The remaining 108 subjects were classified provisionally with normocalcemic primary hyperparathyroidism (prevalence 3.1%).
Of the 108 subjects who were provisionally identified with normocalcemic primary hyperparathyroidism by their baseline values from the DHS study, 64 had follow-up laboratory data 8 years later. There were no differences in age, gender, BMI, calcium, phosphorus, creatinine, or bone turnover markers between subjects that had follow-up laboratory values versus subjects that did not. Hypercalcemic primary hyperparathyroidism developed in 1 individual (1.6% of cohort), and 13 (20%) continued to show evidence of normocalcemic primary hyperparathyroidism (prevalence 0.6% in the total cohort with follow-up data). Subjects with normocalcemic primary hyperparathyroidism were predominantly white (85% of subjects with normocalcemic primary hyperparathyroidism vs 32% of the normal PTH cohort, P = .0016) (Table 3). There were no differences in age, gender, BMI, calcium, phosphorus, creatinine, or bone turnover markers. Of the remaining subjects, 1 developed hypercalcemia in the setting of subsequent renal insufficiency and thiazide use; 20 continue to show evidence of hyperparathyroidism but no longer met criteria due to renal insufficiency, vitamin D deficiency, or thiazide use; and 29 had normal PTH on follow-up testing. Of the 29 subjects that had normal PTH on follow-up testing, 8 had an increase in 25-hydroxyvitamin D in the interim, mean 5.75 ng/mL (range 0.9–16).
Table 3.
DHS: Characteristics of Subjects With Normocalcemic Primary Hyperparathyroidism vs Normal PTHa
| Parameter | Normocalcemic Primary Hyperparathyroidism (n = 13) | Normal PTH (n = 2659) | P Value |
|---|---|---|---|
| Age, y | 41.3 ± 12 | 43.2 ± 10 | .37 |
| Female, % | 5 (38) | 1435 (54) | .28 |
| Height, cm | 172.2 ± 9 | 167.8 ± 10 | .12 |
| Weight, kg | 86.2 ± 22 | 84.6 ± 21 | .89 |
| BMI, kg/m2 | 28.4 ± 8 | 29.0 ± 7 | .48 |
| Ethnicity, % | .0016 | ||
| Black | 8 | 48 | |
| White | 85 | 32 | |
| Native American | 8 | 18 | |
| Asian | 0 | 2 | |
| Serum calcium adjusted for albumin, mg/dL | 9.32 ± 0.6 | 9.37 ± 0.3 | .58 |
| Intact PTH, pg/mLb | 94.8 ± 46 | 34.3 ± 10 | <.0001 |
| Serum phosphorus, mg/dL | 3.12 ± 0.6 | 3.23 ± 0.6 | .33 |
| 25-Hydroxyvitamin D, ng/mLc | 30.1 ± 11 | 19.8 ± 9 | .0002 |
| Creatinine, mg/dL | 0.93 ± 0.1 | 0.87 ± 0.2 | .09 |
| Osteoprotegerin | 1216 ± 280 | 1305 ± 720 | .81 |
| C-terminal telopeptide, ng/mL | 0.39 ± 0.2 | 0.36 ± 0.2 | .47 |
Results are shown as mean ± SD. Values in bold remain significant with Bonferroni correction.
By definition, PTH was >55.0 pg/mL in the subjects with normocalcemic primary hyperparathyroidism.
By definition, 25-hydroxyvitamin D was >20 pg/mL in the subjects with normocalcemic primary hyperparathyroidism.
We identified 1 subject with overt hypoparathyroidism (excluded from further analysis). We identified 68 subjects (1.9%) with a provisional diagnosis of normocalcemic hypoparathyroidism. Of the 26 subjects with follow-up laboratory data 8 years later, none developed overt hypoparathyroidism whereas 2 of the initial subjects (7.7%) continued to show evidence of normocalcemic hypoparathyroidism (prevalence 0.09% in the total cohort with follow-up data) (Table 4). Of the remaining subjects, 1 had hypercalcemia with low PTH, 2 had high PTH with development of renal insufficiency or vitamin D deficiency, 1 had normocalcemic primary hyperparathyroidism, and 20 had normal PTH.
Table 4.
Prevalence (95% CI) of Normocalcemic Primary Hyperparathyroidism and Normocalcemic Hypoparathyroidism in the Studied Cohorts
| Cohort | Normocalcemic Primary Hyperparathyroidism | Normocalcemic Hypoparathyroidism |
|---|---|---|
| MrOS study, % | 0.4 (0.2–0.7) | 1.1 (0.8–1.6) |
| DHS, % | ||
| Baseline | 3.1 (2.5–3.7) | 1.9 (1.4–2.4) |
| Follow-up | 0.6 (0.4–1.0) | 0.09 (0.02–0.3) |
Discussion
This is one of only a few studies to investigate the epidemiology of normocalcemic primary hyperparathyroidism in an unselected community-based sample (8–11) and the first to investigate normocalcemic hypoparathyroidism. This is also one of the first studies to track subjects with normocalcemic primary hyperparathyroidism and normocalcemic hypoparathyroidism over time from an unselected, nonreferral population (11). The results provide new insights into the natural history of these 2 subclinical disorders in community-dwelling populations. In the cohort of 2364 older men from the MrOS study, we provisionally identified 9 subjects with normocalcemic primary hyperparathyroidism (prevalence 0.4%) and 26 with normocalcemic hypoparathyroidism (prevalence 1.1%). In the cohort of 3509 adult men and women from the DHS, we provisionally identified 108 subjects with normocalcemic primary hyperparathyroidism (prevalence 3.1%). In the 64 subjects with follow-up data approximately 8 years later, 1 developed hypercalcemic primary hyperparathyroidism (1.5% of those identified with the disorder at the baseline visit) and 13 remained with persistent evidence of normocalcemic primary hyperparathyroidism on follow-up (prevalence 0.6% in the follow-up cohort). We provisionally identified 68 subjects with normocalcemic hypoparathyroidism (prevalence 1.9%), none of whom developed overt hypoparathyroidism on follow-up. Persistent disease was noted in 2 of 26 subjects with follow-up (prevalence 0.09% in the follow-up cohort).
The issue of high or low PTH levels in the setting of normal serum calcium is frequent in clinical practice and often difficult to interpret. The follow-up studies from DHS indicate that although these 2 subclinical disorders can be suspected after an initial screening profile, monitoring to document persistence of the abnormal PTH level leads to a substantially smaller number of identifiable subjects. In addition, the upper and lower limits of normal of serum calcium and PTH values are defined by the 97.5th percentile of the normal distribution, and so one might expect to find some individuals who appear to be abnormal who are in fact normal. These points underscore a premise of the diagnostic workup for any abnormal calcium or PTH state, namely, that the results have to be verified to be secure. We do not know, from DHS, whether repeat testing over a much shorter time interval would have quickly ruled out subjects who eventually, 8 years later, became part of the normal population or developed other issues that would have excluded them. Further investigation, including provocative testing of subjects with normocalcemic hypoparathyroidism to determine parathyroid gland reserves and vitamin D supplementation in subjects with normocalcemic primary hyperparathyroidism and monitoring over time to ascertain whether hypercalcemia develops, is necessary to determine whether a true disease entity is present. The prevalence of normocalcemic primary hyperparathyroidism, using the 8-year figures, is more consistent with epidemiological expectations. The prevalence of normocalcemic hypoparathyroidism, using the 8-year figures, places this subclinical disease as much more uncommon than its counterpart. This is not surprising because hypoparathyroidism is much more uncommon than hyperparathyroidism.
This investigation can be distinguished from previous studies that have described cohorts of normocalcemic primary hyperparathyroidism from a referral-based population (12–15, 36). The individuals in the current study come from nonreferral-based, community-dwelling cohorts. The subjects identified with normocalcemic primary hyperparathyroidism have bone densities similar to that of the normal PTH cohort, and it is likely, but not yet clear, whether these patients represent an asymptomatic phenotype. The results are consistent with the hypothesis that there are 2 phenotypes of normocalcemic primary hyperparathyroidism. The originally described cohort in which the overwhelming majority of subjects had target organ involvement would appear to be different from the group described here in which there was no selection bias. The development of hypercalcemic primary hyperparathyroidism as noted in the DHS cohort is consistent with our hypothesis that normocalcemic primary hyperparathyroidism precedes the hypercalcemic form of the disease in some cases (1–6). The prevalence of normocalcemic primary hyperparathyroidism has been investigated in a number of community-dwelling populations, but the results are confounded among the various studies by differing methods to exclude secondary hyperparathyroidism (8–11). In the present study, we excluded renal disease, vitamin D deficiency, and use of medications known to be associated with hyperparathyroidism. The prevalence values we detected are consistent with the expected values given the overall prevalence of hypercalcemic primary hyperparathyroidism (37–39). Possible explanations for the difference in prevalence between the cohorts include age, gender, and race/ethnicity differences between the populations. We were unable to measure ionized calcium and urine calcium excretion, which are requisite for a secure clinical diagnosis of normocalcemic primary hyperparathyroidism. In addition, there are a number of different etiologies for high or low PTH levels, such as PTH or calcium-sensing receptor mutations, which could not be excluded.
The results also provide evidence for the existence of a cohort of free-living community-dwelling individuals who have normocalcemic, subclinical hypoparathyroidism. As such, it provides a pathophysiological counterpart to normocalcemic primary hyperparathyroidism. The higher phosphorus levels, albeit within the normal range, in the subjects with normocalcemic hypoparathyroidism in the MrOS cohort is consistent with the more overt disease in which hyperphosphatemia is common. Previously reported patients have exhibited frank hyperphosphatemia at the time of the symptomatic hypocalcemia (19–22). It is likely that the higher calcium intake in the MrOS cohort represents greater calcium needs in the context of normocalcemic hypoparathyroidism. The doses of calcium supplementation taken by the subjects in the MrOS cohort in the setting of normal serum calcium should not suppress PTH to levels below the reference range (40, 41), however, there are reports indicating this may be possible in some circumstances (42, 43).
Limitations of this analysis include the lack of data regarding past medical or surgical history, including previous parathyroid or other neck surgery, and single laboratory values at each time point. Due to the limited numbers of subjects identified with normocalcemic primary hyperparathyroidism and hypoparathyroidism, we may not have had sufficient power to determine differences between groups. Population-based studies in other cohorts with larger numbers of subjects, including postmenopausal women who would be expected to have a higher prevalence of both diseases, will be needed to further document these observations and determine the true prevalence and natural history of normocalcemic primary hyperparathyroidism and normocalcemic hypoparathyroidism. Nevertheless, this study identifies normocalcemic primary hyperparathyroidism and hypoparathyroidism among community-dwelling individuals and provides important insights into these two newly described variants of classical hyper- and hypoparathyroidism.
Acknowledgments
We acknowledge Elzbieta Dworakowski, the Osteoporotic Fractures in Men (MrOS) Research Group, and the Dallas Heart Study staff.
This work was supported by National Institutes of Health (NIH) Grants DK32333, DK069350, DK095944, and AR051926. The Osteoporotic Fractures in Men (MrOS) Study is supported by NIH funding. Support was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, the National Center for Research Resources, and the NIH Roadmap for Medical Research under the following grant numbers: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01 AG027810, and UL1 RR024140. The Dallas Heart Study is funded by a center grant from the Donald W. Reynolds Foundation and in part by Grant UL1TR000451 from the National Center for Advancing Translational Sciences, NIH.
Disclosure Summary: J.P.B. is a consultant for Amgen, Eli Lilly, Radius, NPS Pharmaceuticals, Merck, Warner Chilcott, and GSK and receives research support from NPS Pharmaceuticals and Amgen. No conflicts of interest are reported for the other authors.
Footnotes
- BMD
- bone mineral density
- BMI
- body mass index
- cQCT
- central quantitative computed tomography
- CV
- coefficient of variation
- DHS
- Dallas Heart Study
- DXA
- dual-energy x-ray absorptiometry
- MrOS study
- The Osteoporotic Fractures in Men study.
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