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• W2014559520 abstract "Related Article, p. 747 Related Article, p. 747 Treating chronic kidney disease−mineral and bone disorder (CKD-MBD) is an ongoing challenge, especially in patients with kidney failure treated by dialysis. Derangements in calcium, phosphate, and parathyroid hormone (PTH) homeostasis cause soft-tissue calcification and bone abnormalities. Such derangements increase the risk for adverse outcomes, including fracture, cardiovascular disease, and death. Based largely on studies of general-population cohorts, CKD stages 3-4 have been associated with a hip fracture prevalence as high as 5% in the United States.1Nickolas T.L. McMahon D.J. Shane E. Relationship between moderate to severe kidney disease and hip fracture in the United States.J Am Soc Nephrol. 2006; 17: 3223-3232Crossref PubMed Scopus (284) Google Scholar, 2Fried L.F. Biggs M.L. Shlipak M.G. et al.Association of kidney function with incident hip fracture in older adults.J Am Soc Nephrol. 2007; 18: 282-286Crossref PubMed Scopus (169) Google Scholar Prevalence rates in the general population are ∼1.3% and ∼0.7% in women and men, respectively.3Marks R. Hip fracture epidemiological trends, outcomes, and risk factors, 1970-2009.Int J Gen Med. 2010; 3: 1-17PubMed Google Scholar, 4Centers for Disease Control and Prevention (CDC)Fatalities and injuries from falls among older adults—United States, 1993-2003 and 2001-2005.MMWR Morb Mortal Wkly Rep. 2006; 55: 1221-1224PubMed Google Scholar Less is known about hip fracture risk in hemodialysis patients, but there is considerable evidence that a diagnosis of hip fracture predicts mortality in hemodialysis patients as in the general population.5Kannegaard P.N. van der Mark S. Eiken P. Abrahamsen B. Excess mortality in men compared with women following a hip fracture National analysis of comedications, comorbidity and survival.Age Ageing. 2010; 39: 203-209Crossref PubMed Scopus (379) Google Scholar, 6Danese M.D. Kim J. Doan Q.V. Dylan M. Griffiths R. Chertow G.M. PTH and the risks for hip, vertebral, and pelvic fractures among patients on dialysis.Am J Kidney Dis. 2006; 47: 149-156Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 7Mittalhenkle A. Gillen D.L. Stehman-Breen C.O. Increased risk of mortality associated with hip fracture in the dialysis population.Am J Kidney Dis. 2004; 44: 672-679PubMed Scopus (169) Google Scholar, 8Coco M. Rush H. Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone.Am J Kidney Dis. 2000; 36: 1115-1121Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar, 9Nair SS, Mitani AA, Goldstein BA, Chertow GM, Lowenberg DW, Winkelmayer WC. Temporal trends in the incidence, treatment, and outcomes of hip fracture in older patients initiating dialysis in the United States [published online ahead of print May 9, 2013]. Clin J Am Soc Nephrol. doi:10.2215/CJN.10901012.Google Scholar, 10Bliuc D. Nguyen N.D. Milch V.E. Nguyen T.V. Eisman J.A. Center J.R. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women.JAMA. 2009; 301: 513-521Crossref PubMed Scopus (1190) Google Scholar In the study by Arenson et al11Arneson T.J. Li S. Liu J. Kilpatrick R.D. Newsome B.B. St. Peter W.L. Trends in hip francture rates in US hemodialysis patients, 1993-2010.Am J Kidney Dis. 2013; 62: 747-754Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar published in this issue of the AJKD, Medicare data were used to evaluate rates of hip fracture in hospitalized hemodialysis patients. Using data from the Medicare 5% sample and data for hemodialysis patients from the US Renal Data System, the authors compared the rates of older hemodialysis patients being admitted to the hospital for hip fractures with Medicare enrollees who were not on dialysis therapy. Arenson et al11Arneson T.J. Li S. Liu J. Kilpatrick R.D. Newsome B.B. St. Peter W.L. Trends in hip francture rates in US hemodialysis patients, 1993-2010.Am J Kidney Dis. 2013; 62: 747-754Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar demonstrated that there were substantially higher rates of hip fracture among hemodialysis patients compared to the general population. Even more interesting, annual rates in hemodialysis patients demonstrated a recent trend toward decline, which raises the question: is it possible that bone-related outcomes are improving based on some specific treatment related to dialysis? The study investigators assembled a retrospective 2-point prevalent cohort for each year from 1993 to 2010. The first cohort consisted of patients in the United States receiving hemodialysis for at least 90 days whose primary payer was Medicare. The second cohort consisted of Medicare beneficiaries older than 66 years who were enrolled in both Part A and Part B and also not enrolled in a Medicare maintenance health organization. Patients were excluded if they had a history of kidney transplantation, were registered as dialysis patients prior to January 1 of the cohort year, or were not continuously enrolled in Medicare Parts A and B. Hemodialysis patients were censored if their kidney function recovered or they were lost to follow-up. Hospitalized hip fractures were identified using Medicare Part A claims, using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 820.xx (femoral neck fracture) and 733.14 (pathologic fracture of the neck of the femur). Unadjusted rates of hospitalized hip fracture were measured using the number of events per 1,000 person-years in cohort years 1993-2010. In the dialysis population, rates then were adjusted for age, sex, race, duration of end-stage renal disease, Medicare/Medicaid dual enrollment, comorbidity index (including the primary cause of end-stage renal disease), and number of hospital days at baseline; the 2010 cohort was the reference group. A model-based direct adjustment method was used to address the expected postadjustment strata-specific low event rate. Poisson models were used to estimate strata-specific event rates. To analyze hip fracture trends for the 2 cohorts, hip fracture rates were calculated for a subset of hemodialysis patients 66 years or older and the nondialysis cohort for each year. Rates were adjusted for the following common covariates: age, sex, and race. The incidence of hip fracture was statistically higher in hemodialysis patients older than 66 years compared with their age-matched nondialysis counterparts. The adjusted event rate in hemodialysis patients in 1993 was 11.9 events/1,000 person-years; it peaked in 2004 with an event rate of 21.9/1,000 person-years. The average adjusted event rate increased over this period by 4.6% per year (95% confidence interval [CI], 4.1%-5.2%). This was followed by an observed decline in hip fracture rate, with an annual decline of 5.2% per year (95% CI, 4.4%-5.9%) through 2010 (16.6 events/1,000 person-years; P for trend < 0.001). These event rates were substantially higher than those of the nondialysis cohort, in which the peak event rate only reached 10.6 events/1,000 person-years. The authors simultaneously evaluated CKD-MBD treatments over the same period. As one would expect, the number of individuals receiving intravenous vitamin D analogues was noted to be high (86% by 2009), with a higher proportion of individuals being treated with paricalcitol by 2009 (∼70%). Of note, the timing of the decline in hip fracture rate coincided with increased use of cinacalcet. While the aim of the study by Arenson et al11Arneson T.J. Li S. Liu J. Kilpatrick R.D. Newsome B.B. St. Peter W.L. Trends in hip francture rates in US hemodialysis patients, 1993-2010.Am J Kidney Dis. 2013; 62: 747-754Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar was not to evaluate the association of CKD-MBD treatments with current hip fracture prevalence, the data lend themselves to inferences about practice patterns and whether differences in treatment methods and population characteristics may have contributed to the observed decline in fracture rates. Are newer therapies improving hip fracture risk? As the authors discuss, treatment patterns for CKD-MBD have evolved. Cinacalcet is used when calcium- and non–calcium-based phosphate binders fail to adequately suppress PTH and phosphorus. In 2005, Cunningham et al12Cunningham J. Danese M. Olson K. Klassen P. Chertow G.M. Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism.Kidney Int. 2005; 68: 1793-1800Crossref PubMed Scopus (433) Google Scholar published a meta-analysis of 4 small trials in participants with elevated PTH levels that demonstrated that cinacalcet therapy was associated with a significant reduction in risk of fracture (relative risk, 0.46; 95% CI, 0.22-0.95). In transplant recipients, bone biopsies of patients using cinacalcet demonstrated that although bone formation rate decreased, bone volume did not and bone mineral density increased.13Borchhardt K.A. Diarra D. Sulzbacher I. Benesch T. Haas M. Sunder-Plassmann G. Cinacalcet decreases bone formation rate in hypercalcemic hyperparathyroidism after kidney transplantation.Am J Nephrol. 2010; 31: 482-489Crossref PubMed Scopus (36) Google Scholar With regard to other current therapies, sevelamer is a safe and effective treatment of hyperphosphatemia in the dialysis population,14Chertow G.M. Dillon M.A. Amin N. Burke S.K. Sevelamer with and without calcium and vitamin D: observations from a long-term open-label clinical trial.J Ren Nutr. 2000; 10: 125-132Abstract Full Text PDF PubMed Scopus (27) Google Scholar but its association with reductions in fracture risk has not been evaluated. Similarly, studies of the effectiveness of calcium-based phosphate binders have been limited to risks related to vascular calcification. However, CKD-MBD is complicated and likely is multifactorial. Some fractures in dialysis patients have been associated with low vitamin D levels, low PTH levels, and low bone mass. Elder et al suggested that low 25 hydroxyvitamin D levels and diabetes mellitus predict low bone mineral density and fracture at any site.15Boudville N. Inderjeeth C. Elder G.J. Glendenning P. Association between 25-hydroxyvitamin D, somatic muscle weakness and falls risk in end-stage renal failure.Clin Endocrinol. 2010; 73: 299-304Crossref PubMed Scopus (65) Google Scholar, 16Elder G.J. Mackun K. 25-Hydroxyvitamin D deficiency and diabetes predict reduced BMD in patients with chronic kidney disease.J Bone Miner Res. 2006; 21: 1778-1784Crossref PubMed Scopus (73) Google Scholar Limited data suggest that the benefit of vitamin D treatment in preventing hip fractures may be related to improvements in muscle mass and/or function.15Boudville N. Inderjeeth C. Elder G.J. Glendenning P. Association between 25-hydroxyvitamin D, somatic muscle weakness and falls risk in end-stage renal failure.Clin Endocrinol. 2010; 73: 299-304Crossref PubMed Scopus (65) Google Scholar, 16Elder G.J. Mackun K. 25-Hydroxyvitamin D deficiency and diabetes predict reduced BMD in patients with chronic kidney disease.J Bone Miner Res. 2006; 21: 1778-1784Crossref PubMed Scopus (73) Google Scholar, 17Gordon P.L. Sakkas G.K. Doyle J.W. Shubert T. Johansen K.L. Relationship between vitamin D and muscle size and strength in patients on hemodialysis.J Ren Nutr. 2007; 17: 397-407Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Conversely, one must ponder whether changes in hip fracture rates may be more related to changing characteristics in the hemodialysis population, such as frailty or higher body mass index (BMI). Frailty is defined as a syndrome of decreased reserve and resistance to physiologic stressors leading to adverse outcomes.17Gordon P.L. Sakkas G.K. Doyle J.W. Shubert T. Johansen K.L. Relationship between vitamin D and muscle size and strength in patients on hemodialysis.J Ren Nutr. 2007; 17: 397-407Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 18Fried L.P. Tangen C.M. Walston J. et al.Frailty in older adults: evidence for a phenotype.J Gerontol A Biol Sci Med Sci. 2001; 56: M146-M156Crossref PubMed Google Scholar Prevalence rates of frailty in the dialysis population are as high as 73%.19Bao Y. Dalrymple L. Chertow G.M. Kaysen G.A. Johansen K.L. Frailty, dialysis initiation, and mortality in end-stage renal disease.Arch Intern Med. 2012; 172: 1071-1077Crossref PubMed Scopus (227) Google Scholar Adverse outcomes in this population have been documented and include early initiation of dialysis therapy, increased hospitalizations, loss of activities of daily living, and death.19Bao Y. Dalrymple L. Chertow G.M. Kaysen G.A. Johansen K.L. Frailty, dialysis initiation, and mortality in end-stage renal disease.Arch Intern Med. 2012; 172: 1071-1077Crossref PubMed Scopus (227) Google Scholar, 20Johansen K.L. Chertow G.M. Jin C. Kutner N.G. Significance of frailty among dialysis patients.J Am Soc Nephrol. 2007; 18: 2960-2967Crossref PubMed Scopus (455) Google Scholar, 21Roshanravan B. Khatri M. Robinson-Cohen C. et al.A prospective study of frailty in nephrology-referred patients with CKD.Am J Kidney Dis. 2012; 60: 912-921Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 22Shlipak M.G. Stehman-Breen C. Fried L.F. et al.The presence of frailty in elderly persons with chronic renal insufficiency.Am J Kidney Dis. 2004; 43: 861-867Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar Although there is no direct evidence on the risk of hip fracture in frail dialysis patients, data about frailty in the general population suggest that the risk of fracture is even more profound in frail individuals.23Fried L.P. Ferrucci L. Darer J. Williamson J.D. Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care.J Gerontol A Biol Sci Med Sci. 2004; 59: 255-263Crossref PubMed Google Scholar, 24Woods N.F. LaCroix A.Z. Gray S.L. et al.Frailty: emergence and consequences in women aged 65 and older in the Women's Health Initiative observational study.J Am Geriatr Soc. 2005; 53: 1321-1330Crossref PubMed Scopus (775) Google Scholar, 25Gerber Y. Melton III, L.J. McNallan S.M. Jiang R. Weston S.A. Roger V.L. Cardiovascular and noncardiovascular disease associations with hip fractures.Am J Med. 2013; 126 (169 e119-e126)Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar In the Cardiovascular Health Study, a cohort in which frailty has been examined extensively, lower glomerular filtration rate estimated by cystatin C level was correlated with higher hip fracture rates.2Fried L.F. Biggs M.L. Shlipak M.G. et al.Association of kidney function with incident hip fracture in older adults.J Am Soc Nephrol. 2007; 18: 282-286Crossref PubMed Scopus (169) Google Scholar Higher BMI is associated with lower risk for hip fracture in dialysis patients, but not in the general population.26DiPietro L. Welch G.A. Davis D.R. Drane J.W. Macera C.A. Body mass and risk of hip fracture among a national cohort of postmenopausal white women: a reanalysis.Obes Res. 1993; 1: 357-363Crossref PubMed Scopus (8) Google Scholar, 27Langlois J.A. Mussolino M.E. Visser M. Looker A.C. Harris T. Madans J. Weight loss from maximum body weight among middle-aged and older white women and the risk of hip fracture: the NHANES I epidemiologic follow-up study.Osteoporos Int. 2001; 12: 763-768Crossref PubMed Scopus (102) Google Scholar, 28Stehman-Breen C.O. Sherrard D.J. Alem A.M. et al.Risk factors for hip fracture among patients with end-stage renal disease.Kidney Int. 2000; 58: 2200-2205Crossref PubMed Google Scholar, 29De Laet C. Kanis J.A. Oden A. et al.Body mass index as a predictor of fracture risk: a meta-analysis.Osteoporos Int. 2005; 16: 1330-1338Crossref PubMed Scopus (1168) Google Scholar Stehman-Breen et al28Stehman-Breen C.O. Sherrard D.J. Alem A.M. et al.Risk factors for hip fracture among patients with end-stage renal disease.Kidney Int. 2000; 58: 2200-2205Crossref PubMed Google Scholar found a relative risk of 0.89 (95% CI, 0.86-0.93) for hip fracture per 1-unit higher BMI. With the overall increase in incidence of obesity in dialysis patients, a decline in hip fracture rate may be a reflection of higher BMI. Despite the limitations inherent in using ICD-9-CM coding and using the available data, which are limited to dialysis patients who had Medicare fee-for-service as their primary payer, this study from Arenson et al11Arneson T.J. Li S. Liu J. Kilpatrick R.D. Newsome B.B. St. Peter W.L. Trends in hip francture rates in US hemodialysis patients, 1993-2010.Am J Kidney Dis. 2013; 62: 747-754Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar suggests that we may be seeing fewer fractures for hemodialysis patients who require cinacalcet for phosphorus and PTH control. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests. Trends in Hip Fracture Rates in US Hemodialysis Patients, 1993-2010American Journal of Kidney DiseasesVol. 62Issue 4PreviewChanges in mineral and bone disorder treatment patterns and demographic changes in the dialysis population may have influenced hip fracture rates in US dialysis patients in 1993-2010. Full-Text PDF" @default.
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