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Secondary Hyperparathyroidism and Bone Turnover in Elderly Blacks and Whites

Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University (S.S.H., B.D.-H.), Boston, Massachusetts 02111; and Framingham Heart Study (E.S.), Boston University, School of Medicine, Boston, Massachusetts

Address all correspondence and requests for reprints to: Susan Harris, D.Sc., Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, Massachusetts 02111.

Abstract

This study was undertaken to describe the prevalence of secondary hyperparathyroidism in African-American and Caucasian participants in the Boston Low-Income Elderly Osteoporosis Study and to examine and compare associations of hyperparathyroidism with biochemical markers of bone turnover and bone density in the two racial groups. Serum osteocalcin and serum cross-linked N-telopeptides of type I collagen, and calcaneal bone mineral density were measured in February or March in 255 men and women, 64 yr of age and older. Subjects were categorized as normal or as having hyperparathyroidism, based on a serum PTH concentration below or above the top of the normal range (6.9 pmol/liter), respectively. The prevalence of hyperparathyroidism was 38% in the 144 black subjects and 20% in the 111 white subjects. Serum osteocalcin and cross-linked N-telopeptides of type I collagen were significantly higher in both black and white hyperparathyroid subjects (P < 0.05), and the hyperparathyroid-related difference in osteocalcin was greater among black than white subjects. Hyperparathyroidism was significantly associated with reduced heel bone mineral density in blacks (P = 0.008) but not in whites. This study provides evidence that secondary hyperparathyroidism is prevalent in elderly adults, both black and white, and that it should not be viewed as a benign condition in either group. Recent public health efforts to promote higher calcium and vitamin D intakes, targeted predominantly to older Caucasians, should also be directed to older African-Americans.

WE PREVIOUSLY REPORTED that a substantial percentage of participants in the Boston Low-Income Elderly Osteoporosis Study had low 25-hydroxyvitamin D (25OHD) concentrations in winter, that African-American participants had lower concentrations than Caucasians, and that low concentrations were associated with higher PTH concentrations (1) in both Caucasians and African-Americans. This finding was consistent with reports describing other elderly populations (2, 3, 4, 5). Although higher PTH is normally associated with higher bone turnover and lower bone density, African-American adults have been reported to have lower concentrations of biochemical markers of bone turnover (6, 7, 8, 9) and higher bone density (8, 10, 11) than Caucasians of similar age. This has led to the hypothesis that African-Americans may have a skeletal resistance to the bone-resorbing effects of PTH (6), and to experimental studies that support this hypothesis (12, 13). The purpose of the present report is to describe the prevalence of secondary hyperparathyroidism (HPTH) among Caucasian and African-American participants in the Boston Low-Income Elderly Osteoporosis Study, and to examine and compare associations of HPTH with markers of bone turnover and with bone density in the two racial groups.

Subjects and Methods

Subjects

As previously described, the subjects were recruited from 14 low-income, elderly housing units in urban Boston (1). The only exclusion criterion for enrollment was age younger than 64 yr, and a total of 349 subjects were enrolled. For the present analysis, the following additional exclusions were applied: race other than black or white (n = 44); missing measurements of PTH, serum calcium, osteocalcin, or NTx (n = 35); medical conditions associated with abnormal bone metabolism (n = 2); and use of hormone replacement therapy or medications for osteoporosis (n = 13). The remaining 255 subjects are included in this report.

Measurements

Study measurements were made in February and March of 1999. Laboratory measurements were made in the Nutrition Evaluation Laboratory, United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University. Serum osteocalcin was measured with osteocalcin-I125 RIA kits (DiaSorin, Inc., Stillwater, MN). The interassay coefficient of variation (CV) is 10%, the intraassay CV is 5%, and the manufacturer’s reference range is 1.17–5.17 nmol/liter for women and 1.91–5.55 nmol/liter for men. Serum cross-linked N-telopeptides of type I collagen (NTx), a marker of bone resorption, was measured with a competitive, enzyme-linked immunosorbent assay (Osteomark NTx Serum, Ostex International, Inc., Seattle, WA). The interassay CV is 6.9%, the intraassay CV is 4.6%, and the manufacturer’s reference range is 3.2–40 nmol/liter bone collagen equivalents (BCE). Plasma 25OHD was measured by the competitive protein binding method of Chen et al. (14), without the optional chromatography step; and the intra- and interassay CVs are 5.0% and 7.3%, respectively. The laboratory reference range for 25OHD is 20–137 nmol/liter. Serum intact PTH was measured with Allegro intact RIA kits from Nichols Institute Diagnostics (San Juan Capistrano, CA); and the intra- and interassay CVs are 5.6% and 6.6%. The reference range for PTH is 1.1–6.9 pmol/liter. Subjects were categorized as having secondary HPTH if they had PTH greater than 6.9 pmol/liter and serum total calcium that was within the reference range. Serum total calcium was measured with a Nova 7 calcium analyzer (Nova Biochemical, Waltham, MA); and the intra- and interassay CVs are 1.2% and 3.0%. The reference range for serum calcium is 2.08–2.56 nmol/liter.

Bone mineral density of the left heel was measured with a PIXI dual-energy x-ray absorptiometer (Lunar Corp., Madison, WI). The manufacturer’s reported CV of measurements made with this instrument is 2%. Heights and weights were measured by interviewers with portable measuring devices.

Information about education, smoking, travel, diet, medication use, and use of walking aids was obtained by questionnaire. As previously described (1), vitamin D intake was categorized as low (<8 ounces/d milk and no vitamin D supplement use), medium (8 ounces/d milk and/or < daily vitamin D supplement use), or high (daily vitamin D supplement use, regardless of milk intake). Similarly, calcium intake was defined as low (<2 servings/d dairy products and no calcium supplement use), medium (2 servings/d of dairy products and/or < daily calcium supplement use), or high (daily calcium supplement use, regardless of dairy product intake).

Statistical analysis

Characteristics of HPTH and normal subjects were compared with two-tailed t tests for two independent samples and with the chi-square test for differences in proportion. Group means were adjusted and compared with analysis of covariance (ANCOVA), and possible interactions were investigated by including interaction terms in the ANCOVA models. Use of a walking aid was considered a potential confounder in analyses of bone turnover and BMD by PTH status, because limited mobility has been found to be a predictor of increased bone turnover in elderly subjects, independent of their PTH status (15). Linear associations were investigated and described with Pearson correlation coefficients and with multivariable linear regression. ANCOVA and regression analyses were conducted with the General Linear Models procedure of SPSS, Inc. (Chicago, IL). Missing measurements included 25OHD in one subject, height and weight in one subject, and BMD in seven subjects, resulting in reduced sample sizes for analyses involving those variables. P values below 0.05 were considered to indicate statistical significance.

Results

Ages of the 255 subjects in this study ranged from 64–100 yr. The prevalence of secondary HPTH was 30.2% in the group as a whole but was significantly higher in black than in white subjects (Table 1). Characteristics of subjects with and without HPTH are shown in Table 2. The subjects with HPTH were significantly more likely to report current use of a walking aid (cane, walker, or both). Other characteristics did not differ significantly by PTH status. Biochemical characteristics of the 2 groups are shown in Table 3. By definition, PTH was substantially higher in the HPTH group and, as expected, 25OHD was lower. Serum calcium did not differ significantly between the groups, and mean values were in the mid-normal range.

Adjusted and unadjusted heel BMD differed significantly by PTH status in blacks but not in whites (Table 3), and there was a statistically significant interaction of race with PTH status (P = 0.041). Among blacks, heel BMD was significantly lower in subjects with HPTH than in normal subjects.

Mean bone marker concentrations, adjusted for age, sex, weight, and use of a walking aid, did not differ significantly by race in the group as a whole; but within the HPTH subset, osteocalcin tended to be higher in blacks than whites (P = 0.057). BMD, adjusted for age, sex, weight, and use of a walking aid, was significantly higher in blacks than in whites overall (P = 0.005), but the race difference was smaller and not significant in the subset with HPTH (P = 0.991).

Both bone markers were significantly and similarly associated with BMD in blacks and whites. In the group as a whole, partial correlations of osteocalcin and NTx with BMD, adjusted for age, sex, weight, and use of a walking aid, were -0.30 (P < 0.001) and -0.24 (P < 0.001), respectively.

Mean adjusted values of bone markers and BMD are shown separately, by sex, in Figs. 1 and 2. Though associations of PTH status with bone markers and BMD tended to be modestly weaker in men than women, there were no statistically significant interactions of sex with PTH status in any of these analyses.

View larger version (44K): [in this window] [in a new window]   Figure 1. Mean concentrations of serum osteocalcin and serum NTx, adjusted for age, weight, and use of a walking aid in black and white men and women, by normal (N, bars with diagonal lines) and hyperparathyroid (HPTH, solid bars) status. Error bars, SEM; asterisks, differences by PTH status within race/sex groups (P < 0.05); parentheses, sample sizes.

View larger version (42K): [in this window] [in a new window]   Figure 2. Mean heel BMD adjusted for age, sex, weight, and use of a walking aid in black and white adults by normal (N: bars with diagonal lines) and hyperparathyroid (HPTH: solid bars) status. Error bars, SEM; asterisks, differences by PTH status within race/sex groups (P < 0.05); parentheses, sample sizes.

This study demonstrates a high prevalence of secondary HPTH among elderly Caucasian adults and an even higher prevalence among African-Americans. Secondary HPTH was associated with higher bone turnover and lower heel bone density in both groups. This finding is consistent with many previous reports in elderly Caucasians (16, 17, 18, 19), but it adds new evidence to support a harmful effect of poor calcium and vitamin D status in African-Americans. Two carefully conducted experimental studies have demonstrated that, at least over short periods and in young adults, an acute increase in PTH causes less skeletal calcium release in blacks than in whites (12, 13). The present study indicates that in elderly black adults in whom PTH concentrations are at stable levels, the harmful effects of elevated PTH on bone turnover and bone density are as strong or stronger than in whites of similar age and socioeconomic background. This apparent contradiction may indicate that the adaptive skeletal response of blacks is reduced with aging or that it is reduced with sustained HPTH , but long-term studies would be needed to test these hypotheses.

We did not observe lower rates of bone turnover in black, compared with white, subjects. This finding differs from that of Kleerekoper and colleagues (8), who observed lower concentrations of osteocalcin and other bone markers among blacks in a large group of health maintenance organization members. Perhaps this difference was observed because that population was younger than ours (mean age, 65 vs. 75 yr). A cross-sectional study by Perry and colleagues (3) indicated that osteocalcin may increase more rapidly with age in blacks than in whites. Although we, like others, observed higher BMD among blacks than whites overall, the race difference in BMD was much smaller among subjects with HPTH. Although blacks have higher peak bone mass than whites (10), their higher prevalence of HPTH in old age may partially diminish their BMD advantage.

The study included a relatively small number of men with secondary HPTH, reflecting both the enrollment of fewer men and their lower prevalence of secondary HPTH. There was some suggestion that the associations of secondary HPTH with bone markers and BMD were modestly weaker in men than women; but because of the small number of hyperparathyroid white men (n = 4), the lack of a statistically significant PTH by sex interaction, and the absence of a good physiological argument for such an interaction, we are inclined to attribute this finding to chance. Others may wish to address this question in a larger group of men and women.

The PTH concentration we used to define HPTH was the upper limit of the laboratory’s reference range. This is a somewhat arbitrary way to distinguish normal from abnormal values, because the reference range is derived from a population that undoubtedly includes individuals whose calcium and vitamin D status is not optimal. If a lower cutoff had been selected, the prevalence of secondary HPTH would have been even higher than that reported.

Though other factors (including declines in renal function) also influence age-related increases in PTH (20), poor calcium and vitamin D intakes are among the most easily modified factors. The recommended calcium intake for adults over 50 is 1200 mg/d (21), but Caucasian adults in that age group consume less than 800 mg/d (22), and African-Americans consume less than 600 mg/d. Similarly, vitamin D insufficiency is common in both groups, but it is especially common in African-Americans (1). This study provides evidence that secondary HPTH is prevalent in elderly adults, both black and white, and that it may be associated with adverse effects on bone metabolism in both groups. Recent public health efforts to promote higher calcium and vitamin D intakes, targeted predominantly at older Caucasians, should also be directed at older African-Americans.

Acknowledgments

Footnotes

This material is based on work supported by the U.S. Department of Agriculture, under agreement No. 58-1950-9-001, and by Merck & Co., Inc. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture.

Abbreviations: ANCOVA, Analysis of covariance; BCE, bone collagen equivalents; BMD, bone mineral density; CV, coefficient of variation; HPTH, hyperparathyroidism; NTx, cross-linked N-telopeptides of type I collagen; 25OHD, 25-hydroxyvitamin D.

Received January 10, 2001.

Accepted April 25, 2001.

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