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Original Article |
Department of Medicine (I.A.N., M.A.M., K.I.), Section of Endocrinology, and Departments of Orthopedic Surgery (C.G.) and Surgery (B.K.), Yale University School of Medicine, New Haven, Connecticut 06520-8020; and Osteoporosis Center (R.L.), Hamden, Connecticut 06517
Address all correspondence and requests for reprints to: Karl Insogna, M.D., Yale School of Medicine, 333 Cedar Street, FMP 106, P.O. Box 208020, New Haven, Connecticut 06520-8020. E-mail: karl.insogna{at}yale.edu.
Abstract
It remains unclear whether mild primary hyperparathyroidism results in accelerated bone loss, with recent studies reaching different conclusions. This could be due to intrinsic differences in disease activity not captured by the classical biochemical markers of the disease. Because circulating levels of IL-6 and IL-6 soluble receptor (IL-6sR) are reportedly elevated in patients with hyperparathyroidism, we sought to determine whether measures of this cytokine axis could be helpful in determining the risk for bone loss in hyperparathyroidism. We prospectively followed 23 patients with hyperparathyroidism for 22 ± 1.5 months and found that baseline circulating levels of IL-6sR correlated significantly with rates of bone loss at the total femur (r = -0.53, P < 0.01). Furthermore, the combination of a serum IL-6sR in the upper tertile (
45.6 ng/ml) and IL-6 in the upper half (11.8 pg/ml) of values in the whole group defined a subset of patients with a significantly greater rate of yearly bone loss at the total femur than the remainder of the group (-2.6 ± 1.3% vs. +0.4 ± 0.3%, P < 0.05). We conclude that the combined measurements of serum IL-6sR and IL-6 may be helpful in identifying patients with untreated hyperparathyroidism who are more likely to experience bone loss at the total femur.
WHETHER MILD ASYMPTOMATIC primary hyperparathyroidism, as is typically encountered in clinical practice, is detrimental to the skeleton remains uncertain. This issue is clinically important because primary hyperparathyroidism often is diagnosed in older women and could potentially accelerate postmenopausal and age-related bone loss in these individuals.
The only definitive therapy available for the treatment of hyperparathyroidism is surgery. In a study by Silverberg et al. (1), parathyroidectomy in 34 patients with primary hyperparathyroidism was associated with a mean increase in lumbar spine bone mineral density (BMD) of 12.8% and in the femoral neck of 12.7%. These impressive gains in BMD were also seen when the analysis was restricted to postmenopausal women. However, many patients do not meet the criteria for urgent surgical intervention as set forth by the 1991 NIH Consensus Development Conference, leaving a significant number who have the choice to be followed conservatively or undergo surgery. Concern about the detrimental effect of a conservative approach on the skeleton has prompted a number of studies. In one of the largest, Silverberg et al. (1) found little change in BMD over a period of 10 yr in patients who did not meet the criteria for urgent surgical intervention at presentation. In contrast, two smaller studies, by Guo et al. (2) and Grey et al. (3), reported accelerated bone loss in postmenopausal women with primary hyperparathyroidism. Furthermore, two recent studies (4, 5) have suggested that primary hyperparathyroidism is associated with a greater risk of fracture when affected individuals are compared with eucalcemic controls.
These divergent data could be the result of subtle differences in the populations studied or methodologic differences in study design. Alternatively, differences in disease activity could be responsible for the variable degrees of bone loss in patients with mild primary hyperparathyroidism. Neither classical biochemical markers of disease activity such as PTH, 1,25(OH)2 vitamin D, and nephrogenous cAMP nor indirect markers of bone resorption have proved useful in predicting changes in BMD in patients with primary hyperparathyroidism (1).
The mechanisms by which PTH exerts its effects on the skeleton are incompletely understood. The effects on bone resorption appear to occur indirectly. PTH binds to high-affinity receptors expressed by osteoblasts or osteoblastlike cells in bone and induces these cells to release factors including cytokines that directly modulate the number and/or activity of osteoclasts. Variability in the clinical spectrum of disease in hyperparathyroidism could be due to differing cytokine profiles induced by PTH. Among the cytokines thought to participate in PTH-induced bone resorption, recent interest has focused on IL-6 and IL-6 soluble receptor (IL-6sR). Circulating levels of IL-6 and IL-6sR have been shown to be significantly elevated in patients with primary hyperparathyroidism and to correlate with markers of bone resorption in these patients (6). The case for the IL-6/IL-6sR cytokine system playing a role in mediating the catabolic effects of PTH on the skeleton has been further strengthened by the work of Grey et al. (7), who reported that neutralizing IL-6 in vivo attenuates PTH-induced bone resorption in mice. The resorptive response to PTH was also reduced in IL-6 knockout mice (7).
Whether these findings are relevant to longer-term changes in skeletal mass or are of clinical use is uncertain. To begin to address these questions, we conducted a prospective longitudinal observational study in patients with primary hyperparathyroidism to determine whether circulating components of the IL-6/IL-6sR cytokine system predict rates of bone loss in patients with this disease.
Patients and Methods
Patients
Patients with primary hyperparathyroidism were enrolled in the study if they had proven primary hyperparathyroidism, and a decision had been made to follow their disease conservatively, either by their physician or the patient. Women who were receiving the same dose of hormone replacement therapy (HRT) for more than 2 yr were eligible for study. Patients who were treated with supraphysiologic doses of corticosteroids, receiving bisphosphonates, or begun on hormone replacement therapy less than 2 yr before the start of the study were excluded. Patients were not allowed to start or change any medications or nutritional supplements known or thought to affect mineral metabolism. Patients were dropped from the study if they started, stopped, or changed the dose of HRT.
Sixty-two patients were identified as having elevated serum PTH values by reviewing weekly records from the Yale Mineral Metabolism Laboratory. Of these, 45 proved to have primary hyperparathyroidism as determined by elevated fasting serum calcium and PTH and no other clinical, biochemical, or historical evidence for other causes of hypercalcemia. Thirty-nine patients could be contacted. Three of these had already undergone parathyroid adenomectomy at the time they were contacted, leaving 36 potentially eligible subjects. One patient had just started HRT, one was being treated with alendronate, one was taking large doses of corticosteroids intermittently for advanced emphysema, and four refused to participate in the study. This left 29 subjects eligible for study. These 29 patients, all of whom fulfilled study entry criteria, were included in the biochemical analyses. Three subjects underwent curative surgery after the first study visit, and three more study subjects were followed up for only 6 months. These six patients were excluded from the longitudinal analyses correlating change in BMD with circulating cytokine levels.
Study protocol
At baseline and every 6 months thereafter, blood was drawn and 2- and 24-hr urine specimens were collected. Bone density at the femur, lumbar spine, wrist, and total body were measured every 6 months with a Hologic 4500 machine (Hologic, Inc., Waltham, MA), which uses fan beam technology. Only BMD data for patients followed up for at least 1 yr were included in the analyses. As noted, six patients who had BMD measurements only at baseline (three patients) or only at baseline and 6 months (three patients) were not included in the BMD analyses.
Measurements
Serum biochemistries and circulating levels of calcitropic hormones. Serum calcium was measured using an atomic absorptiometer (model 2380; Perkin-Elmer, Norwalk, CT). Urinary creatinine was measured in the Yale-New Haven Hospital Clinical Chemistry laboratory using an automatic analyzer (model 744; Hitachi). Midmolecule PTH, plasma 1,25 (OH)2vitamin D, and urine and plasma cAMP were measured as previously reported (8, 9, 10, 11). Nephrogenous cAMP was calculated as previously reported (12).
Circulating levels of IL-6 and IL-6sR. Serum levels of IL-6 and IL-6sR were measured every 3 months by highly sensitive solid-phase ELISA (R&D Systems, Minneapolis, MN). The lower limits of detection for these assays are 0.09 pg/ml for IL-6 and 0.14 ng/ml for IL-6sR. The precision of these assays in our laboratory are: IL-6—intraassay coefficient of variation (CV) 3.3%, interassay CV 3.6%; IL-6sR—intraassay CV 2.3%, interassay CV 4.7%. The normal range for IL-6 in postmenopausal women is 0.5–4.4 pg/ml as determined in our laboratory and for IL-6sR 16.4–25.1 ng/ml as determined by the manufacturer.
Markers of bone turnover. Serum type I collagen carboxyterminal telopeptide (ICTP) was measured by an equilibrium RIA (INCSTAR Corp., Stillwater, MN) with a sensitivity of 0.5 µg/liter. The intraassay CV for this assay in our laboratory was 3.8%, and the interassay CV was 4.6%. Serum N-telopeptide of type I collagen (NTX) were measured by ELISA (Ostex, Seattle, WA). Urinary deoxypyridinoline (DPD) cross-links were also measured by ELISA (Metra Biosystems, Mountain View, CA). The CV for these measurements in our laboratory are: serum NTX—intraassay 4.2%, interassay 5.4%; urine DPD—intraassay 4.3%, interassay 4.6%. Urine DPD was corrected for urinary creatinine, which was measured by a colorimetric method using alkaline picrate solution. The sensitivity of the serum NTX assay is 3.2 nM bone collagen equivalents (BCE), and 1.1 nM/mmol creatinine for urine DPD. The normal ranges as provided by the respective manufacturers are serum ICTP: 1.8–5.0 µg/liter; serum NTX: 6.2–19.0 nM BCE; and urine DPD: 3.0–7.4 nM/mmol creatinine. Osteocalcin was measured using a RIA as previously reported (13). The CV for this measurement are: intraassay 3.8%, interassay 6.2%, with a normal range of 2–12 ng/ml for females and 2–14 ng/ml for males.
Bone density analyses. BMD at the femur, lumbar spine, wrist, and total body was measured every 6 months using a Hologic 4500 machine and then independently reviewed by two trained physicians. A reading was omitted only when suggested by both physicians. One patient’s femoral neck and another patient’s wrist BMD were omitted in the final analyses on the recommendation of both densitometrists because of obvious repositioning inconsistency. Changes in BMD were expressed as a yearly percentage change from baseline using both the raw BMD values and the machine-calculated averaged rates of change. Only cytokine values correlating with both values are reported. The machine-calculated averaged rates of change are the data presented in the text and graphically.
Statistical analyses. All analyses were performed using the SPSS statistical package (version 9.0; SPSS, Inc., Chicago, IL). Comparisons of clinical and biochemical characteristics between the study groups were performed using the t test (or Wilcoxon test when appropriate) for paired or unpaired data as appropriate. Bivariate correlations between biochemical parameters were assessed using Pearson’s r correlation coefficient. Based on prior published data, the working hypothesis was that IL-6 and/or IL-6sR would correlate positively with rates of bone loss; as a consequence, one-tailed analyses were used in this context only. Results are expressed as mean ± SEM.
Informed consent
The study was approved by the Yale University Human Investigation Committee. All patients gave informed, written consent.
Results
Clinical and biochemical characteristics of the study group
The baseline clinical and biochemical characteristics of the study group are shown in Table 1
. Twenty-six patients were followed up for at least 6 months. The mean duration of follow-up was 22 ± 1.5 months with 14 subjects followed up for at least 2 yr. Upward trends in circulating levels of PTH (104
130 nleq/ml, P < 0.001), 1,25 (OH)2vitamin D (156180 pmol/liter, P < 0.001), and nephrogenous cAMP (2.983.18 nmoles/100 ml glomerular filtrate, P < 0.001) were noted over the 22 months of study. There was no change in mean serum calcium.
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). Cytokine profile in the study group
Circulating levels of IL-6 and IL-6sR were elevated in the study group as a whole (IL-6 12.1 ± 0.4 pg/ml, IL-6sR 42.5 ± 2.1 ng/ml vs. mean values of 1.1 ± 0.1 and 25.1 ± 1.0, respectively, in eucalcemic controls (Table 1) (6). During the 22 months of observation, both baseline and mean IL-6 values for each patient were significantly correlated with baseline and mean PTH values (baseline IL-6 vs. baseline PTH: r = 0.44, P < 0.05, n = 29; mean IL-6 vs. mean PTH: r = 0.44, P < 0.05, n = 26). Neither baseline nor mean IL-6sR values over the course of study correlated with either baseline or mean PTH values in the group as a whole.
Mean values for serum IL-6 remained stable over time (Fig. 1). This suggests that IL-6 production may be maximally stimulated in patients with primary hyperparathyroidism. Serum levels of IL-6sR showed a slight but statistically significant upward trend (Fig. 1).
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Baseline levels of IL-6sR were significantly higher in estrogen-deficient women than in women on HRT, 47.2 ± 2.5 vs. 37.7 ± 3.4 ng/ml (Table 2). Rates of bone resorption were higher in the estrogen-deficient women as assessed by serum NTX, (estrogen-deficient vs. estrogen-treated 31.8 ± 1.7 vs. 24.2 ± 2.2 nM BCE, P < 0.05). Interestingly, as noted above, serum calcium, PTH, and circulating levels of 1,25(OH)2vitamin D were similar in the two groups (Tables 1 and 2).
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The baseline Z- and T-scores are provided in Table 1. Using a T-score of -2.5 or less, nine patients were osteoporotic at the lumbar spine, femoral neck, total femur, or wrist (3, 5, 3, and 8, respectively). Of these nine patients, four were osteoporotic at multiple sites.
During the period of study, a decrease in BMD was noted at all sites with mean yearly rates of decline of -0.6 ± 0.3% at the lumbar spine, -0.2 ± 0.4% at the total femur, -0.9 ± 0.5% at the femoral neck, -0.5 ± 0.5% at the wrist, and -0.8 ± 0.3% at the total body.
If the data are divided into tertiles based on rates of bone loss, the mean serum osteocalcin in the group of subjects who lost bone at the greatest rate (the lowest tertile) was no different than that in the highest tertile (11.9 ± 2.6 vs. 12.9 ± 1.6 ng/ml, P = 0.74).
IL-6sR correlates with changes in BMD
In the study cohort, baseline and mean values of serum IL-6sR correlated significantly with the annual decline in BMD at the total femur (r = -0.53, P < 0.01 for baseline values, Fig. 2). The correlation remained significant when the data from the patient with the greatest rate of bone loss (2) are not included in the analysis (r = -0.37, P < 0.05).
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In vitro data indicate that neither IL-6 nor IL-6sR alone can induce osteoclast formation in vitro. Only the simultaneous addition of both IL-6 and IL-6sR results in osteoclastogenesis (14). In addition, both IL-6 and IL-6sR are often coregulated by the same factors. We, therefore, analyzed rates of bone loss in those patients with the highest serum IL-6 and IL-6sR to determine whether this combination was predictive of a greater rate of bone loss. Six of the 23 study subjects had an IL-6sR of 45.6 ng/ml or greater and an IL-6 of 11.8 pg/ml or greater. This group evidenced significantly greater rates of bone loss at the total femur than the remainder of the group in whom bone mass remained relatively stable (-2.6 ± 1.3% vs. +0.4 ± 0.3%; n = 6 vs. n = 17, P < 0.005).
Interaction between HRT and the IL-6/IL-6sR cytokine system
To eliminate the confounding effect of gender, we separately analyzed the data from female study subjects. In women, as in the group as a whole, serum IL-6sR levels at baseline and after 1 yr of follow-up correlated with the yearly rate of bone loss at the total femur (r = -0.51, P < 0.05 for baseline values). In the group of women as a whole, a serum IL-6sR of 45.6 or greater and an IL-6 of 11.8 or greater identified individuals with significantly higher rates of total femur bone loss, compared with the rest of the women (-2.6 ± 1.3% vs. +0.4 ± 0.3%; n = 6 vs. n = 15, respectively; P < 0.05). However, there were no significant differences in mean levels of PTH, 1,25(OH)2vitamin D, and nephrogenous cAMP when this subgroup was compared with the remainder of the women.
In the estrogen-treated women, baseline, mean, and 1-yr mean serum values of IL-6sR all correlated significantly with rates of bone loss at the femoral neck and the wrist (r = -0.85, P < 0.005, and r = -0.81, P < 0.05, respectively, for baseline values; Fig. 3, a and b). The association between IL-6sR and rates of bone loss at the femoral neck was not affected by eliminating the data from the patient with the highest rate of bone loss (r = -0.77, P < 0.05). In the estrogen-treated group, only two women had values of IL-6sR of 45.6 or greater and IL-6 of 11.8 or greater. Both these women had higher rates of femoral neck and wrist bone loss.
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). Excluding the patient with the greatest rate of bone loss resulted in a loss of significance for this correlation in this subgroup analysis. However, the relationship between serum IL-6sR and rates of bone loss in the group as a whole remained significant, even when this patient was eliminated from the analysis. A serum IL-6sR of 45.6 or greater and an IL-6 of 11.8 or greater identified women in this group with significantly higher rates of total femur bone loss (-2.7 ± 1.7% vs. +0.3 ± 0.5, n = 4 vs. n = 9 respectively; P < 0.05).
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The principal findings of this study are: 1) Serum levels of both IL-6 and IL-6sR are markedly elevated in patients with primary hyperparathyroidism and correlate with markers of bone resorption; 2) although biochemical markers of disease activity were similar in women receiving HRT, compared with estrogen-deficient women, circulating levels of IL-6sR were significantly higher in the estrogen-deficient women; 3) circulating levels of IL-6sR correlated positively with rates of bone loss at the total femur in the whole group; in estrogen-treated women, circulating levels of IL-6sR correlated with rates of bone loss at the femoral neck and wrist; and 4) a combined circulating IL-6sR of 45.6 ng/ml or greater and IL-6 of 11.8 pg/ml or greater identified a subset of patients with the greatest rates of bone loss at the total femur.
Our findings that circulating levels of IL-6 and IL-6sR are increased in patients with primary hyperparathyroidism are consistent with the findings of Grey et al. (6). They reported serum levels of IL-6 (18.6 ± 2.1 pg/ml) and IL-6sR (41.7 ± 1.2 ng/ml) in patients with hyperparathyroidism that were significantly higher than those in euparathyroid controls, with values close to those we observed in our study cohort, 12.1 ± 0.4 pg/ml and 42.5 ± 2.1 ng/ml, respectively.
There were no significant differences in the mean levels of PTH, serum calcium, and 1,25(OH)2vitamin D when estrogen-treated women were compared with estrogen-deficient women. Others have reported similar findings. In a 2-yr randomized, placebo-controlled study of HRT in postmenopausal women with primary hyperparathyroidism, mean levels of PTH and serum calcium were no different at the end of 2 yr in the group receiving estrogen, compared with the placebo-treated group (3). Similarly, Marcus et al. (15) found no change in serum PTH and 1,25 (OH)2vitamin D levels in women with hyperparathyroidism before and after receiving HRT. Interestingly, in both of these studies, bone resorption was significantly suppressed by estrogen. Together with the current findings, these data support the hypothesis that estrogen restrains the resorbing actions of PTH by inhibiting PTH’s actions on the IL-6/IL-6sR cytokine system rather than by influencing circulating levels of PTH or 1,25(OH)2vitamin D. Recent experimental work by Masiukiewicz et al. (16, 17) demonstrating that estrogen directly suppresses PTH induced IL-6 and IL-6sR production in vivo and in vitro are also consistent with this conclusion.
In our study, IL-6 levels did not consistently correlate with changes in BMD. This may reflect the requirement for the ligand-binding subunit of the IL-6 receptor to be present for IL-6 to be bioactive in bone (18). Thus, Tamura et al. (14) found that neither IL-6 nor IL-6sR alone induced osteoclast formation in vitro. Only the simultaneous addition of both IL-6 and IL-6sR resulted in osteoclastogenesis. This suggests that the presence of a simultaneous elevation in both IL-6 and IL-6sR may confer a stronger proresorptive signal in hyperparathyroidism. Consistent with this idea, we found that the combination of a circulating level of IL-6sR of 45.6 ng/ml or greater and IL-6 of 11.8 pg/ml or greater was associated with the greatest rate of bone loss, compared with patients who had an elevation in only one of the two cytokines or low levels of both.
The positive correlation observed between circulating levels of IL-6sR and rates of femoral bone loss is the first to directly support the conclusion that the IL-6/IL-6sR cytokine system plays a clinically relevant role in hyperparathyroidism. Recent evidence has suggested that in early menopause the IL-6/IL-6sR system also plays an important role in bone loss. In a prospective, observational study of 89 women, Scheidt-Nave et al. (19) found that serum IL-6 was by far the strongest determinant of femoral bone loss among women within the first decade after menopause and explained 34% of the variability in rates of bone loss during this time period. Abrahamsen et al. (20) recently reported that IL-6sR levels were lowered by HRT, and the extent of the decline paralleled the degree of protection from bone loss afforded by HRT.
Our study subjects had mild primary hyperparathyroidism with average Z-scores that were similar to or slightly reduced, compared with eucalcemic controls. Therefore, our patients are typical of those who might be considered candidates for conservative management. Indeed, consistent with the findings of Silverberg et al. (1), bone loss rates were low in the group as a whole over nearly 2 yr of observation. Our finding that measures of serum IL-6 and IL-6sR might help to better define the risk for bone loss in hyperparathyroid patients may, therefore, be relevant to a large proportion of patients with this disease.
The mechanisms by which IL-6/IL-6sR might participate in the resorptive actions of PTH are not entirely clear. It is clear that PTH induces the production of both cytokines in vivo and that in vitro, PTH stimulates IL-6 production by bone cells and IL-6 and IL-6sR by liver cells (16, 21). Blocking IL-6 in vivo inhibits PTH-induced bone resorption (7). It is also clear that together both cytokines can stimulate osteoclastogenesis in marrow cultures, and some recent in vitro evidence suggests that IL-6 may act independently of receptor activator of NF
B ligand (RANKL) to induce osteoclastogenesis (22, 23). Thus, it may be that IL-6 and IL-6sR together are among the direct mediators of PTH-induced osteoclastogenesis. Other recent evidence suggests that IL-6 can induce RANKL production in bone, so the IL-6/IL-6sR system may lie upstream of RANKL in a cytokine cascade PTHIL-6/IL-6sRRANKL (24).
Our study has some limitations. The number of subjects was relatively small and the duration of follow-up relatively short. Larger studies with patients followed up for longer periods of time will be needed to corroborate our findings. Nonetheless, the findings in this study combined with our earlier work and that of others strongly support a key role for the IL-6/IL-6sR cytokine system in determining the risk for bone loss in primary hyperparathyroidism. Serum measurements of these cytokines may have clinical use as markers for skeletal disease in this condition.
Acknowledgments
We acknowledge the expert nursing staff of the Yale General Clinical Research Center. We are also deeply indebted to our patients and the study volunteers without whom this work would not have been possible.
Footnotes
This work was supported by Grant AG15345 from the National Institute on Aging (to K.L.I.) and analytical support of the Yale General Clinical Research Center (NCRR Grant RR00125).
Abbreviations: BMD, Bone mineral density; CV, coefficient(s) of variation; DPD, deoxypyridinoline; HRT, hormone replacement therapy; ICTP, type I collagen carboxyterminal telopeptide; IL-6sR, IL-6 soluble receptor; NTX, serum N telopeptide of type I collagen; RANKL, receptor activator of NFB ligand.
Received November 14, 2001.
Accepted August 14, 2002.
References
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