Ethnic differences in bone and mineral metabolism in healthy people and patients with CKD

Transcription

1 & 2013 International Society of Nephrology Ethnic differences in bone and mineral metabolism in healthy people and patients with CKD Vanda Jorgetti 1, Luciene M. dos Reis 1 and Susan M. Ott 2 1 Nephrology Division, Medical School, University of São Paulo, São Paulo, Brazil and 2 Department of Medicine, University of Washington, Seattle, Washington DC, USA Several studies have shown racial differences in the regulation of mineral metabolism, in the acquisition of bone mass and structure of individuals. In this review, we examine ethnic differences in bone and mineral metabolism in normal individuals and in patients with chronic kidney disease. Black individuals have lower urinary excretion and increased intestinal calcium absorption, reduced levels of 25(OH)D, and high levels of 1.25(OH) 2 D and parathyroid hormone (PTH). Body phosphorus concentration is higher and the levels of FGF-23 are lower than in whites. Mineral density and bone architecture are better in black individuals. These differences translate into advantages for blacks who have stronger bones, less risk of fractures, and less cardiovascular calcification. In the United States of America, the prevalence of kidney disease is similar in different ethnic groups. However, black individuals progress more quickly to advanced stages of kidney disease than whites. This faster progression does not translate into increased mortality, higher in whites, especially in the first year of dialysis. Some ethnicity-related variations in mineral metabolism persist when individuals develop CKD. Therefore, black patients have lower serum calcium concentrations, less hyperphosphatemia, low levels of 25(OH)D, higher levels of PTH, and low levels of FGF-23 compared with white patients. Bone biopsy studies show that blacks have greater bone volume. The rate of fractures and cardiovascular diseases are also less frequent. Further studies are required to better understand the cellular and molecular bases of these racial differences in bone mineral metabolism and thus better treat patients. Kidney International (2013) 85, ; doi: /ki ; published online 18 December 2013 KEYWORDS: bone histomorphometry; bone mineral density; chronic kidney disease; ethnic differences; mineral metabolism; vascular calcification Correspondence: Vanda Jorgetti, Faculdade de Medicina da Universidade de São Paulo, LIM 16 Laboratório de Fisiopatologia Renal, Av Dr Arnaldo, 455, 31 andar, sala nr 3342, Cerqueira César, São Paulo CEP: , Brazil. vandajor@usp.br Received 21 June 2013; revised 7 August 2013; accepted 15 August 2013; published online 18 December 2013 The risk of osteoporosis and fractures is different in various populations. 1 Individuals of African descent have higher bone density and fewer fractures than Caucasians, whereas Asians have lower fracture rates despite lower bone density. Ethnic variations are found in mineral metabolism, Ca homeostasis, serum concentrations of 25(OH)D and parathyroid hormone (PTH), as well as in acquisition of bone mass and structure These differences in bone metabolism may also be related to the differences seen in the frequency and severity of vascular calcifications (VCs). 11 The analysis of US databases has revealed that although the prevalence of early stages of chronic kidney disease (CKD) is similar in different ethnic groups, black individuals progress to advanced stages of the disease four times faster than do Caucasians. 12 In a large health-care program, blacks had more extreme rates of renal function decline, and Asians progressed more slowly than the other groups. 13 However, once on dialysis, black patients have lower mortality rates In this review, we examine ethnic differences in bone and mineral metabolism in normal individuals. As kidney disease progresses, patients develop CKD-MBD (mineral and bone disorder) that can be described by abnormalities in serum laboratory measures, bone disease, and VCs, 18 which all vary according to race. ETHNIC DIFFERENCES IN LABORATORY MEASUREMENTS OF MINERAL METABOLISM IN HEALTHY INDIVIDUALS The intake of Ca varies among different ethnic groups, some populations consuming between 300 and 400 mg/day, and others consuming three times these values. 19 Studies on calcium metabolic balance and kinetics have shown that African Americans ingest less Ca, have a more efficient intestinal absorption, and lower urinary excretion than whites. 6 Similar differences have also been observed between South African blacks and whites. 20 Braun et al. 6 compared Ca intake and retention in white and black American adolescents and found that black teenagers retained more Ca in their skeleton (mean difference of 185±32 mg Ca/day). For any amount of Ca intake, they excreted less Ca in the urine. Mechanisms involved in lower Ca urinary excretion in blacks are not yet fully known. In this study, the serum PTH and 25(OH)D Kidney International (2014) 85,

2 V Jorgetti et al.: Ethnic differences in mineral metabolism levels did not explain the urine calcium results. 6 Na et al. 21 demonstrated the existence of two black-specific variants in the gene encoding the renal epithelial channel TRPV 5 (A563T), a key protein in the regulation of renal tubular Ca handling. This variant, which is relatively common in blacks, might help to explain the lower urinary Ca excretion in these individuals. Another study evaluating Ca-sensing receptor polymorphism in blacks showed that the alleles associated with elevated blood pressure were associated with a decrease in urinary Ca excretion. 22 Few studies have assessed ethnic differences in the metabolism of phosphate (Pi). Arunabh et al. 23 used delayed gamma neutron activation and studied total body Pi in 90 black females and 143 white females ranging in age from 20 to 70 years. Results showed that total body Pi was lower in whites (401±58 vs. 448 ±58 g) even after correction for body mass index. Total body Pi decreases with age, but the differences between black and white females remain over time. Gutiérrez et al. 24 reported that blacks had a fractional excretion of Pi lower than that of whites, with similar serum PTH and fibroblast growth factor 23 (FGF23) serum levels. The results may have been altered by pre-treatment of black patients with high doses of vitamin D. The serum concentration of 25(OH)D is consistently lower in blacks and hispanics than in whites, even after adjusting for age, gender, body mass index, intake of Ca, serum Ca and serum albumin. 25 This is related to greater skin pigmentation that inhibits cutaneous synthesis of cholecalciferol. 26 After an oral dose of vitamin D, blacks increase the serum levels to the same extent as whites. 27 Serum concentrations of PTH and 1,25(OH) 2 D are higher in blacks. 28 In a multi-ethnic study from the United States, Chinese subjects had lower PTH than white, black, or Hispanic subjects. 29 Serum 25(OH)D concentrations 420 ng/ml are not associated with further suppression of PTH in blacks, in contrast to what is observed in whites or Mexican-Americans. 25 In Japan, PTH levels are lower than in Western countries, and there was no correlation between PTH and 25(OH)D when the concentrations were 437 nmol/l. 30 Fuleihan et al. 10 studied the sigmoidal Ca-PTH curve in the two ethnic groups and demonstrated that the maximum and minimum PTH response to hypocalcemia and hypercalcemia were higher in blacks, with no change in set point or slope of the curve. Autopsy findings revealed heavier parathyroid glands with higher cell numbers. 31 The higher serum levels of 1,25(OH) 2 D in black people probably contribute to higher intestinal Ca absorption than in white people. 6 In some studies, serum FGF23 concentrations do not appear to differ between normal black and white people 32,33 or between races in patients with coronary artery disease. 34 In the Cardiovascular Health Study, which included 497 normal black subjects 465 years, the FGF23 concentrations were lower in blacks than in whites. 35 ETHNIC DIFFERENCES IN BONE MINERAL DENSITY AND FRACTURES IN HEALTHY INDIVIDUALS Black persons have substantially lower fracture rates and higher bone density than individuals of other races. Asians have lower bone density than whites, but they also have lower fracture rates Hispanic people have also lower fracture rates than whites, with similar bone density. 25 The increased bone density in blacks is already seen during childhood and adolescence. It is associated with better hip structural parameters and thicker cortices. 39 Femoral neck morphology differences between Chinese and white persons living in Australia are complex; the Chinese had a lower risk of fracture by buckling but a higher risk by bending. 40 Although serum PTH levels are consistently higher in blacks, the bone formation rate is lower. They appear to have lower skeletal response to the PTH than whites. This was also demonstrated in a study by Cosman et al., 41 who infused the biological active PTH fragment, PTH 1 34, and found that bone resorption markers showed lower responses in black subjects. Ethnic differences in the relationship between serum 25(OH)D and fractures were reported from the Women s Health Initiative. In white women, those with 25(OH)D levels 420 ng/ml had fewer fractures (odds ratio 0.82), but the reverse was seen in black women, who had more fractures (odds ratio 1.45). 42 A similar trend was seen in older adults from the NHANES survey, where a standard deviation decrease in 25(OH)D concentration was associated with an odds ratio of 1.24 for fracture in whites but 0.81 in blacks. 43 Furthermore, a randomized clinical trial of vitamin D supplementation in black women found no improvement in fracture rates compared with placebo. 44 Bone turnover markers (collagen-cross-links and osteocalcin) are lower in normal black men and women than in whites. 45,46 In a longitudinal study of perimenopausal women living in the United States, the increase in urine N-telopeptide was smaller in blacks and greater in Asians compared with whites. 47 Circulating sclerostin has been reported in one study of women aged 480 years, and it was lower in the blacks than in whites. 48 Genome-wide analysis surveys have recently been conducted to search for possible relationship between genetic variation and bone density. These have found some significant polymorphisms that associate with bone density, but still there is no explanation for the racial differences. ETHNIC DIFFERENCES IN BONE HISTOMORPHOMETRY FINDINGS AMONG HEALTHY SUBJECTS Few studies have evaluated the histomorphometric parameters of bone tissue in normal individuals of different ethnicities. Some analyzed ethnic differences in the course of age, others analyzed differences in the premenopause, 52 and others analyzed them in the premenopause and postmenopausal state Schnitzler et al. 49 studied blacks and whites in South Africa ranging in age from 21 to 83 years. The results showed 1284 Kidney International (2014) 85,

3 V Jorgetti et al.: Ethnic differences in mineral metabolism that the bone microarchitecture was better in black than in white males. In females, only bone trabeculae were thicker in black than in white individuals. With age, bone volume decreased in both genders, but the changes of microarchitecture were lower in blacks of both genders. The authors did not evaluate dynamic parameters. Schnitzler et al. 50 also studied the cortical bone from 97 blacks (49 males, 48 females) aged 22 to 80 years and from 111 whites (60 males, 51 females) aged 21 to 84 years. Fortythree subjects, 20 blacks (7 males, 13 females) aged 23 to 66 years and 23 whites (9 males, 14 females) aged 23 to 78 years, were also given tetracycline to allow measurement of the dynamic parameters of bone histomorphometry. The results showed that blacks had thicker cortical bone, less porous cortices, greater endocortical wall thickness, and fewer harvesian osteons than whites. Cortical bone deteriorated with age in both; however, the endocortical wall thickness decreased with age only in whites. The authors suggested that the preserved endocortical wall may contribute to a lower fragility rates in blacks due to greater mineral apposition and formation rates. The study of Dos Reis et al., 51 conducted in Latin America evaluated men and women aged 0 90 years. In this study, the authors assessed the influence and interaction of age, race, and gender on bone tissue. The study included blacks and whites as well as mulatto (mixed race) and individuals of Asian descent. The results showed that bone volume was influenced by race and gender. Black women and white men have greater bone volume than do white women. Microarchitecture was better in black women and worse in Asian women. Weinstein et al. 56 performed bone biopsies in 12 black and 13 white subjects who were matched for age and body weight. They found no differences in static measurements, but the bone formation rate in blacks was only 35% of that measured in whites. In another study, Parisien et al. 52 evaluated both static and dynamic bone parameters in black (aged years) and white women (aged years). Results showed similarities in volume and microarchitecture in both races. However, bone formation was again lower in black women. The authors suggested differences in the mechanism of bone formation, that is, the rate of mineral apposition in each remodeling unit was lower, leading to a longer formation period, which would allow more time for mineralization, leading to increased bone mineral density. Finally, a study from the United States that evaluated 144 black and white women in premenopause and postmenopause (aged years) showed that the effects of ethnicity are independent of age and menopause. The trabecular volume and microarchitecture parameters were larger in black women while remodeling was lower than in whites. The black women had a lower ratio of mineralizing surface to osteoid surface and therefore a prolonged bone formation period. The authors suggested that the greater bone mass reduced the need for remodeling, because there would be less microdamage Differences in osteocytes and lacunar density between blacks and whites were also evaluated. 57 In this study, the authors measured 34 bone biopsies from 34 healthy black women (aged years) and 94 white women (aged years) separately in whole trabeculae in superficial and deep bone. They concluded that blacks had more osteocytes than whites, contributing to increased bone strength. The authors speculated that osteocyte density depends more upon the age of the bone than the age of the subject. Figure 1 summarizes the results of studies that evaluated bone turnover, mineralization, and volume of white and black individuals of both genders in different age groups. ETHNIC DIFFERENCES IN VC IN PEOPLE WITHOUT KNOWN CKD Black diabetic patients have fewer arterial calcifications than their white counterparts. 11 In one study, the extent of the calcifications was inversely related to serum concentrations of Dickkopf (DKK1), which may inhibit the transformation of vascular smooth muscle cells into an osteoblastic phenotype. 58 In another study of diabetic black patients, the VCs were correlated with the serum levels of 25(OH)D, unlike white patients in whom the relationship was inverse. In these patients, serum PTH was high but not correlated to bone mineral density. Serum levels of 1,25(OH) 2 D was also high and showed a negative correlation with bone density. 59 ETHNIC DIFFERENCES IN LABORATORY MEASUREMENTS OF MINERAL METABOLISM AMONG PATIENTS WITH CKD The treatment of CKD-MBD is considered one of the most challenging tasks for nephrologists. Compared with other complications, studies show that laboratory abnormalities of mineral metabolism are associated with a percentage of death risk higher than that of anemia or low dialysis dose (17.5% vs. 11.3% and 5.1%, respectively). In an analysis of laboratory data from 40,538 hemodialysis patients, Block et al. 60 found that black patients had less hyperphosphatemia, lower serum calcium concentrations, and higher PTH values compared with white patients. In recent years, it has been shown that some ethnicityrelated variations in mineral metabolism persist when individuals develop CKD. 24,61 64 Gutiérrez et al. 24 studied 19 patients with CKD (10 blacks and 9 whites) with stage 3 4 CKD and normal serum Ca and Pi levels who received diets with known Ca and Pi content. Blacks had lower postprandial fractional urinary excretion of Ca and Pi when compared with whites. In addition, serum Ca decreased in whites but not in blacks. 24 Gupta et al. 62 were among the first authors to show that black patients receiving dialysis therapy developed more severe secondary hyperparathyroidism than did whites. The study was retrospective and was carried out in 1367 patients. Mean serum PTH levels were almost double in blacks when compared with whites. Other reports of serum PTH in black dialysis patients consistently described increased serum PTH and decreased 25(OH)D concentrations. 65 Kidney International (2014) 85,

4 V Jorgetti et al.: Ethnic differences in mineral metabolism Turnover BFR/BS (µm 3 /µm 2 /day) Mineralization OV/BV (%) Volume BV/TV (%) Premenopause Years Years Years Serum FGF23 concentrations are lower in black than in white patients with pre-dialysis CKD. 66 This bone-derived hormone has been repeatedly shown to be closely associated with increased risk of mortality and cardiovascular disease. In the Homocysteine in Kidney and End Stage Renal Disease study, there were 285 black subjects with late stages of CKD, whose average serum FGF23 levels were lower than in white subjects. Black patients with higher FGF23 had greater risk of cardiovascular events and all-cause mortality than those with lower levels. 67 In that study, the serum FGF23 of dialysis 3 Postmenopause Years Figure 1 Bone histomorphometry findings in white and black subjects without known kidney disease. Histomorphometric parameters that assessed turnover, mineralization, and volume (TMV classification), were obtained from studies of white ( ) and black ( ) individuals, women (~) and men (#), in two age brackets: years old, near the peak bone mass, and years old corresponding to postmenopausal women. Turnover was assessed only in women in premenopause and postmenopause from the values of BFR/BS (mm 3 /mm 2 /day). The values of OV/BV and BV/TV both expressed as percentages were used to evaluate mineralization and volume, respectively. Bone turnover was not different among women in both ethnic groups and in both the periods analyzed. In general, mineralization was slower in black women and bone volume was higher. The figure was constructed with results from studies by (1) Schnitzler et al. 49 (2) Han et al. 53 (3) Han et al. 54 (4) Parisien et al. 52 (5) Parfitt et al. 55 and (6) Dos Reis et al. 51 BFR/BS, bone formation rate; BV/TV, trabecular bone volume; OV/BV, osteoid volume. patients did not show differences among races. 61 However, in a larger study of 10,044 incident dialysis patients (32% black and 13% Hispanic), the serum FGF23 concentrations were significantly lower, by 22 34%, than in the white patients. Mortality during the first year of dialysis was substantially lower in black and Hispanic patients (odds ratio 0.5 and 0.4). 66 ETHNIC DIFFERENCES IN THE BONE AMONG PATIENTS WITH CKD White dialysis patients have more hospitalizations for fractures than patients of other races. 60 In a large clinical trial of cinacalcet, black subjects had a significantly longer time to fracture (hazard ratio 0.48 compared with whites). 68 In a cohort study of 101,039 patients on a renal transplant waiting list, which included 29,183 black patients, the risk of a hip fracture was 62% lower in black patients. 69 Bone density is also higher in black than in white patients with CKD. One study found that black patients had a mean of 1.15 s.ds. greater bone density at the hip than whites. 70 Although PTH levels are higher in blacks, they do not necessarily develop a more severe bone disease. Sawaya et al. 63 evaluated bone biopsies in 76 patients receiving dialysis treatment (48 whites and 28 blacks) who did not have evidence of aluminum overload, negative aluminum staining in bone, and had not undergone parathyroidectomy. The authors found no racial differences in bone volume. Low bone turnover was seen in 64% of white and 53% of black patients, and serum PTH and alkaline phosphatase levels were higher in blacks irrespective of the type of bone remodeling. The serum PTH showed significant correlations to bone formation in white patients but not in black patients. In a recent study, Malluche et al. 71 revised biopsies from a bank of bone biopsies performed between 2003 and Of these patients, 87 were black and 543 were white. The authors classified the results in accordance with the newly recommended histological classification system for renal osteodystrophy: 18 Turnover (T) Mineralization (M) Volume (V), in addition to Architecture (A) both in the cancellous bone and in cortical bone. Low bone turnover was seen in 62% of white patients but only in 32% of black patients. Only 3% of all patients showed mineralization defect. As for the volume, white patients had approximately the same proportion of low, normal, and high bone volume, whereas black patients had predominantly high bone volume. Black patients had thicker cortical bone, but with higher porosity. Caucasian patients, however, had similar low or normal cortical thickness but normal and high porosity. Black patients had higher serum PTH levels, but for the same PTH level, they had lower bone turnover, suggesting lower skeletal response to PTH. Shin et al. 72 carried out bone biopsies in 58 Korean predialysis patients to investigate the distribution of different types of renal osteodystrophy and possible ethnic differences between Asians and whites. The turnover was different from that of end-stage kidney disease patients in Western 1286 Kidney International (2014) 85,

5 V Jorgetti et al.: Ethnic differences in mineral metabolism Table 1 Main differences in bone and mineral metabolism parameters in black individuals compared with white individuals Normal or early CKD Late stage CKD, including dialysis Disease/mortality More rapid progression Better survival Serum calcium Similar Lower Serum phosphate Similar Lower Intestinal calcium More efficient absorption Urine calcium Lower excretion Serum 25(OH)D Lower Lower Serum 1,25(OH) 2 D Higher Serum PTH Higher Higher Serum FGF23 Similar or lower Lower Fracture rates Lower Lower Bone mineral density Higher Higher Bone formation rates Lower Higher Bone volume Higher or similar Higher Bone response to PTH Less resorption Less resorption Fracture association with vitamin D level Fewer fractures with low vitamin D Vascular calcifications Fewer in diabetic patients Fewer or similar Hospitalization for cardiovascular disease Higher (or similar with equal access to care) Fewer Abbreviations: CKD, chronic kidney disease; FGF23, fibroblast growth factor 23; PTH, parathyroid hormone. countries, with fewer cases of adynamic bone disease (24.6%) or severe osteitis fibrosis (8.6%). Mineralization abnormalities were seen in 22.4%. The average bone volume per tissue volume was between 30 and 40% in all the categories of renal osteodystrophy, except the adynamic bone disease in which it was 23%. ETHNIC DIFFERENCES IN CARDIOVASCULAR CALCIFICATIONS AMONG PATIENTS WITH CKD Cardiovascular disease is the leading cause of death in patients with CKD. Its etiology is multifactorial and VC is considered to be one of the major contributory factors. Black individuals have better survival rates than whites, especially at the start of dialysis. This survival advantage is attributed to a lower prevalence of VC and cardiovascular disease. 12 In a descriptive cohort study (Multi-Ethnic Study of Atherosclerosis) the authors examined the incidence and progression of coronary artery calcification (CAC) in a multiethnic population with predominantly stage 3 CKD. The CAC score was measured at baseline and again approximately 1.6 or 3.2 years later. CAC prevalence at baseline was 66%, and its adjusted prevalence was 24% lower in blacks as compared with whites. Incident CAC developed at a rate of 14.8% per year in men and 6.1% per year in women, similar by ethnicity and sex, and associated with the presence of diabetes. 73 Similar results were obtained in a study carried out in South African patients. 74 Bellasi et al. 75 evaluated dialysis patients with a high prevalence of diabetes and long dialysis vintage. They found no differences in the prevalence of VC between the two ethnic groups. White hemodialysis patients were reported to have more hospitalizations for cardiovascular disease and for vascular access problems than patients of other races. 60 Table 1 summarizes the main differences in bone and mineral parameters between black and white individuals with normal kidney function or early stage CKD as compared with late stage CKD patients. SUMMARY Ethnicity has an important role in all aspects of mineral metabolism, both in healthy persons and in patients with chronic kidney disease. Black persons have a significant advantage in this respect: they have stronger bones and less cardiovascular calcification. Black patients receiving dialysis therapy have fewer hospitalizations for cardiovascular disease, fewer fractures, and lower mortality rates. The limited studies enrolling both Asian and non-asian patients suggest differences in bone parameters and fracture rates. Currently, there is still no recognized molecular basis for these ethnic differences in mineral and skeletal metabolism, highlighting a serious gap in our understanding of bone and vascular diseases, our lack of knowledge of the optimal treatment according to ethnic background, and the need for further research into this area. Note added in proof: A recent article found that Vitamin D-binding protein was lower in black Americans, which explains much of the difference in vitamin D levels between black and white individuals. 76 DISCLOSURE VJ is an advisor/consultant for Sanofi-Genzyme, Abbott, and Amgen, and a lecturer for Sanofi-Genzyme, Abbott, and Amgen. All the other authors declared no competing interests. ACKNOWLEDGMENTS We acknowledge the technical assistance provided by Wagner Vasques Dominguez and also in editing of the figure. REFERENCES 1. Kanis JA, Odén A, McCloskey EV et al. A systematic review of hip fracture incidence and probability of fracture worldwide. Osteoporos Int 2012; 23: Looker A, Melton LJ 3rd, Borrud LG et al. Changes in femur neck bone density in US adults between and : demographic patterns and possible determinants. Osteoporos Int 2012; 23: Bachrach LK, Hastie T, Wang MC et al. Bone mineral acquisition in healthy Asian, Hispanic, Black, and Caucasian youth: a longitudinal study. J Clin Endocrinol Metab 1999; 84: Jackman L, Millane SS, Martin BR et al. Calcium retention in relation to calcium intake and post menarcheal age in adolescent females. Am J Clin Nutr 1997; 66: Abrams SA, O Brien KO, Liang LK et al. Differences in calcium absorption and kinetics between black and white girls aged 5 16 years. J Bone Miner Res 1995; 10: Braun M, Palacios C, Wigertz K et al. Racial differences in skeletal calcium retention in adolescent girls with varied controlled calcium intakes. Am J Clin Nutr 2007; 85: Zadshir A, Tareen N, Pan D et al. The prevalence of hypovitaminosis D among US adults: data from the NHANES III. Ethn Dis 2005; 15: Kidney International (2014) 85,

6 V Jorgetti et al.: Ethnic differences in mineral metabolism 8. Clemens TL, Adams JS, Henderson SL et al. Increased skin pigment reduces the capacity of skin to synthesize vitamin D3. Lancet 1982; 1: Nesby-O Dell S, Scanlon KS, Cogswell ME et al. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, Am J Clin Nutr 2002; 76: Fuleihan GE, Gundberg CM, Gleason R et al. Racial differences in parathyroid hormone dynamics. JClinEndocrinolMetab1994; 79: Freedman BI, Register TC. Effect of race and genetics on vitamin D metabolism, bone and vascular health. Nat Rev Nephrol 2012; 8: US Renal Data System. USRDS 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda, MD, USA, Derose SF, Rutkowski MP, Crooks PW et al. Racial differences in estimated GFR decline, ESRD, and mortality in an integrated health system. Am J Kidney Dis 2013; 62: Kovesdy CP, Quarles LD, Lott EH et al. Survival advantage in black versus white men with CKD: effect of estimated GFR and case mix. Am J Kidney Dis 2013; 62: Kritchevsky SB, Tooze JA, Neiberg RH et al. 25-Hydroxyvitamin D, parathyroid hormone, and mortality in black and white older adults: the health ABC study. J Clin Endocrinol Metab 2012; 97: Kalantar-Zadeh K, Golan E, Shohat T et al. Survival disparities within American and Israeli dialysis populations: learning from similarities and distinctions across race and ethnicity. Semin Dial 2010; 23: Wolf M, Betancourt J, Chang Y et al. Impact of activated vitamin D and race on survival among hemodialysis patients. J Am Soc Nephrol 2008; 19: Moe S, Drueke T, Cunningham J et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006; 69: Broadus AE. Physiological functions of calcium, magnesium, and phosphorus and mineral ion balance. In: Primer on the Metabolic Bone Disease and Disorders of Mineral Metabolism (ed. Favus MJ) Raven Press: New York, USA, pp Daniels ED, Pettifor JM, Schnitzler CM et al. Differences in mineral homeostasis, volumetric bone mass and femoral neck axis length in black and white South African women. Osteoporosis Int 1997; 7: Na T, Zhang W, Jiang Y et al. The A563T variation of the renal epithelial calcium channel TRPV5 among African Americans enhances calcium influx. Am J Physiol Renal Physiol 2009; 296: F1042 F Jung J, Foroud TM, Eckert GJ et al. Association of the calcium-sensing receptor gene with blood pressure and urinary calcium in African- Americans. J Clin Endocrinol Metab 2009; 94: Arunabh S, Feuerman M, Ruimei MA et al. Total body phosphorus in healthy women and ethnic variations. Metabolism 2002; 51: Gutiérrez OM, Isakova T, Smith K et al. Racial differences in postprandial mineral ion handling in health and in chronic kidney disease. Nephrol Dial Transplant 2010; 25: Gutiérrez OM, Farwell WR, Kermah D et al. Racial differences in the relationship between vitamin D, bone mineral density, and parathyroid hormone in the National Health and Nutrition Examination Survey. Osteoporos Int 2011; 22: Jablonski NG, Chaplin G. Human skin pigmentation, migration and disease susceptibility. Philos Trans R Soc Lond B Biol Sci 2012; 367: Gallagher JC, Peacock M, Yalamanchili V et al. Effects of vitamin D supplementation in older African American women. J Clin Endocrinol Metab 2009; 93: Bell NH, Greene A, Epstein S et al. Evidence for alteration of the vitamin D-endocrine system in blacks. J Clin Invest 1985; 76: Bosworth C, Sachs MC, Duprez D et al. Parathyroid hormone and arterial dysfunction in the multi-ethnic study of atherosclerosis. Clin Endocrinol 2013; 79: Nakamura K, Nashimoto M, Hori Y et al. Serum parathyroid hormone in healthy Japanese women in relation to serum 25-hydroxyvitamin D. Int J Vitam Nutr Res 2000; 70: Ghandur-Mnaymneh L, Cassady J, Hajianpour MA et al. The parathyroid gland in health and disease. Am J Pathol 1986; 125: Dalal M, Sun K, Cappola AR et al. Relationship of serum fibroblast growth factor 23 with cardiovascular disease in older community-dwelling women. Eur J Endocrinol 2011; 165: Ix JH, Chonchol M, Laughlin GA et al. Relation of sex and estrogen therapy to serum fibroblast growth factor 23, serum phosphorus, and urine phosphorus: the Heart and Soul Study. Am J kidney Dis 2011; 58: Parker BD, Schurgers LJ, Brandenburg VM et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann Intern Med 2010; 152: Ix JH, Katz R, Kestenbaum BR et al. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol 2012; 60: Xu L, Lu A, Zhao X et al. Very low rates of hip fracture in Beijing, People s Republic of China: the Beijing Osteoporosis Project. Am J Epidemiol 1996; 144: Lau EM, Lee JK, Suriwongpaisal P et al. The incidence of hip fracture in four Asian countries: the Asian Osteoporosis Study (AOS). Osteoporos Int 2001; 12: Ross PD, Norimatsu H, Davis JW et al. A comparison of hip fracture incidence among native Japanese, Japanese Americans, and American Caucasians. Am J Epidemiol 1991; 133: Norris SA, Nelson DA. Ethnic differences in bone acquisition.. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism (ed. Rosen CJ) John Wiley & Sons: New Jersey, USA, pp Wang XF, Duan Y, Beck TJ et al. Varying contributions of growth and ageing to racial and sex differences in femoral neck structure and strength in old age. Bone 2005; 36: Cosman E, Morgan DC, Nieves JW et al. Resistance to bone resorbing effects of PTH in black women. J Bone Miner Res 1997; 12: Cauley JA, Danielson ME, Boudreau R et al. Serum 25-hydroxyvitamin D and clinical fracture risk in a multiethnic cohort of women: the Women s Health Initiative (WHI). J Bone Miner Res 2011; 26: Looker AC. Serum 25-hydroxyvitamin D and risk of major osteoporotic fractures in older U.S. adults. J Bone Miner Res 2013; 28: Aloia JE, Talwar SA, Pollack S et al. A randomized controlled trial of vitamin D3 supplementation in African American women. Arch Intern Med 2005; 165: Leder BZ, Araujo AB, Travison TG et al. Racial and ethnic differences in bone turnover markers in men. J Clin Endoclin Metab 2007; 92: Sowers M, Derby C, Jannausch ML et al. Insulin resistance, hemostatic factors, and hormone interactions in pre- and perimenopausal women: SWAN. J Clin Endoclin Metab 2003; 88: Sowers MR, Zheng H, Greendale GA et al. Changes in bone resorption across the menopause transition: effects of reproductive hormones, body size, and ethnicity. J Clin Endocrinol Metab 2013; 98: Thorson S, Prasad T, Sheu Y et al. Sclerostin and bone strength in women in their 10 th decade of life. J Bone Miner Res 2013; 28: Schnitzler CM, Pettifor JM, Mesquita JM et al. Histomorphometry of iliac crest in 346 normal black and white South African adults. Bone Miner 1990; 10: Schnitzler CM, Mesquita JM. Cortical bone histomorphometry of the iliac crest in normal black and white South Africans adults. Calcif Tissue Int 2006; 79: Dos Reis LM, Batalha JR, Muñoz DR et al. Brazilian normal static bone histomorphometry: effects of age, sex and race. J Bone Miner Metab 2007; 25: Parisien M, Cosman F, Morgan D et al. Histomorphometric assessment of bone mass, structure, and remodeling: a comparison between healthy black and white premenopausal women. J Bone Miner Res 1997; 12: Han ZH, Palnitkar S, Rao DS et al. Effect of ethnicity and age or menopause on the structure and geometry of iliac bone. J Bone Miner Res 1996; 11: Han ZH, Palnitkar S, Rao DS et al. Effects of ethnicity and age or menopause on the remodeling and turnover of iliac bone: implications for mechanisms of bone loss. J Bone Miner Res 1997; 12: Parfitt AM, Han ZH, Palnitkar S et al. Effects of ethnicity and age or menopause on osteoblast function, bone mineralization, and osteoid accumulation in iliac bone. J Bone Miner Res 1997; 12: Weinstein RS, Bell NH. Diminished rates of bone formation in normal black adults. N Engl J Med 1988; 319: Qiu S, Rao DS, Palnitkar S et al. Differences in osteocyte and lacunar density between black and white American women. Bone 2006; 38: Register TC, Hruska KA, Divers J et al. Plasma Dickkopft1 (DKK1) concentrations negatively associate with atherosclerotic clacified plaque 1288 Kidney International (2014) 85,

7 V Jorgetti et al.: Ethnic differences in mineral metabolism in African-Americans with type 2 diabetes. J Clin Endocrinol Metab 2013; 98: E60 E Freedman BI, Wagenknecht LE, Hairston KG et al. Vitamin D, adiposity, and calcified atherosclerotic plaque in African-Americans. J Clin Endocrinol Metab 2010; 95: Block GA, Klassen PS, Lazarus JM et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004; 15: Jovanovich A, Chonchol M, Cheung AK et al. Racial differences in markers of mineral metabolism in advanced chronic kidney disease. Clin J Am Soc Nephrol 2012; 7: Gupta A, Kallenbach LR, Zasuwa G et al. Race is a major determinant of secondary hyperparathyroidism in uremic patients. J Am Soc Nephrol 2000; 11: Sawaya BP, Butros R, Naqvi S et al. Differences in bone turnover and intact PTH levels between African American and caucasian patients with end-stage renal disease. Kidney Int 2003; 64: Ennis J, Worcester EM, Coe F et al. Contribution of calcium, phosphorus, and 25-hydroxyvitamin D to the excessive severity of secondary hyperparathyroidism in African Americans with CKD. Nephrol Dial Transplant 2012; 27: Gutiérrez OM, Isakova T, Andress DL et al. Prevalence and severity of disordered mineral metabolism in Blacks with chronic kidney disease. Kidney Int 2008; 73: Gutiérrez OM, Mannstadt M, Isakova T et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008; 359: Kendrick J, Cheung AK, Kaufman JS et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J Am Soc Nephrol 2011; 22: EVOLVE Trial Investigators, Chertow GM, Block GA et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367: Ball AM, Gillen DL, Sherrard D et al. Risk of hip fracture among dialysis and renal transplant recipients. JAMA 2002; 288: Stehman-Breen CO, Sherrard D, Walker A et al. Racial differences in bone mineral density and bone loss among end-stage renal disease patients. Am J Kidney Dis 1999; 33: Malluche HH, Mawad HW, Monier-Faugere MC. Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients. J Bone Miner Res 2011; 26: Shin SK, Kim DH, Kim HS et al. Renal osteodystrophy in pre-dialysis patients: ethnic difference? Perit Dial Int 1999; 19: S402 S Kestenbaum BR, Adeney KL, de Boer IH et al. Incidence and progression of coronary calcification in chronic kidney disease: the Multi-Ethnic Study of Atherosclerosis. Kidney Int 2009; 76: Freercks R, Swanepoel C, Carrara H et al. Vascular calcification in South African dialysis patients: ethnic variation, prevalence, detection and haemodynamic correlates. Nephrology 2012; 17: Bellasi A, Veledar E, Ferramosca E et al. Markers of vascular disease do not differ in black and white hemodialysis patients despite a different risk profile. Atherosclerosis 2008; 197: Powe CE, Evans MK, Wenger J et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013; 369: Kidney International (2014) 85,