low normal serum magnesium concentrations compared to those with mild hypermagnesemia. However, those with the lowest serum magnesium values tended to be older, with greater comorbidity and lower predialysis serum urea, albumin, and phosphate concentrations. This may suggest that magnesium may not be the agent provocateur, but importantly because magnesium plays such a key role in intracellular metabolism, it is unlikely to be a totally innocent bystander. Even so, this observation should generate interest in developing interventional trials of magnesium supplementation in those patients with low or low normal magnesium concentrations. However, this was a relatively short observational study, and as such the longer term effects of mild hypermagnesemia are unknown, and as there was increased mortality for those with moderate hypermagnesemia, caution is advised before advocating increased dialysate magnesium concentrations and magnesium-containing medications for all hemodialysis patients. The data contained in this paper have not been previously published in part or whole or in abstract form. DISCLOSURE
The authors declared no competing interests. REFERENCES 1.
Sakaguchi Y, Fujii N, Shoji T et al. Hypomagnesemia as a significant predictor of cardiovascular and non-cardiovascular mortality in patients undergoing hemodialysis. Kidney Int 2013; 85: 174–181. Sontia B, Touyz RM. Role of magnesium in hypertension. Arch Biochem Biophys 2007; 458: 33–39. Del Gobbo LC, Imamura F, Wu JH et al. Circulating and dietary magnesium and risk of cardiovascular disease: a systematic review and meta-analysis of prospective studies. Am J Clin Nutr 2013; 98: 160–173. Maier JA. Endothelial cells and magnesium: implications in atherosclerosis. Clin Sci (Lond) 2012; 122: 397–407. Rosanoff A, Seelig MS. Comparison of mechanism and functional effects of magnesium and statin pharmaceuticals. J Am Coll Nutr 2004; 23: 501S–505S. Barbagallo M, Dominguez LJ. Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance. Arch Biochem Biophys 2007; 458: 40–47. Turgut F, Kanbay M, Metin MR et al. Magnesium supplementation helps to improve carotid intima thickness in patients on hemodialysis. Int Urol Nephrol 2008; 40: 1075–1082.
Kupetsky-Rincon EA, Li Q, Uitto J. Magnesium reduces carotid intima-media thickness in a mouse model of pseudoxanthoma elasticum: a novel treatment biomarker. Clin Transl Sci 2012; 5: 259–264. Kelber J, Slatopolsky E, Delmez JA. Acute effects of different concentrations of
dialysate magnesium during high-efficiency dialysis. Am J Kidney Dis 1994; 24: 453–460. Kanbay M, Goldsmith D, Uyar ME et al. Magnesium in chronic kidney disease: challenges and opportunities. Blood Purif 2010; 29: 280–292.
see clinical investigation on page 166
Fractures in chronic kidney disease: neglected, common, and associated with sickness and death Maria Fusaro1, Maurizio Gallieni2 and Sophie A. Jamal3 Bone fractures in dialysis patients have been poorly studied in the past. Tentori et al. partially fill this gap, assessing the incidence of postfracture morbidity and mortality in patients of the Dialysis Outcomes and Practice Patterns Study (DOPPS). A high frequency of fractures and increased adverse outcomes following a fracture were observed. The nephrology community should pay more attention to bone fractures in dialysis patients. Kidney International (2013) 85, 20–22. doi:10.1038/ki.2013.302
Worldwide, one in three women and one in five men over the age of 50 will have a fracture.1 In the general population there is a wealth of prospective studies documenting the clinical risk factors for fracture, and more recently tools have been developed to quantify fracture risk and guide treatment decisions. Our understanding of fracture risk in the general population is very different from what is known in men and women with chronic kidney disease (CKD). After almost half a century of dialysis, there are only a 1 Aging Section, Consiglio Nazionale delle Ricerche—Institute of Neuroscience, Padua, Italy; 2 Nephrology and Dialysis Unit, Ospedale San Carlo Borromeo, Milan, Italy and 3University of Toronto, Women’s College Hospital and Women’s College Research Institute, Toronto, Ontario, Canada Correspondence: Maria Fusaro, Aging Section, Consiglio Nazionale delle Ricerche (CNR)—Institute of Neuroscience, Via Giustiniani 2, Padua 35128, Italy. E-mail: [email protected]
few studies, most of which are crosssectional, that report on risk factors for fracture in CKD.2 The paucity of studies on risk factors for fractures in CKD is despite the fact that, as reported by Tentori et al.3 (this issue) using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), the incidence of fractures is high among those on dialysis. Of the 34 579 subjects participating in DOPPS between 2002 and 2011, 1134, or 3%, had a fracture. Further, the fracture incidence is higher in those with CKD than in the general population. As well, the morbidity and mortality are higher in those with CKD and fractures than in those with CKD without fractures.4 Note that while Tentori et al.3 report on fractures only among those on dialysis, other studies have demonstrated that fracture risk is increased even among those with impaired renal function not requiring dialysis.5 For example, data from a large cohort of patients of the Third National Kidney International (2014) 85
Health and Nutrition Examination Survey (NHANES III) in the United States demonstrate that compared with those with an estimated glomerular filtration rate (eGFR) of X60 ml/min, those with an eGFR less than 60 ml/min had a twofold increased risk of hip fractures.6 On the other hand, the prevalence of vertebral fractures in CKD patients is similar to that in the general population.7 This discrepancy might be due to the different effects of secondary hyperparathyroidism, which impairs primarily cortical bone, while vertebrae are mainly constituted of trabecular bone. Why might those with impaired renal function be at particularly high fracture risk? Tentori and colleagues offer several explanations, including an increased risk for falls, altered bone structure and function—including abnormalities in bone turnover, mineralization, and volume—and altered levels of parathyroid hormone (PTH), both high and low. There are data indicating that impaired neuromuscular function, probably resulting in increased incidence of falls, is associated with fractures in patients with CKD.8 Similarly, altered bone quality (an impairment of structure and function) can increase fracture risk.2 And, although not directly addressed by Tentori et al.,3 the concept that serum PTH influences fracture risk independent of effects on bone turnover is intriguing. A study of hemodialysis patients who underwent transiliac bone biopsies demonstrated that in the group of patients with serum PTH levels between 150 and 300 pg/ml, 88% had low bone turnover, and even patients with PTH levels higher than 300 pg/ml had low-turnover bone disease in a high proportion (38%), underscoring the limitations of serum PTH in predicting the risk of fractures and suggesting that other biochemical markers may be required to accurately measure bone-remodeling status in hemodialysis patients.9 Indeed, the use of serum biomarkers, including PTH, to predict fracture risk in CKD has not been well studied. Our group has reported that among 387 subjects on dialysis, vitamin K1 Kidney International (2014) 85
deficiency is a strong predictor of vertebral fractures (odds ratio 2.94, 95% confidence interval 1.38–6.26).10 Consistent with our findings is the fact that Tentori and colleagues3 report a lower incidence of fractures in the Japanese population, where dietary intake of vitamin K is very high. Future research should determine whether raising serum vitamin K levels decreases fractures in CKD. As well, the ability of other biochemical markers (such as fibroblast growth factor 23, osteoprotegerin, and sclerostin) to predict fracture risk in CKD remains to be determined. Although many patients with CKD have vitamin D (25OHD3) deficiency, no significant association between vitamin D (25OHD3) status and fractures in dialysis patients has been reported so far.7 The possible role in fracture risk of protein energy wasting, inflammation, and reduced sex hormones should be explored. Not only did Tentori and colleagues3 demonstrate high rates of fractures in those with CKD, but those with
fractures had high rates of death and hospitalization compared with those with CKD without fractures and compared with those with fractures but without CKD. The most common cause of morbidity and mortality in those with fractures (classified as hip or other) was cardiovascular disease (accounting for 45% of all deaths), highlighting the potential link between fractures and vascular calcification. The link between vascular calcification and fractures is thought to be particularly strong in the case of vertebral fractures,9 although this could not be addressed by DOPPS data. The association between vascular calcification and bone is also supported by a recent case–control study that demonstrated that vertebral fractures were higher (prevalence 14%) in those with acute coronary syndrome compared with controls (prevalence 1.3%).11 The paper by Tentori et al.3 highlights the fact that fractures are common in dialysis patients and are associated with substantial morbidity
Figure 1 | Example of assessment of vertebral fractures with the aid of quantitative vertebral morphometry (QVM). Turquoise dots allow the delimitation of vertebral heights and the computerized diagnosis of vertebral fractures. In this figure, the following fractures were identified: T11, biconcave, moderate; T12, biconcave, mild; L2, biconcave, moderate; L3, biconcave, severe (associated with crush, moderate). Aortic vascular calcifications are also clearly visible (red arrows). QVM is a valuable research and clinical tool that allows a more precise characterization of vertebral fractures, compared with semiquantitative methods, which are more operator dependent. 21
and mortality. Despite the sickness and death associated with fractures, bone health, particularly among those on dialysis, is generally neglected both by patients with CKD and by physicians taking care of them. There are at least three potential explanations for this finding. First, the clinical utility of bone mineral density (BMD) to predict fracture risk in CKD is unclear, and as such, BMD testing by dual-energy X-ray absorptiometry is not widely used. That said, recent data suggest that BMD testing may be associated with fractures in stages 3 and 4 CKD, and among those with stage 5 CKD, BMD at a cortical site, such as the radius, can discriminate fracture status.2 Second, fractures are difficult to treat in those with CKD because bisphosphonates, the most commonly prescribed agents for osteoporosis, are contraindicated in those with creatinine clearance lower than 30 ml/min.12 However, post hoc analyses of the pivotal fracture trials of alendronate and risedronate included some subjects with reduced creatinine clearance, and there was no increase in adverse events or difference in fracture efficacy by level or renal function. Third, physicians and patients may neglect bone health and techniques to prevent fractures in the presence of more acute medical conditions.
How can we improve our care of CKD patients with bone disease? More publications like that by Tentori et al.3 reporting on the burden of illness due to bone disease in men and women with CKD are needed. Further research should include prospective studies determining whether noninvasive assessments of cortical and trabecular bone components—for example, peripheral quantitated computed tomography— can categorize fracture risk in CKD. Quantitative vertebral morphometry in a lateral X-ray of the vertebral column is also an effective clinical research tool for the direct assessment of vertebral fractures (Figure 1).7,10 The applicability of the World Health Organization Fracture Risk Assessment Tool in those with CKD needs to be tested. As well, we need to ensure broader education about bone health and fracture prevention for both patients with CKD and physicians taking care of them. DISCLOSURE
All the authors declared no competing interests. REFERENCES 1.
Melton LJ 3rd, Atkinson EJ, O’Connor MK et al. Bone density and fracture risk in men. J Bone Miner Res 1998; 13: 1915–1923. Ott SM. Review article: Bone density in patients with chronic kidney disease stages 4-5. Nephrology (Carlton) 2009; 14: 395–403.
Tentori F, McCullough K, Kilpatrick RD et al. High rates of death and hospitalization follow bone fracture among hemodialysis patients. Kidney Int 2013; 85: 166–173. Jamal SA, West SL, Miller PD. Fracture risk assessment in patients with chronic kidney disease. Osteoporos Int 2012; 23: 1191–1198. Ensrud KE, Lui LY, Taylor BC et al. Renal function and risk of hip and vertebral fractures in older women. Arch Intern Med 2007; 167: 133–139. Nickolas TL, McMahon DJ, Shane E. Relationship between moderate to severe kidney disease and hip fracture in the United States. J Am Soc Nephrol 2006; 17: 3223–3232. Fusaro M, Tripepi G, Noale M et al. High prevalence of vertebral fractures assessed by quantitative morphometry in hemodialysis patients, strongly associated with vascular calcifications. Calcif Tissue Int 2013; 93: 39–47. West SL, Jamal SA, Lok CE. Tests of neuromuscular function are associated with fractures in patients with chronic kidney disease. Nephrol Dial Transplant 2012; 27: 2384–2388. Barreto FC, Barreto DV, Moyse´s RM et al. K/DOQI-recommended intact PTH levels do not prevent low-turnover bone disease in hemodialysis patients. Kidney Int 2008; 73: 771–777. Fusaro M, Noale M, Viola V et al. Vitamin K, vertebral fractures, vascular calcifications, and mortality: VItamin K Italian (VIKI) dialysis study. J Bone Miner Res 2012; 27: 2271–2278. Silva HC, Pinheiro MM, Genaro PS et al. Higher prevalence of morphometric vertebral fractures in patients with recent coronary events independently of BMD measurements. Bone 2013; 52: 562–567. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. Kidney Int Suppl 2009; 113: S1–S130.
Kidney International (2014) 85