Differences in bone turnover and intact PTH levels between African American and Caucasian patients with end-stage renal disease

Kidney International, Vol. 64 (2003), pp. 737 742 Differences in bone turnover and intact PTH levels between African American and Caucasian patients with end-stage renal disease B. PETER SAWAYA, REZKALLA BUTROS, SHEHZAB NAQVI, ZHAOPO GENG, HANNA MAWAD, ROBERT FRIEDLER, PAOLO FANTI, MARIE-CLAUDE MONIER-FAUGERE, and HARTMUT H. MALLUCHE Division of Nephrology, Bone and Mineral Metabolism, Department of Medicine, University of Kentucky, Lexington, Kentucky Differences in bone turnover and intact PTH levels between African American and Caucasian patients with end-stage renal disease. Background. Evidence derived from healthy subjects suggests that African Americans have higher serum parathyroid hormone (PTH) levels and decreased bone responsiveness to PTH than Caucasians. African American patients with endstage renal disease (ESRD) also have higher serum PTH than Caucasians. Studies that correlate intact PTH (ipth) levels with bone turnover in ESRD patients were performed in a predominantly Caucasian population. Methods. In this study, serum ipth and bone histomorphometric data were analyzed for racial differences in 76 ESRD patients (Caucasian 48, African Americans 28). Bone turnover was determined by histomorphometric measurement of activation frequency in all patients. Results. Age, duration of dialysis, and calcium and phosphorus levels were similar between the two groups. ipth levels (pg/ml; mean SE) were significantly higher in the African American group (534 79 vs. 270 46, P 0.01). Also, alkaline phosphatase levels (IU/L) were significantly higher in the African American group (162 31 vs. 144 43, P 0.01). Correlations between PTH levels and activation frequency were r 0.60, P 0.01 in Caucasians and r 0.22, P NS in African Americans. The mean PTH level in African American patients with histologic findings of low bone turnover was 460 115 vs. 168 41 in Caucasian patients with similar bone turnover (P 0.01). In patients with low bone turnover, African Americans had significantly higher osteoid volume and thickness, number of osteoblasts and osteoclasts, erosion surface, peritrabecular fibrosis, and single-label surface than Caucasians. However, erosion depth, bone formation rate per osteoblast and mineralization apposition rate were similar between the two groups. Key words: race, adynamic bone disease, dialysis, bone histology. Received for publication August 19, 2002 And in revised form March 26, 2003 Accepted for publication April 7, 2003 2003 by the International Society of Nephrology Conclusion. There is no correlation between ipth and bone turnover in African Americans with ESRD. A substantial number of African American patients with low bone turnover have very high serum PTH levels. Bone histomorphometric results reveal differences in remodeling dynamics and responses to PTH between African American and Caucasian patients. Further studies utilizing newer PTH measurement assays are needed to better delineate the correlation between PTH and bone turnover in the various racial groups. African Americans with normal kidney function have higher parathyroid hormone (PTH) serum levels and larger parathyroid glands than Caucasians [1 7]. They also have higher bone mineral density [7, 8] and lower serum osteocalcin levels [1, 2, 6], findings that are suggestive of lower bone turnover. Weinstein and Bell [9] have demonstrated, by histomorphometric analysis, that normal African American subjects have a lower bone formation rate than Caucasians. Cosman et al [10] have shown that the bone response to PTH (1-34) infusion, assessed by measuring bone resorption markers (pyridinoline, N-telopeptide, C-telopeptide), is less in African Americans than Caucasian women. We have recently reported that African American patients with end-stage renal disease (ESRD) have higher serum PTH levels than Caucasian patients at the time of dialysis initiation [11]. This was also observed in crosssectional studies of patients on maintenance dialysis [12, 13]. However, whether the higher serum levels of PTH in African American patients are also associated with more severe hyperparathyroid bone disease has not been established. Potential differences are important to consider when defining target PTH levels in ESRD patients, since oversuppression of parathyroid glands can lead to adynamic bone disease [14]. The purposes of this study were (1) to evaluate the 737

738 Sawaya et al: PTH in African Americans relationship between intact PTH (ipth) levels and bone turnover in African Americans and Caucasian ESRD patients on maintenance dialysis, and (2) to compare ipth levels and bone histomorphometric parameters between the two races in patients with similar bone turnover rate. METHODS Subjects Patients who underwent bone biopsy between 1992 and 2000 were evaluated for this study. All patients were from Central and Southeastern Kentucky. They were all managed in the same dialysis units from which the subjects were chosen. The following patients were excluded: (1) patients followed by nephrologists other than the University of Kentucky group, patients with incomplete relevant clinical or biochemical data, or those with incomplete tetracycline labeling of bone; (2) patients who had a history of renal transplant or parathyroidectomy; and (3) patients with positive aluminum stain on bone biopsy. Patients with aluminum accumulation and those who had renal transplant or underwent parathyroidectomy were excluded since in these patients the relationship between PTH levels and bone turnover is variable and not systematically defined. From a total of 170 patients in whom complete bone histomorphometric data were available, 76 met the above criteria. Forty-eight patients were Caucasians (63%) and 28 were African Americans (37%). The percent of African American patients in this study is very similar to that of the total pool of dialysis patients from which the study population is derived (African Americans 30%). Fifty-four bone biopsies (71%) were performed as baseline biopsies in various prospective clinical studies. Twenty-two biopsies (29%) were performed for diagnostic purposes. Biochemical analysis Total serum calcium, phosphorus, and alkaline phosphatase levels were measured by standard techniques. All blood samples were obtained within 3 weeks of the bone biopsy. On the day of biopsy, concentrations of serum ipth were determined in duplicate by the two-site immunoradiometric assay (IRMA) for ipth using the Allegro ipth Assay Kit (Nichols Institute, San Juan Capistrano, CA, USA). Normal values were 15 to 65 pg/ml; intra- and interassay coefficients of variations were 4% and 7%, respectively.) Bone biopsy, mineralized bone histology, and bone histomorphometry Twenty days before bone biopsy, patients received tetracycline hydrochloride for bone labeling at a dose of 500 mg orally twice a day for 2 days. No tetracycline antibiotic was administered for the following 10 to 14 days. A second label of oral tetracycline hydrochloride (500 mg twice a day) or demeclocycline hydrochloride (Declomycin; Lederle, Wayne, NJ, USA) (300 mg twice a day) was administered for the next 4 days. Phosphate binders and other antacids were not given on days of tetracycline administration. All patients underwent bone biopsy 3 to 4 days after receiving the second label. Bone samples were taken from the anterior iliac crest with an electric drill (Straumann Medical, Waldenburg, Switzerland; or MDTECH, Inc., Gainesville, FL, USA). Bone samples were processed as previously described [15]. Sections were stained with the modified Masson-Goldner trichrome stain [16]. The aurin tricarboxylic acid stain [17] was used to measure the extent of aluminum deposits at the bone-osteoid interface, and solochrome azurine [18] was used as control and for detection of aluminum within bony trabeculae. Unstained sections were prepared for phase contrast and fluorescent light microscopy. Histomorphometric parameters were measured using the Osteoplan System II (Kronton, Munich, Germany) as previously described [19, 20]. Activation frequency represents the inverse of total remodeling period, which includes formation, reversal, resorption, and quiescent periods and is the histomorphometric parameter of bone turnover [21]. Activation frequency in normal control subjects studied in our laboratory is 0.65 0.04 year 1. Statistical analysis Results are expressed as mean values SEM. All statistical tests were two-sided and an assigned significance level of 0.05 was used. Differences between numerical variables were tested using the nonparametric Mann- Whitney U test. Differences in categoric variables were checked with the chi-square tests. Pearson s coefficients of correlation were obtained between activation frequency and serum PTH levels. All computations were performed using the SPSS software for Windows, version 7.5.1 (SPSS, Chicago, IL, USA). RESULTS There was no difference in age, gender, diabetes status, duration of dialysis, or the use of vitamin D therapy between the African American and Caucasian groups (Table 1). There were more Caucasian patients on peritoneal dialysis than African American patients. However, similar results were obtained when only hemodialysis patients were compared between the two racial groups. Therefore, the combined results of both hemodialysis and peritoneal dialysis patients were reported. African American patients had higher serum levels of ipth, despite similar serum phosphorus and calcium concentrations (Table 2). Alkaline phosphatase was also higher in the African American group (Table 2).

Sawaya et al: PTH in African Americans 739 Table 1. Patients characteristics and demographic data Caucasians (C) African Americans (AA) P value (N 48) (N 28) (C vs. AA) Age years 47.7 2.2 48 2.6 NS Male/female % 62/38 46/54 NS Diabetics % 31 18 NS Hemodialysis/peritoneal dialysis % 56/44 86/14 0.01 Duration of dialysis months 20.1 3.0 13.6 2.9 NS Vitamin D therapy % 20 23 NS Table 2. Intact parathyroid hormone (PTH) and biochemical profile Caucasians (C) African-Americans (AA) P value (N 48) (N 28) (C vs. AA) PTH (15 65 pg/ml) 270 46 534 79 0.01 Calcium (8.4 10.2 mg/dl) 9.6 0.2 9.1 0.2 NS Phosphorus (2.7 4.5 mg/dl) 6.4 0.3 6.2 0.4 NS Alkaline phosphatase (20 70 U/L) 144 43 162 31 0.01 In Caucasian patients, there was a positive correlation between serum ipth levels and activation frequency (Fig. 1A) (r 0.60, P 0.01). However, no correlation between these two parameters was demonstrated in African American patients (Fig. 1B) (r 0.22, P NS). Similar results were obtained when patients receiving vitamin D were excluded from the analysis. PTH levels in Caucasian patients with low bone turnover were significantly lower than in Caucasian patients with high bone turnover (Fig. 2). However, in African American patients, no differences in PTH levels were found between the two groups. The mean PTH level of African American patients with low bone turnover was 460 115 pg/ml, which is significantly higher than that of Caucasian patients with similar bone turnover (168 41 pg/ml; P 0.01). A comparison of the histomorphometric parameters of African American and Caucasian patients with low bone turnover revealed that African American patients had significantly higher osteoid volume and thickness, number of osteoblasts and osteoclasts, erosion surface, peritrabecular fibrosis, and single-label surface (Table 3). Erosion depth, bone formation rate per osteoblast, and mineralization apposition rate were similar in the two groups (Table 3). Histomorphometric parameters of patients with high bone turnover were similar in both racial groups, except osteoid thickness was significantly higher in African American patients (data not shown). DISCUSSION For more than a decade, the two-site IRMA for serum ipth levels has been used in dialysis patients to evaluate secondary hyperparathyroidism and to indicate the need for vitamin D therapy. Assays that measure ipth were more reliable than those directed to the C-terminal or midregion of the PTH molecule [22]. We and others have recently reported that African American patients with ESRD have significantly higher serum ipth levels than Caucasians [11, 12]. Whether the target PTH level in ESRD patients should be different across racial groups is unknown [11, 23]. Recent studies describing serum ipth levels and bone histology in ESRD patients have been performed, predominantly in Caucasian populations [22, 24 28]. There is sufficient evidence in normal subjects to suggest that African Americans may require higher PTH levels to maintain a bone turnover rate similar to Caucasians. The results of this study confirm that African American patients with ESRD have higher serum PTH levels than Caucasians. A significant positive correlation between PTH and bone turnover is found only in Caucasian patients. The correlation coefficient for ipth and bone turnover in this racial group is similar to what was previously reported [24, 26, 28]. However, there is no correlation between PTH and bone turnover in African American patients. In patients with low bone turnover, the presence of significantly higher ipth levels in African Americans, as compared to Caucasians, indicates that many African American patients have either end-organ resistance to the bone effect of PTH or the ipth measurement in these patients cross reacts with inert PTH fragments. It has been recently reported that the commercially available kits for determinations of ipth also measure a large

740 Sawaya et al: PTH in African Americans Fig. 2. Intact parathyroid hormone (PTH) in African-Americans (AA) and Caucasians (C) with low and high bone turnover (BT). *P 0.01 compared to PTH levels in all other groups. Fig. 1. Correlation between intact parathyroid hormone and activation frequency in (A) Caucasians (r 0.60, P 0.01), and (B) African Americans (r 0.22, P NS). C-terminal fragment (7-84 amino acid) that may have antagonistic effects on the intact 1-84 amino acid molecule [29, 30]. It remains to be determined whether African American patients have higher circulating levels of these antagonistic C-terminal fragments. Skeletal resistance to the hypercalcemic effects of PTH in uremic patients was observed decades ago [31 33]. However, resistance of uremic bone to the remodeling effects of PTH is not well documented. Evidence for such resistance is presumed on the basis that ESRD patients require higher serum PTH levels to maintain normal bone turnover [24, 26 28]. Since, in these studies, PTH was measured by the commercially available IRMAs, the role of PTH fragments in those results is not clear. In studies that measured the true ipth (1-84), a number of patients still exhibited low bone turnover in the face of normal or even high ipth levels [22, 30]. However, this finding may be explained by the presence of an imbalance between the ratio of 1-84 PTH and antagonistic PTH fragments [30]. This difference in bone remodeling effects of PTH between African American and Caucasian ESRD patients has not been previously addressed. The observation that African American patients with low bone turnover have higher osteoid volume and thickness, number of osteoblasts and osteoclasts, erosion surface, and peritrabecular fibrosis than Caucasian patients with low bone turnover is consistent with African American patients having higher PTH activity on bone. However, erosion depth, bone formation rate per osteoblast, and mineralization apposition rate, which are parameters of cellular activity, were not different between these two groups. These results suggest differences in remodeling dynamics between African American and Caucasian patients. The finding of higher single-label surface in the African American group corroborates this notion. The mechanism of this difference in bone remodeling activity remains speculative at this time. The effect of PTH is mediated through the PTH/ PTHrP receptor. Results regarding the status of this receptor in uremic patients are contradictory [34, 35]. Racial differences in the bone concentration of this receptor have not been assessed. It is conceivable that African American patients have lower receptor concentration that may explain at least part of the observed results. Vitamin D is a known modulator of PTH action [33, 36]. A traditional interpretation of the skeletal resistance to PTH in healthy African Americans is attributed to an adaptive mechanism to compensate for the commonly seen relative 25-hydroxy vitamin D deficiency in African Americans [37, 38]. However, Cosman et al [10] have demonstrated that the role of 25-hydroxy vitamin D in this apparent PTH resistance is minor at most. In our study, there was no difference in the use of vitamin D metabolites between the two racial groups, and similar results were obtained when patients receiving vitamin D were excluded from the analysis. However, we have not assessed vitamin D levels in these patients. Racial differences in vitamin D receptor gene polymorphism have been reported in some studies [39], but not in all [40]. Whether vitamin D receptor polymor-

Sawaya et al: PTH in African Americans 741 Table 3. Static and dynamic histomorphometric parameters in patients with low bone turnover Caucasians (C) African Americans (AA) Normal P value (N 31) (N 15) values a (C vs. AA) Bone volume/tissue volume % 21.4 1.8 21.1 2.5 16.8 22.9 NS Osteoid volume/tissue volume % 5.0 1.3 8.9 2.3 0.57 6.0 0.02 Osteoid surface/bone surface % 32.7 3.9 41.8 5.0 3.45 37.9 NS Osteoid thickness lm 7.2 1.2 9.8 1.2 4.38 11.8 0.01 Osteoblast number/bone length (per 100 mm) 52 10 266 110 10 240 0.01 Erosion surface/bone surface % 3.6 0.6 7.4 1.2 1 5.7 0.01 Erosion depth lm 10.9 1.0 13.6 1.6 1.63 11.2 NS Osteoclast number/bone length (per 100 mm) 39 10 55 9 0.01 36.1 0.05 Fibrosis surface/bone surface % 0.4 0.2 6.5 3.7 0 0.01 Mineralization apposition rate lm/day 0.68 0.07 0.51 0.05 0.43 0.63 NS Single-label surface/bone surface % 2.6 0.6 6.0 1.5 0.29 26.4 0.01 Bone formation rate/tissue volume mm 3 /cm 3 /year 27.4 13 37.6 19.8 11.5 110 NS Bone formation rate/osteoblast number mm 2 /ob/year 32 11 10 4.0 N/A NS Activation frequency (year-1) 0.19 0.03 0.22 0.05 0.49 0.72 NS N/A is not available. a Available in Caucasian subjects only phism plays a role in the histologic differences between African American and Caucasian ESRD patients remains to be examined. Finally, it is currently recognized that numerous local factors and cytokines affect bone remodeling [41, 42]. Possible racial differences among these factors await further research. Limitations of this study include potential patient selection bias. This would have been particularly important if the objective of the study was to evaluate the prevalence of the various renal osteodystrophy histologic patterns in the two racial groups. However, in this study we are attempting to evaluate the relationship between ipth and bone turnover in a given racial group. Also, the number of patients on peritoneal dialysis is too small to allow analysis of the effect of this modality on the observed racial differences in bone remodeling. CONCLUSION This study demonstrates that ipth levels in African American patients with ESRD do not correlate with bone turnover as they do in Caucasian patients. Many African American patients with low bone turnover have substantially high ipth levels. These findings have an impact on current clinical practice in defining the target ipth level in ESRD patients. ACKNOWLEDGMENTS This research was supported by NCRR #MO1RR02602 and NIDDK #RO1-51531. Parts of this research have been presented in abstract form at the ASN/ISN World Congress of Nephrology, San Francisco, CA, USA, in October 2001. Reprint requests to Peter Sawaya, M.D., Associate Professor of Medicine, Division of Nephrology, Bone and Mineral Metabolism, MN 560 UKMC, 800 Rose St., Lexington, KY 40536-0298. E-mail: besawa0@uky.edu REFERENCES 1. Aloia JF, Vaswani A, Yeh JK, Flaster E: Risk of osteoporosis in black women. Calcif Tissue Int 59:415 423, 1996 2. Bell NH, Greene A, Epstein S, et al: Evidence for alteration of the vitamin D-endocrine system in blacks. J Clin Invest 76:470 473, 1985 3. Dawson-Hughes B, Harris SS, Finneran S, Rasmussen HM: Calcium absorption responses to calcitriol in black and white premenopausal women. J Clin Endocrinol Metab 80:3068 3072, 1995 4. Dufour DR, Wilkerson SY: Factors related to parathyroid weight in normal persons. Arch Pathol Lab Med 107:167 172, 1983 5. Joffe BI, Seftel HC, Goldberg RC, et al: Metabolic bone disease in the elderly: Biochemical studies in three different racial groups living in South Africa. S Afr Med J 49:965 966, 1975 6. Perry HM 3rd, Miller DK, Morley JE, et al: A preliminary report of vitamin D and calcium metabolism in older African Americans. J Am Geriatr Soc 41:612 616, 1993 7. Perry HM 3rd, Horowitz M, Morley JE, et al: Aging and bone metabolism in African American and Caucasian women. J Clin Endocrinol Metab 81:1108 1117, 1996 8. Meier DE, Luckey MM, Wallenstein S, et al: Calcium, vitamin D, and parathyroid hormone status in young white and black women: Association with racial differences in bone mass. J Clin Endocrinol Metab 72:703 710, 1991 9. Weinstein RS, Bell NH: Diminished rates of bone formation in normal black adults. New Engl J Med 319:1698 1701, 1988 10. Cosman F, Morgan DC, Nieves JW, et al: Resistance to bone resorbing effects of PTH in black women. J Bone Miner Res 12:958 966, 1997 11. Sawaya BP, Monier-Faugere M-C, Ratanapanichkich P, et al: Racial differences in parathyroid hormone levels in patients with secondary hyperparathyroidism. Clin Nephrol 57:51 55, 2002 12. Gupta A, Kallenbach LR, Zasuwa G, Divine GW: Race is a major determinant of secondary hyperparathyroidism in uremic patients. J Am Soc Nephrol 11:330 334, 2000 13. Chertow GM, Plone M, Dillon MA, et al: Hyperparathyroidism and dialysis vintage. Clin Nephrol 54:295 300, 2000

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