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Chronic kidney disease (CKD) is rapidly becoming a significant public health problem. A staggering 19.2 million Americans, or 11% of the adult population, are currently living with CKD.1 Moreover, there are nearly 400 000 people in the United States with end-stage kidney disease (ESKD), a number that is almost certain to rise owing to the high prevalence of CKD.2 Adding to the morbidity of CKD is the development of disturbances of mineral metabolism, which occurs in virtually all patients during the progression of their disease and is associated with bone loss and fractures, cardiovascular disease, immune suppression, and increased mortality.3 In addition to the public health impact, CKD and ESKD also impose a tremendous economic burden. In fact, the cost to treat patients with ESKD in the United States was estimated to be more than $25 billion in 2002.4 While dialysis treatment accounts for the majority of these costs, hip and vertebral fractures contribute to the excessive economic burden.5 Because patients with CKD and ESKD have reduced bone mineral density (BMD) in association with several metabolic disturbances, in particular hyperparathyroidism and vitamin D deficiency, it stands to reason that they are at increased risk of hip fracture. Although essentially all patients with CKD have decreased BMD, it has not been a useful tool to determine fracture risk in this patient population. While several studies have shown an increased risk of hip fracture in patients with CKD who are undergoing dialysis, to my knowledge the existence of a similar correlation has not previously been explored in patients with milder stages of CKD. In this issue of the ARCHIVES, Ensrud et al6 report the findings of a prospective case-cohort study in which they examined the association of hip fracture in patients with mild to moderate impairments in renal function. Within a cohort of more than 9700 women 65 years or older, they compared the baseline kidney function in women who subsequently had either hip or vertebral fractures with that in randomly selected matched controls. Patients were sorted into 1 of 3 groups based on estimated glomerular filtration rate (eGFR): moderate decrease (<45 mL/min per 1.73 m2), mild decrease (45-59 mL/min per 1.73 m2), and normal (>60 mL/min per 1.73 m2). When the GFR was estimated using the Cockcroft-Gault method, there was a significant increase in the hip fracture hazards ratio in women with a below-normal eGFR. Moreover, this increased hazards ratio was observed even after adjustment for age, weight, and either calcaneal or femoral neck BMD (P = .02). Interestingly, no significant increase was observed in the vertebral fracture hazards ratio (P = .04). The investigators' choice of equations for determining the eGFR significantly affected the findings. In fact, when Ensrud and colleagues calculated the eGFR using the 4-variable version of the Modification of Diet in Renal Disease index,7 the hazard ratios were smaller in magnitude and did not reach statistical significance (P = .09). While it is concerning, as the authors state, that 2 different methods yielded different results, previous studies have shown that limitations associated with the Modification of Diet in Renal Disease index include underestimation of the basal GFR and inaccuracies when the GFR is greater than 60 mL/min per 1.73 m2 as well as when individuals are at the extremes in weight.8 Thus, an underestimation of the GFR would incorrectly place some patients with a “normal” GFR into either the mild or the moderate decrease eGFR group. Furthermore, the determination of the independent impact of CKD on fractures was compromised, as Ensrud and colleagues selected a population of women with a high prevalence of postmenopausal osteoporosis. Although it has been demonstrated that patients with CKD have decreased BMD,3 the value of BMD in the evaluation of the bone diseases associated with CKD is not well established.9 Findings on the correlation of BMD values to fracture risk in the CKD population are inconsistent.10 Therefore, the decreased bone mass and increased bone fragility in this particular population are most likely the result of the relative contribution of postmenopausal osteoporosis and the metabolic disturbances associated with CKD.9 There are several disorders in CKD, independent of osteoporosis, that may contribute to an increased risk of hip fracture. Specifically, the development of secondary hyperparathyroidism and vitamin D deficiency will lead not only to bone loss but also to defects in bone quality.3,9,11 In addition, the elevated circulating concentrations of fibroblast growth factor 23, which is produced to maintain normophosphatemia, further inhibit renal 1α-hydroxylase activity and may also have a direct detrimental effect on bone quality.3,12,13 Although metabolic disturbances were not independently associated with increased hip fractures in Ensrud and colleagues' analysis, an earlier study, using patients from the same cohort, that did not specifically consider CKD found an association between reduced serum 1,25-dihydroxyvitamin D and increased risk of hip fracture.14 Clearly, the pathogenesis of bone disease in patients with CKD is extremely heterogeneous, and it is not surprising that any single factor would be predictive of fracture in this patient population. To address the complexity associated with the bone and mineral disorders associated with CKD, an international consensus conference was held in October 2005 under the auspices of Kidney Disease: Improving Global Outcomes (www.kdigo.org) to define and classify “renal osteodystrophy.”10 This expert panel concluded that because the manifestations of mineral and bone abnormalities were so diverse and included extraskeletal manifestations, a new systemic disorder should be defined and should be called CKD–mineral and bone disorder. The diagnosis of CKD–mineral and bone disorder would include patients who manifest one or a combination of the following symptoms: (1) abnormalities of calcium, phosphorus, parathyroid hormone, or vitamin D metabolism; (2) abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and (3) vascular or other soft tissue calcification.10 Therefore, the findings reported by Ensrud et al6 are potentially very important, as they further support the concept that a diagnosis of osteoporosis based on BMD criteria should not be made in patients with CKD and used as a predictor of fracture outcome. Because of the rapidly increasing prevalence of CKD, it is virtually guaranteed that there will be a corresponding increase in the incidence of CKD-associated hip fractures. Importantly, the mortality associated with hip fracture ranges from 13% to 37%, with only 60% of surviving patients returning to their prefracture level of walking.15-17 Moreover, the estimated cost to treat a single hip fracture is more than $30 000.5 Thus, it is extremely important to understand the pathophysiologic mechanisms that cause CKD-associated fractures and to realize that therapy should be directed toward the underlying disorders. Because patients with CKD have an extremely high prevalence of hyperparathyroidism and vitamin D deficiency, effective treatments that can correct these disorders may reduce the burden of fractures in patients with CKD. Several active vitamin D compounds, such as calcitriol and paricalcitol, as well as the prohormones alfacalcidol and doxercalciferol have been shown to significantly reduce parathyroid hormone levels and moderate the symptoms that are commonly associated with hyperparathyroidism.11,18-20 It has been shown that treatment with the prohormone alfacalcidol improves BMD while reducing parathyroid hormone concentrations in patients with CKD.11 Moreover, it has also been shown that administration of paricalcitol prevents CKD-associated decreases in BMD in the femoral neck and the femoral midshaft and restores bone strength in the femoral neck in experimental animals.21 Thus, while mild to moderate kidney impairment puts patients at an increased risk for hip fracture, proper control of hyperparathyroidism and vitamin D deficiency has the potential to reduce the risk of CKD-associated hip fractures. In summary, it is important to recognize that the risk of fracture in patients with CKD is not just a function of having decreased bone density or of being given the diagnostic label of osteoporosis. It is important to recognize that in the presence of CKD the underlying pathogenesis may be the result of altered mineral metabolism associated with CKD-MBD. Therefore, before antiosteoporosis therapy is initiated, these patients should be further evaluated and treated for any existing underlying disorders. Correspondence: Dr Sprague, Evanston Northwestern Healthcare, Northwestern University Feinberg School of Medicine, Division of Nephrology and Hypertension, 2650 Ridge Ave, Evanston, IL 60201 (email@example.com). Financial Disclosure: None reported. References 1. Coresh JAstor BCGreene TEknoyan GLevey AS Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003;411- 12PubMedGoogle ScholarCrossref 2. Schoolwerth ACEngelgau MMHostetter TH A public health action plan is needed for chronic kidney disease. Adv Chronic Kidney Dis 2005;12418- 423PubMedGoogle ScholarCrossref 3. Andress DL Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int 2006;6933- 43PubMedGoogle ScholarCrossref 4. Collins AJKasiske BHerzog C et al. Excerpts from the United States Renal Data System 2004 annual data report: atlas of end-stage renal disease in the United States. Am J Kidney Dis 2005;45 ((suppl 1)) A5- A7PubMedGoogle ScholarCrossref 5. Alem AMSherrard DJGillen DL et al. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int 2000;58396- 399PubMedGoogle ScholarCrossref 6. Ensrud KELui L-YTaylor BC et al. Study of Osteoporotic Fractures Research Group, Renal function and risk of hip and vertebral fractures in older women. Arch Intern Med 2007;167133- 139Google ScholarCrossref 7. Levey ASBosch JPLewis JBGreene TRogers NRoth D A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation: Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130461- 470PubMedGoogle ScholarCrossref 8. Kuan YHossain MSurman JEl Nahas AMHaylor J GFR prediction using the MDRD and Cockcroft and Gault equations in patients with end-stage renal disease. Nephrol Dial Transplant 2005;202394- 2401PubMedGoogle ScholarCrossref 9. Cunningham JSprague SMCannata-Andia J et al. Osteoporosis in chronic kidney disease. Am J Kidney Dis 2004;43566- 571PubMedGoogle ScholarCrossref 10. Moe SDrueke TCunningham J et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006;691945- 1953PubMedGoogle ScholarCrossref 11. Rix MEskildsen POlgaard K Effect of 18 months of treatment with alfacalcidol on bone in patients with mild to moderate chronic renal failure. Nephrol Dial Transplant 2004;19870- 876PubMedGoogle ScholarCrossref 12. Gutierrez OIsakova TRhee E et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005;162205- 2215PubMedGoogle ScholarCrossref 13. Liu STang WZhou J et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 2006;171305- 1315PubMedGoogle ScholarCrossref 14. Cummings SRBrowner WSBauer D et al. Endogenous hormones and the risk of hip and vertebral fractures among older women: Study of Osteoporotic Fractures Research Group. N Engl J Med 1998;339733- 738PubMedGoogle ScholarCrossref 15. Siu ALBoockvar KSPenrod JD et al. Effect of inpatient quality of care on functional outcomes in patients with hip fracture. Med Care 2006;44862- 869PubMedGoogle ScholarCrossref 16. Zuckerman JD Hip fracture. N Engl J Med 1996;3341519- 1525PubMedGoogle ScholarCrossref 17. Magaziner JHawkes WHebel JR et al. Recovery from hip fracture in eight areas of function. J Gerontol A Biol Sci Med Sci 2000;55M498- M507PubMedGoogle ScholarCrossref 18. Coburn JWMaung HMElangovan L et al. Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. Am J Kidney Dis 2004;43877- 890PubMedGoogle ScholarCrossref 19. Coyne DAcharya MQiu P et al. Paricalcitol capsule for the treatment of secondary hyperparathyroidism in stages 3 and 4 CKD. Am J Kidney Dis 2006;47263- 276PubMedGoogle ScholarCrossref 20. Andress DL Vitamin D treatment in chronic kidney disease. Semin Dial 2005;18315- 321PubMedGoogle ScholarCrossref 21. Jokihaara JPorsti IPajamaki I et al. Paricalcitol [19-nor-1,25-(OH)2D2] in the treatment of experimental renal bone disease. 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Archives of Internal Medicine – American Medical Association
Published: Jan 22, 2007
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