Bone 64 (2014) 235–239
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Original Full Length Article
Epidemiology and mortality of hip fracture among patients on dialysis: Taiwan National Cohort Study Zhe-Zhong Lin a,1, Jhi-Joung Wang b,1, Chi-Rung Chung c, Po-Chang Huang c, Bo-an Su d,e, Kuo-Chen Cheng a,f, Chung-Ching Chio g, Chih-Chiang Chien h,i,⁎ a
Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan Department of Orthopedics, Chi-Mei Medical Center, Tainan, Taiwan d Department of Infectious Diseases, Chi-Mei Medical Center, Tainan, Taiwan e Development of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan f Department of Safety Health and Environmental Engineering, Chung Hwa University of Medical Technology, Tainan, Taiwan g Department of Neurology, Chi-Mei Medical Center, Tainan, Taiwan h Department of Nephrology, Chi-Mei Medical Center, Tainan, Taiwan i Department of Food Nutrition, Chung Hwa University of Medical Technology, Tainan, Taiwan b c
a r t i c l e
i n f o
Article history: Received 16 October 2013 Revised 16 April 2014 Accepted 17 April 2014 Available online 26 April 2014 Edited by: Sundeep Khosla Keywords: Hip fracture End-stage renal disease Dialysis Mortality
a b s t r a c t Chronic kidney disease increases the risk for hip fractures. Hip fractures are associated with increased mortality, decreased quality of life, and higher economic burden. To determine whether dialysis modality is associated with a higher incidence of hip fractures in patients with end-stage renal disease (ESRD), we used the Taiwan National Health Insurance Research Database to examine the records of 51,473 patients who began dialysis between 1999 and 2005. The patients were followed until death, transplantation, dialysis cessation, or 31 December 2008. The follow-up period was (mean ± SD) 4.14 ± 2.48 years. The cumulative incidence rate of hip fracture was calculated using Kaplan–Meier methods. Predictors of hip fracture were determined using Cox models. During the study period, 1903 patients had a hip fracture. The overall incidence rate of hip fracture was 89.21/10,000 patient-years. Patients on hemodialysis (HD) had a 31% higher incidence of hip fracture than those on peritoneal dialysis (PD) (HR 1.31, 95% CI: 1.01–1.70). Patients ≥65 years old had more than 13 times the risk of a hip fracture than did those 18–44 years old (HR: 13.65; 95% CI: 10.12–18.40). Other factors that increased the risk of a hip fracture were a prior hip fracture (HR: 1.44; 95% CI: 1.15–1.80), osteoporosis (HR: 1.24; 95% CI: 1.07–1.45), DM (HR: 1.66; 95% CI: 1.51–1.83), and liver cirrhosis (HR: 1.37, 95% CI: 1.15–1.64). The overall in-hospital mortality rate was 3.2%. The cumulative survival rates after a hip fracture were 74.6% at one year and only 29.6% at seven years. Our findings supported the notion that being on HD is a risk for hip fracture. Additionally, old age, female gender, a prior hip fracture, osteoporosis, DM and liver cirrhosis were also risk factors for hip fracture in patients with ESRD and undergoing dialysis. © 2014 Elsevier Inc. All rights reserved.
Introduction The number of people with chronic kidney disease (CKD) is increasing [1]. Hip fractures occur more frequently in patients with CKD and end-stage renal disease (ESRD) [2], and they are an important complication associated with a high mortality rate [3], decreased quality of life [4], and large economic burden [3,5]. The mechanisms of impaired skeletal strength in patients with ESRD are either osteoporosis [3,6,7] or renal bone disease, such as adynamic
⁎ Corresponding author at: Department of Nephrology, Chi-Mei Medical Center, 901 Jung-Hua Road, Yung Kang District, Tainan City 710, Taiwan. Fax: +886 6 2832639. E-mail address: [email protected] (C.-C. Chien). 1 Zhe-Zhong Lin and Jhi-Joung Wang contributed equally and are first authors for this article.
http://dx.doi.org/10.1016/j.bone.2014.04.017 8756-3282/© 2014 Elsevier Inc. All rights reserved.
bone disease [8,9]. Stein et al. [6] reported a prevalence of osteopenia up to 20% at sites clinically associated with fracture in a large sample of patients on dialysis. Kosei et al. [7] also reported that low bone mineral density predicts fracture in patients on dialysis. Various bone lesions occurring in patients with CKD share the general term of renal osteodystrophy [8]. The prevalence of adynamic bone disease is high in patients with ESRD and on dialysis [9], and there is a close relationship between a higher incidence of fracture and adynamic bone disease [8,10]. Increasing age [11], female gender [11], white race [12], diabetes [12], and duration of dialysis [12] are also risk factors for hip fractures in patients with CKD. Compared with maintenance dialysis, renal transplantation is associated with a greater risk of hip fractures within 630 days beyond transplantation [12]. However, few studies have investigated whether the modality of dialysis is a risk factor for hip fractures. We hypothesized that patients with ESRD on hemodialysis (HD) would
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have a higher incidence of hip fracture than those on peritoneal dialysis (PD). In addition, few studies have evaluated long-term mortality rates after hip fractures in patients with ESRD and on dialysis. The incidence and prevalence rates of ESRD are high in Taiwan [13]. To test our hypothesis and evaluate the epidemiology and the inhospital and long-term mortality rate of hip fractures in patients with ESRD and on dialysis, we used a large dataset from the Taiwan National Health Insurance Research Database (NHIRD) to undertake a nationwide study. Research design and methods Database The National Health Insurance (NHI) program has provided compulsory universal health insurance in Taiwan since 1995. With the exception of prison inmates, all citizens are enrolled in the program. All contracted medical institutions must submit standard computerized claim documents for medical expenses. Patients with ESRD are eligible for any type of renal replacement therapy free of any charge. All chronic dialysis patients are covered by the NHI. Data were obtained from the National Health Insurance Research Database (NHIRD) [Bureau of National Health Insurance. Available at: www.doh.gov.tw/statistic/index.htm [In Chinese] (accessed September 25, 2012); http://www.doh.gov.tw/EN2006/index_EN.aspx [In English]] and released for research by the Taiwan National Health Research Institute. The NHIRD covers nearly all (99%) inpatient and outpatient medical benefit claims for the 23 million residents of Taiwan, is one of the largest and most comprehensive databases in the world, and has been used extensively in various studies [14–18]. Patient gender, birth date, dates of admission and discharge, medical institutions providing the services, the ICD-9-CM (International Classification of Diseases, 9th Revision, Clinical Modification) diagnostic and procedure codes (up to five each), and outcomes are encrypted. This study used the NHIRD for ambulatory care claims, inpatient claims, and the updated registry for beneficiaries from 1998 to 2008; all of these datasets can be interlinked through each patient's unique personal identification number. Patient selection and definition
Statistical analyses The incidence of newly diagnosed hip fractures was expressed as the number of cases of hip fracture per 10,000 person-years. Parametric Pearson chi-square test was used to compare each variable in the groups of patients with and without a hip fracture. Age was entered as a categorical variable (18–44, 45–64, and ≥65 years old). Significance was set at p b 0.05. The cumulative proportion of patients with hip fractures and of survivors after hip fractures was calculated using the Kaplan– Meier method. The log rank test was used to analyze significance. Cox proportional hazards models were used to identify the risk factors for hip fracture. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived from Cox proportional hazards models. The Cox models met the assumption of proportionality of risks. To adjust for potential confounding factors in the relationship between comorbidities, multivariate analysis was used. All statistical analyses were using SPSS 17.0 for Windows (SPSS Inc., Chicago, IL, USA). Results Demographics and clinical characteristics We enrolled 51,473 adult incident dialysis patients. The follow-up period (mean ± SD) was 4.14 ± 2.48 years. During the follow-up period, 1903 (3.70%) patients had a hip fracture (incidence rate: 89.21/ 10,000 patient-years; males: 3%; females: 4.3%; p b 0.001) (Table 1). The incidence of hip fractures was 75.43/10,000 patient-years in males and 101.2/10,000 patient-years in females. Only 0.6% of those 18– 44 years old had a hip fracture; however, 6.1% of those ≥65 years old had a hip fracture (incidence rate: 182.27/10,000 patient-years). Patients on HD had a higher incidence of hip fractures (92.79/ 10,000 patient-years) than did those on PD (40.86/10,000 patientyears). Patients with a hip fracture tended to have more comorbidities than did those without a hip fracture. Many more patients with a hip fracture had a prior hip fracture, osteoporosis, DM, congestive heart failure, cerebrovascular accident, liver cirrhosis, and psychiatric disorders than did those without a hip fracture. Incidence and risk factors for hip fracture
For this longitudinal cohort study, we enrolled 51,473 adult (≥ 18 years old) patients with ESRD on maintenance dialysis who began renal replacement therapy between January 1, 1999, and December 31, 2005. Age was defined on the first reported date of dialysis. Patients with ESRD on maintenance dialysis were defined as having undergone dialysis for more than 90 days. All of the patients were followed-up from the first reported date of dialysis to the date of death, cessation of dialysis, or December 31, 2008. The inpatient claims included the records of all hospitalizations and provide a substantial amount of information. We linked the study participants to the inpatient claim data to identify the first episode of hip fracture (ICD-9-CM: 820.X) after the initiation of dialysis. During the follow-up period, 1903 patients were diagnosed with hip fractures.
The cumulative incidence rates of hip fractures of the patients on HD were 1.1% at one year, 4.6% at five years, and 6.3% at nine years, and in those receiving PD were 0.6% at one year, 2% at five years, and 2.8% at nine years (Fig. 1). Female gender, old age, being on HD, and having baseline comorbidities were risk factors for a hip fracture (Table 2). Patients ≥65 years old had more than 13 times the risk of a hip fracture than did those 18– 44 years old (HR: 13.65; 95% CI: 10.12–18.40). A multivariate analysis showed that patients on HD had a 31% higher risk of a hip fracture than did those on PD (HR: 1.31; 95% CI: 1.01–1.70). Other factors that increased the risk of a hip fracture were a prior hip fracture (HR: 1.44; 95% CI: 1.15–1.80), osteoporosis (HR: 1.24; 95% CI: 1.07–1.45), DM (HR: 1.66; 95% CI: 1.51–1.83), and liver cirrhosis (HR: 1.37, 95% CI: 1.15–1.64).
Ascertaining the demographic and comorbid variables
Survival rate after hip fracture
We linked to the diagnostic codes through the inpatient and outpatient claim databases of the NHI. Survival status, date of death, patient demographics, dialysis modality, prior renal transplantation, and baseline comorbidities were determined and recorded. Baseline comorbidities—hypertension, prior hip fracture, osteoporosis, diabetes mellitus (DM), congestive heart failure, cerebrovascular accident, liver cirrhosis, psychiatric disorder, and dementia—are important factors affecting episodes of hip fracture and were assessed. The ICD-9-CM codes used to define each condition are shown in Supplemental Data.
The overall in-hospital mortality rate was 3.2% (Fig. 2). The cumulative survival rates after hip fractures were 74.6% at one year, 50.6% at three years, and only 36.3% at five years. Incidence and risk factors for hip fracture in patients ≥65 years old The data from 21,042 incident dialysis patients ≥65 years old were analyzed. During the follow-up period, 1281 (6.1%) patients had hip fractures (incidence rate: 182.29/10,000 patient-years). Female gender
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Table 1 Patient characteristics by hip fracture status and dialysis modality in end-stage renal disease patients. Without or with hip fracture
Gender Female Male Age (years) 18–44 45–64 ≥65 Dialysis modality PD HD Prior transplant No Yes Prior hip fracture No Yes Osteoporosis No Yes Diabetes mellitus No Yes Congestive heart failure No Yes Cerebrovascular disease No Yes Liver cirrhosis No Yes Psychiatric disorder No Yes Dementia No Yes
Dialysis modality
Without hip fracture (n = 49,570)
With hip fracture (n = 1903)
n
n
(%)
P value
(%)
PD (n = 3487)
HD (n = 47,986)
n
(%)
n
(%)
2036 1451
(58.4) (41.6)
24,786 23,200
(51.7) (48.3)
1155 1573 759
(33.1) (45.1) (21.8)
6667 21,036 20,283
(13.9) (43.8) (42.3)
3465 22
(99.4) (0.6)
47,701 285
(99.4) (0.6)
3444 43
(98.8) (1.2)
46,708 1278
(97.3) (2.7)
3280 207
(94.1) (5.9)
44,727 3259
(93.2) (6.8)
2365 1122
(67.8) (32.2)
24,102 23,884
(50.2) (49.8)
2950 537
(84.6) (15.4)
35,986 12,000
(75.0) (25.0)
3256 231
(93.4) (6.6)
42,082 5904
(87.7) (12.3)
3348 139
(96.0) (4.0)
45,100 2886
(94.0) (6.0)
3446 41
(98.8) (1.2)
47,272 714
(98.5) (1.5)
3485 7
(99.8) (0.2)
47,688 298
(99.4) (0.6)
b0.001 25,668 23,902
(51.8) (48.2)
1154 749
(60.6) (39.4)
7779 22,033 19,761
(15.7) (44.4) (39.9)
46 576 1281
(2.4) (30.3) (67.3)
3427 46,143
(6.9) (93.1)
60 1843
(3.2) (96.8)
49,267 303
(99.4) (0.6)
1899 4
(99.8) (0.2)
48,333 1237
(97.5) (2.5)
1819 84
(95.6) (4.4)
46,299 3271
(93.4) (6.6)
1708 195
(89.8) (10.2)
25,705 23,865
(51.9) (48.1)
762 1141
(40.0) (60.0)
37,571 11,999
(75.8) (24.2)
1365 538
(71.7) (28.3)
43,713 5857
(88.2) (11.8)
1625 278
(85.4) (14.6)
46,674 2896
(94.2) (5.8)
1774 129
(93.2) (6.8)
48,845 725
(98.5) (1.5)
1873 30
(98.4) (1.6)
49,275 295
(99.4) (0.6)
1893 10
(99.5) (0.5)
P value
b0.001
b0.001
b0.001
b0.001
0.026
0.784
b0.001
b0.001
b0.001
0.052
b0.001
b0.001
b0.001
b0.001
b0.001
b0.001
b0.001
0.088
0.685
0.139
0.698
0.002
Table 2 Risk factor for hip fracture in patients with end-stage renal disease and on dialysis (n = 51,473). Factors
Sex (female v male) Age 18–44 45–64 ≥65 Dialysis modality (HD v PD) Prior transplantation (yes v no) Prior hip fracture (yes v no) Osteoporosis (yes v no) Diabetic Mellitus (yes v no) Congestive heart failure (yes v no) Cerebrovascular disease (yes v no) Liver cirrhosis (yes v no) Psychiatric disorder (yes v no) Dementia (yes v no)
Fig. 1. Cumulative incidence of hip fracture after beginning dialysis stratified by dialysis modality in patients with end-stage renal disease and undergoing dialysis.
Univariate analysis
Multivariate analysis
HR (95% CI)
HR (95% CI)a
1.343 (1.225–1.473)⁎
1.256 (1.143–1.380)⁎
1 5.159 (3.820–6.967)⁎ 17.085 (12.721–22.947)⁎ 2.269 (1.755–2.934)⁎ 0.300 (0.113–0.801)⁎
1 4.269 (3.154–5.780)⁎ 13.649 (10.124–18.401)⁎ 1.311 (1.012–1.698)⁎ 1.094 (0.408–2.930)
2.718 (2.182–3.385)⁎ 1.894 (16.33–2.197)⁎ 2.001 (1.825–2.195)⁎ 1.532 (1.386–1.694)⁎
1.438 (1.149–1.798)⁎ 1.242 (1.066–1.448)⁎ 1.662 (1.511–1.828)⁎ 1.099 (0.992–1.218)
1.654 (1.455–1.879)⁎
1.149 (0.804–1.642)
1.276 (1.067–1.526)⁎ 1.240 (0.865–1.779) 1.617 (0.868–3.012)
1.374 (1.149–1.644)⁎ 1.201 (0.837–1.725) 0.853 (0.457–1.593)
HR, hazard ratio; CI, confidence interval; HD, hemodialysis; PD, peritoneal dialysis. a HR adjusted for sex, age, dialysis modalities, prior transplantation, prior hip fracture, osteoporosis, diabetes mellitus, congestive heart failure, cerebrovascular accident, liver cirrhosis, psychiatric disorder and dementia. ⁎ p b 0.05.
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Fig. 2. Overall survival curves after hip fracture in patients with end-stage renal disease and undergoing dialysis.
(HR: 1.30; 95% CI: 1.16–1.46), osteoporosis (HR: 1.21; 95% CI: 1.02– 1.44), DM (HR: 1.26; 95% CI: 1.13–1.41), and liver cirrhosis (HR: 1.33; 95% CI: 1.05–1.67) were risk factors for hip fractures in these elderly patients. Patients on HD had a 21% higher risk of a hip fracture than did those on PD; however, it was not significant after a multivariate analysis (HR: 1.21; 95% CI: 0.84–1.72). Incidence and risk factors for hip fracture in all patients without a prior hip fracture The data from 51,052 incident dialysis patients without a prior hip fracture were analyzed. During the follow-up period, 1819 (3.6%) patients had hip fractures (incidence rate: 86.71/10,000 patient-years). Female gender (HR:1.27; 95% CI: 1.15–1.40), old age (HR: 13.73; 95% CI: 10.08–18.51), osteoporosis (HR: 1.25; 95% CI: 1.06–1.47), DM (HR: 1.70; 95% CI: 1.54–1.87), cerebrovascular accident (HR: 1.19; 95% CI: 1.04–1.35) and liver cirrhosis (HR: 1.39; 95% CI: 1.16–1.67) were risk factors for a hip fracture. Patients on HD had a 29% higher risk for a hip fracture than did those on PD; however, it was not significant after a multivariate analysis (HR: 1.29; 95% CI: 0.99–1.67). Discussion This study used Taiwan's representative national database, the NHIRD, to investigate the incidence rates of hip fractures in patients with ESRD and undergoing dialysis. We found that patients on HD had a higher incidence of hip fractures than did those on PD. Old age, female gender, a prior hip fracture, osteoporosis, DM and liver cirrhosis were also risk factors for hip fracture. The in-hospital mortality rate was 3.2%. The overall cumulative hip fracture incidence rate was 89.21/ 10,000 patient-years, which is higher than that reported in general populations with any other ethnic groups, such as blacks [19], Hispanics [20], Asians [21], and whites [22–24]. Our data are consistent with reports that the incidence rate of hip fractures in patient with ESRD is higher than that in the general population [3,9]. We found that age was a significant factor for hip fracture in patients with ESRD on dialysis from current data. The incidence rate of hip fractures in the general elderly population has been reported to be 57.54/10,000 patient-years [25], but in the current study, the incidence rate in elderly patients with ESRD was 3.17 times higher than that in the general elderly population in Taiwan. In addition, patients ≥65 years old and on dialysis had
13 times the risk of a hip fracture than did younger patients on dialysis. We also found that female patients had a higher incidence of hip fractures than did the male patients, which is consistent with a previous study on the general population [26]. The higher incidence rate in females might be attributable to postmenopausal osteoporosis [27]. Different dialysis modalities were associated with different incidence rates of hip fractures. The incidence rate of hip fracture in patients on HD was twice that in patients on PD. Patients on PD are younger than patients on HD, and more patients on HD have DM compared to those patients on PD [28]. Both age and DM were risk factors for hip fractures in the current study. After multivariate adjustment for gender, dialysis modality, prior transplantation, prior hip fracture, osteoporosis, and other comorbidities, the patients on HD still had a 31% higher risk for hip fractures than did those on PD. This may be explained by hemodynamic instability [29] and orthostatic hypotension [30,31] in patients on HD. Comorbidities, including prior hip fracture and osteoporosis, were identical risk factors for hip fractures in the current study, which is consistent with other studies [2,32]. Chen et al. [33] also reported that the risks for hip fractures are higher both in men (HR: 1.28; 95% CI: 1.21– 1.34) and in women (HR 1.72, 95% CI: 1.66–1.78) with DM than without DM in the general population. We found that DM was a statistically significant risk factor for hip fracture (HR: 1.66; 95% CI: 1.51–1.83) in patients with ESRD and on dialysis, which is consistent with a previous report [32]. The mechanism of the association between DM and hip fracture is not yet clear. It might be that people with DM are much more likely to fall while suffering hypoglycemia, and to have peripheral neuropathy, stroke, and impaired bone formation [33]. In addition to renal failure, liver dysfunction is a risk factor for hip fracture. In the current study, liver cirrhosis was associated with a 37% increase in hip fracture in patients with ESRD. This might be due to their inability to convert vitamin D into the active form and because of the bone loss seen in cirrhosis [34–38]. Hip fracture have been reported to be associated with subsequent mortality, including in-hospital and long-term mortality [5,33,39]. Chie et al. [25] reported an in-hospital mortality rate of 0.97% in the general population ≥65 years old with hip fracture. Hannan et al. [40] reported an in-hospital mortality rate of 1.6% in patients ≥50 years old with hip fracture. The in-hospital mortality rate in the current study was much higher: 3.2%. Other studies have reported one-year mortality rates of 15–20% after a hip fracture in the general US population [41]. In our study, the one-year cumulative survival rate was only 64.6%. Furthermore, the cumulative survival rate in our study was 50.6% at three years. Both long-term and in hospital mortality rates after hip fractures were much higher than those in the general population. This might be because patients with ESRD have more comorbidities than the general population [28]. There are several limitations to this study. First, the comorbidities relied solely on ICD-9-CM diagnosis codes and no other clinical criteria, which may have resulted in misclassification of some disease. Second, the NHIRD does not indicate the severity of the diseases. Third, there was a lack of specific data on dialysis adequacy, patient compliance, nutritional status, biochemical data, socioeconomic characteristics, causes of death, sarcopenia, and falls. Fourth, whether the female patients had reached menopause was not included in the database. In conclusion, the incidence rate of hip fracture in patients with ESRD was high. Being on HD, old age, female gender, a prior hip fracture, osteoporosis, DM and liver cirrhosis were risk factors for hip fracture. Subsequent mortality rates were high. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.bone.2014.04.017. Acknowledgments The study was supported by grants CMFHR10073 and CMFHR10266 from Chi-Mei Medical Center and grant NHRI-NHIRD-99182 from the National Health Research Institutes in Taiwan.
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Original Full Length Article
Epidemiology and mortality of hip fracture among patients on dialysis: Taiwan National Cohort Study Zhe-Zhong Lin a,1, Jhi-Joung Wang b,1, Chi-Rung Chung c, Po-Chang Huang c, Bo-an Su d,e, Kuo-Chen Cheng a,f, Chung-Ching Chio g, Chih-Chiang Chien h,i,⁎ a
Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan Department of Orthopedics, Chi-Mei Medical Center, Tainan, Taiwan d Department of Infectious Diseases, Chi-Mei Medical Center, Tainan, Taiwan e Development of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan f Department of Safety Health and Environmental Engineering, Chung Hwa University of Medical Technology, Tainan, Taiwan g Department of Neurology, Chi-Mei Medical Center, Tainan, Taiwan h Department of Nephrology, Chi-Mei Medical Center, Tainan, Taiwan i Department of Food Nutrition, Chung Hwa University of Medical Technology, Tainan, Taiwan b c
a r t i c l e
i n f o
Article history: Received 16 October 2013 Revised 16 April 2014 Accepted 17 April 2014 Available online 26 April 2014 Edited by: Sundeep Khosla Keywords: Hip fracture End-stage renal disease Dialysis Mortality
a b s t r a c t Chronic kidney disease increases the risk for hip fractures. Hip fractures are associated with increased mortality, decreased quality of life, and higher economic burden. To determine whether dialysis modality is associated with a higher incidence of hip fractures in patients with end-stage renal disease (ESRD), we used the Taiwan National Health Insurance Research Database to examine the records of 51,473 patients who began dialysis between 1999 and 2005. The patients were followed until death, transplantation, dialysis cessation, or 31 December 2008. The follow-up period was (mean ± SD) 4.14 ± 2.48 years. The cumulative incidence rate of hip fracture was calculated using Kaplan–Meier methods. Predictors of hip fracture were determined using Cox models. During the study period, 1903 patients had a hip fracture. The overall incidence rate of hip fracture was 89.21/10,000 patient-years. Patients on hemodialysis (HD) had a 31% higher incidence of hip fracture than those on peritoneal dialysis (PD) (HR 1.31, 95% CI: 1.01–1.70). Patients ≥65 years old had more than 13 times the risk of a hip fracture than did those 18–44 years old (HR: 13.65; 95% CI: 10.12–18.40). Other factors that increased the risk of a hip fracture were a prior hip fracture (HR: 1.44; 95% CI: 1.15–1.80), osteoporosis (HR: 1.24; 95% CI: 1.07–1.45), DM (HR: 1.66; 95% CI: 1.51–1.83), and liver cirrhosis (HR: 1.37, 95% CI: 1.15–1.64). The overall in-hospital mortality rate was 3.2%. The cumulative survival rates after a hip fracture were 74.6% at one year and only 29.6% at seven years. Our findings supported the notion that being on HD is a risk for hip fracture. Additionally, old age, female gender, a prior hip fracture, osteoporosis, DM and liver cirrhosis were also risk factors for hip fracture in patients with ESRD and undergoing dialysis. © 2014 Elsevier Inc. All rights reserved.
Introduction The number of people with chronic kidney disease (CKD) is increasing [1]. Hip fractures occur more frequently in patients with CKD and end-stage renal disease (ESRD) [2], and they are an important complication associated with a high mortality rate [3], decreased quality of life [4], and large economic burden [3,5]. The mechanisms of impaired skeletal strength in patients with ESRD are either osteoporosis [3,6,7] or renal bone disease, such as adynamic
⁎ Corresponding author at: Department of Nephrology, Chi-Mei Medical Center, 901 Jung-Hua Road, Yung Kang District, Tainan City 710, Taiwan. Fax: +886 6 2832639. E-mail address: [email protected] (C.-C. Chien). 1 Zhe-Zhong Lin and Jhi-Joung Wang contributed equally and are first authors for this article.
http://dx.doi.org/10.1016/j.bone.2014.04.017 8756-3282/© 2014 Elsevier Inc. All rights reserved.
bone disease [8,9]. Stein et al. [6] reported a prevalence of osteopenia up to 20% at sites clinically associated with fracture in a large sample of patients on dialysis. Kosei et al. [7] also reported that low bone mineral density predicts fracture in patients on dialysis. Various bone lesions occurring in patients with CKD share the general term of renal osteodystrophy [8]. The prevalence of adynamic bone disease is high in patients with ESRD and on dialysis [9], and there is a close relationship between a higher incidence of fracture and adynamic bone disease [8,10]. Increasing age [11], female gender [11], white race [12], diabetes [12], and duration of dialysis [12] are also risk factors for hip fractures in patients with CKD. Compared with maintenance dialysis, renal transplantation is associated with a greater risk of hip fractures within 630 days beyond transplantation [12]. However, few studies have investigated whether the modality of dialysis is a risk factor for hip fractures. We hypothesized that patients with ESRD on hemodialysis (HD) would
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have a higher incidence of hip fracture than those on peritoneal dialysis (PD). In addition, few studies have evaluated long-term mortality rates after hip fractures in patients with ESRD and on dialysis. The incidence and prevalence rates of ESRD are high in Taiwan [13]. To test our hypothesis and evaluate the epidemiology and the inhospital and long-term mortality rate of hip fractures in patients with ESRD and on dialysis, we used a large dataset from the Taiwan National Health Insurance Research Database (NHIRD) to undertake a nationwide study. Research design and methods Database The National Health Insurance (NHI) program has provided compulsory universal health insurance in Taiwan since 1995. With the exception of prison inmates, all citizens are enrolled in the program. All contracted medical institutions must submit standard computerized claim documents for medical expenses. Patients with ESRD are eligible for any type of renal replacement therapy free of any charge. All chronic dialysis patients are covered by the NHI. Data were obtained from the National Health Insurance Research Database (NHIRD) [Bureau of National Health Insurance. Available at: www.doh.gov.tw/statistic/index.htm [In Chinese] (accessed September 25, 2012); http://www.doh.gov.tw/EN2006/index_EN.aspx [In English]] and released for research by the Taiwan National Health Research Institute. The NHIRD covers nearly all (99%) inpatient and outpatient medical benefit claims for the 23 million residents of Taiwan, is one of the largest and most comprehensive databases in the world, and has been used extensively in various studies [14–18]. Patient gender, birth date, dates of admission and discharge, medical institutions providing the services, the ICD-9-CM (International Classification of Diseases, 9th Revision, Clinical Modification) diagnostic and procedure codes (up to five each), and outcomes are encrypted. This study used the NHIRD for ambulatory care claims, inpatient claims, and the updated registry for beneficiaries from 1998 to 2008; all of these datasets can be interlinked through each patient's unique personal identification number. Patient selection and definition
Statistical analyses The incidence of newly diagnosed hip fractures was expressed as the number of cases of hip fracture per 10,000 person-years. Parametric Pearson chi-square test was used to compare each variable in the groups of patients with and without a hip fracture. Age was entered as a categorical variable (18–44, 45–64, and ≥65 years old). Significance was set at p b 0.05. The cumulative proportion of patients with hip fractures and of survivors after hip fractures was calculated using the Kaplan– Meier method. The log rank test was used to analyze significance. Cox proportional hazards models were used to identify the risk factors for hip fracture. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived from Cox proportional hazards models. The Cox models met the assumption of proportionality of risks. To adjust for potential confounding factors in the relationship between comorbidities, multivariate analysis was used. All statistical analyses were using SPSS 17.0 for Windows (SPSS Inc., Chicago, IL, USA). Results Demographics and clinical characteristics We enrolled 51,473 adult incident dialysis patients. The follow-up period (mean ± SD) was 4.14 ± 2.48 years. During the follow-up period, 1903 (3.70%) patients had a hip fracture (incidence rate: 89.21/ 10,000 patient-years; males: 3%; females: 4.3%; p b 0.001) (Table 1). The incidence of hip fractures was 75.43/10,000 patient-years in males and 101.2/10,000 patient-years in females. Only 0.6% of those 18– 44 years old had a hip fracture; however, 6.1% of those ≥65 years old had a hip fracture (incidence rate: 182.27/10,000 patient-years). Patients on HD had a higher incidence of hip fractures (92.79/ 10,000 patient-years) than did those on PD (40.86/10,000 patientyears). Patients with a hip fracture tended to have more comorbidities than did those without a hip fracture. Many more patients with a hip fracture had a prior hip fracture, osteoporosis, DM, congestive heart failure, cerebrovascular accident, liver cirrhosis, and psychiatric disorders than did those without a hip fracture. Incidence and risk factors for hip fracture
For this longitudinal cohort study, we enrolled 51,473 adult (≥ 18 years old) patients with ESRD on maintenance dialysis who began renal replacement therapy between January 1, 1999, and December 31, 2005. Age was defined on the first reported date of dialysis. Patients with ESRD on maintenance dialysis were defined as having undergone dialysis for more than 90 days. All of the patients were followed-up from the first reported date of dialysis to the date of death, cessation of dialysis, or December 31, 2008. The inpatient claims included the records of all hospitalizations and provide a substantial amount of information. We linked the study participants to the inpatient claim data to identify the first episode of hip fracture (ICD-9-CM: 820.X) after the initiation of dialysis. During the follow-up period, 1903 patients were diagnosed with hip fractures.
The cumulative incidence rates of hip fractures of the patients on HD were 1.1% at one year, 4.6% at five years, and 6.3% at nine years, and in those receiving PD were 0.6% at one year, 2% at five years, and 2.8% at nine years (Fig. 1). Female gender, old age, being on HD, and having baseline comorbidities were risk factors for a hip fracture (Table 2). Patients ≥65 years old had more than 13 times the risk of a hip fracture than did those 18– 44 years old (HR: 13.65; 95% CI: 10.12–18.40). A multivariate analysis showed that patients on HD had a 31% higher risk of a hip fracture than did those on PD (HR: 1.31; 95% CI: 1.01–1.70). Other factors that increased the risk of a hip fracture were a prior hip fracture (HR: 1.44; 95% CI: 1.15–1.80), osteoporosis (HR: 1.24; 95% CI: 1.07–1.45), DM (HR: 1.66; 95% CI: 1.51–1.83), and liver cirrhosis (HR: 1.37, 95% CI: 1.15–1.64).
Ascertaining the demographic and comorbid variables
Survival rate after hip fracture
We linked to the diagnostic codes through the inpatient and outpatient claim databases of the NHI. Survival status, date of death, patient demographics, dialysis modality, prior renal transplantation, and baseline comorbidities were determined and recorded. Baseline comorbidities—hypertension, prior hip fracture, osteoporosis, diabetes mellitus (DM), congestive heart failure, cerebrovascular accident, liver cirrhosis, psychiatric disorder, and dementia—are important factors affecting episodes of hip fracture and were assessed. The ICD-9-CM codes used to define each condition are shown in Supplemental Data.
The overall in-hospital mortality rate was 3.2% (Fig. 2). The cumulative survival rates after hip fractures were 74.6% at one year, 50.6% at three years, and only 36.3% at five years. Incidence and risk factors for hip fracture in patients ≥65 years old The data from 21,042 incident dialysis patients ≥65 years old were analyzed. During the follow-up period, 1281 (6.1%) patients had hip fractures (incidence rate: 182.29/10,000 patient-years). Female gender
Z.-Z. Lin et al. / Bone 64 (2014) 235–239
237
Table 1 Patient characteristics by hip fracture status and dialysis modality in end-stage renal disease patients. Without or with hip fracture
Gender Female Male Age (years) 18–44 45–64 ≥65 Dialysis modality PD HD Prior transplant No Yes Prior hip fracture No Yes Osteoporosis No Yes Diabetes mellitus No Yes Congestive heart failure No Yes Cerebrovascular disease No Yes Liver cirrhosis No Yes Psychiatric disorder No Yes Dementia No Yes
Dialysis modality
Without hip fracture (n = 49,570)
With hip fracture (n = 1903)
n
n
(%)
P value
(%)
PD (n = 3487)
HD (n = 47,986)
n
(%)
n
(%)
2036 1451
(58.4) (41.6)
24,786 23,200
(51.7) (48.3)
1155 1573 759
(33.1) (45.1) (21.8)
6667 21,036 20,283
(13.9) (43.8) (42.3)
3465 22
(99.4) (0.6)
47,701 285
(99.4) (0.6)
3444 43
(98.8) (1.2)
46,708 1278
(97.3) (2.7)
3280 207
(94.1) (5.9)
44,727 3259
(93.2) (6.8)
2365 1122
(67.8) (32.2)
24,102 23,884
(50.2) (49.8)
2950 537
(84.6) (15.4)
35,986 12,000
(75.0) (25.0)
3256 231
(93.4) (6.6)
42,082 5904
(87.7) (12.3)
3348 139
(96.0) (4.0)
45,100 2886
(94.0) (6.0)
3446 41
(98.8) (1.2)
47,272 714
(98.5) (1.5)
3485 7
(99.8) (0.2)
47,688 298
(99.4) (0.6)
b0.001 25,668 23,902
(51.8) (48.2)
1154 749
(60.6) (39.4)
7779 22,033 19,761
(15.7) (44.4) (39.9)
46 576 1281
(2.4) (30.3) (67.3)
3427 46,143
(6.9) (93.1)
60 1843
(3.2) (96.8)
49,267 303
(99.4) (0.6)
1899 4
(99.8) (0.2)
48,333 1237
(97.5) (2.5)
1819 84
(95.6) (4.4)
46,299 3271
(93.4) (6.6)
1708 195
(89.8) (10.2)
25,705 23,865
(51.9) (48.1)
762 1141
(40.0) (60.0)
37,571 11,999
(75.8) (24.2)
1365 538
(71.7) (28.3)
43,713 5857
(88.2) (11.8)
1625 278
(85.4) (14.6)
46,674 2896
(94.2) (5.8)
1774 129
(93.2) (6.8)
48,845 725
(98.5) (1.5)
1873 30
(98.4) (1.6)
49,275 295
(99.4) (0.6)
1893 10
(99.5) (0.5)
P value
b0.001
b0.001
b0.001
b0.001
0.026
0.784
b0.001
b0.001
b0.001
0.052
b0.001
b0.001
b0.001
b0.001
b0.001
b0.001
b0.001
0.088
0.685
0.139
0.698
0.002
Table 2 Risk factor for hip fracture in patients with end-stage renal disease and on dialysis (n = 51,473). Factors
Sex (female v male) Age 18–44 45–64 ≥65 Dialysis modality (HD v PD) Prior transplantation (yes v no) Prior hip fracture (yes v no) Osteoporosis (yes v no) Diabetic Mellitus (yes v no) Congestive heart failure (yes v no) Cerebrovascular disease (yes v no) Liver cirrhosis (yes v no) Psychiatric disorder (yes v no) Dementia (yes v no)
Fig. 1. Cumulative incidence of hip fracture after beginning dialysis stratified by dialysis modality in patients with end-stage renal disease and undergoing dialysis.
Univariate analysis
Multivariate analysis
HR (95% CI)
HR (95% CI)a
1.343 (1.225–1.473)⁎
1.256 (1.143–1.380)⁎
1 5.159 (3.820–6.967)⁎ 17.085 (12.721–22.947)⁎ 2.269 (1.755–2.934)⁎ 0.300 (0.113–0.801)⁎
1 4.269 (3.154–5.780)⁎ 13.649 (10.124–18.401)⁎ 1.311 (1.012–1.698)⁎ 1.094 (0.408–2.930)
2.718 (2.182–3.385)⁎ 1.894 (16.33–2.197)⁎ 2.001 (1.825–2.195)⁎ 1.532 (1.386–1.694)⁎
1.438 (1.149–1.798)⁎ 1.242 (1.066–1.448)⁎ 1.662 (1.511–1.828)⁎ 1.099 (0.992–1.218)
1.654 (1.455–1.879)⁎
1.149 (0.804–1.642)
1.276 (1.067–1.526)⁎ 1.240 (0.865–1.779) 1.617 (0.868–3.012)
1.374 (1.149–1.644)⁎ 1.201 (0.837–1.725) 0.853 (0.457–1.593)
HR, hazard ratio; CI, confidence interval; HD, hemodialysis; PD, peritoneal dialysis. a HR adjusted for sex, age, dialysis modalities, prior transplantation, prior hip fracture, osteoporosis, diabetes mellitus, congestive heart failure, cerebrovascular accident, liver cirrhosis, psychiatric disorder and dementia. ⁎ p b 0.05.
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Z.-Z. Lin et al. / Bone 64 (2014) 235–239
Fig. 2. Overall survival curves after hip fracture in patients with end-stage renal disease and undergoing dialysis.
(HR: 1.30; 95% CI: 1.16–1.46), osteoporosis (HR: 1.21; 95% CI: 1.02– 1.44), DM (HR: 1.26; 95% CI: 1.13–1.41), and liver cirrhosis (HR: 1.33; 95% CI: 1.05–1.67) were risk factors for hip fractures in these elderly patients. Patients on HD had a 21% higher risk of a hip fracture than did those on PD; however, it was not significant after a multivariate analysis (HR: 1.21; 95% CI: 0.84–1.72). Incidence and risk factors for hip fracture in all patients without a prior hip fracture The data from 51,052 incident dialysis patients without a prior hip fracture were analyzed. During the follow-up period, 1819 (3.6%) patients had hip fractures (incidence rate: 86.71/10,000 patient-years). Female gender (HR:1.27; 95% CI: 1.15–1.40), old age (HR: 13.73; 95% CI: 10.08–18.51), osteoporosis (HR: 1.25; 95% CI: 1.06–1.47), DM (HR: 1.70; 95% CI: 1.54–1.87), cerebrovascular accident (HR: 1.19; 95% CI: 1.04–1.35) and liver cirrhosis (HR: 1.39; 95% CI: 1.16–1.67) were risk factors for a hip fracture. Patients on HD had a 29% higher risk for a hip fracture than did those on PD; however, it was not significant after a multivariate analysis (HR: 1.29; 95% CI: 0.99–1.67). Discussion This study used Taiwan's representative national database, the NHIRD, to investigate the incidence rates of hip fractures in patients with ESRD and undergoing dialysis. We found that patients on HD had a higher incidence of hip fractures than did those on PD. Old age, female gender, a prior hip fracture, osteoporosis, DM and liver cirrhosis were also risk factors for hip fracture. The in-hospital mortality rate was 3.2%. The overall cumulative hip fracture incidence rate was 89.21/ 10,000 patient-years, which is higher than that reported in general populations with any other ethnic groups, such as blacks [19], Hispanics [20], Asians [21], and whites [22–24]. Our data are consistent with reports that the incidence rate of hip fractures in patient with ESRD is higher than that in the general population [3,9]. We found that age was a significant factor for hip fracture in patients with ESRD on dialysis from current data. The incidence rate of hip fractures in the general elderly population has been reported to be 57.54/10,000 patient-years [25], but in the current study, the incidence rate in elderly patients with ESRD was 3.17 times higher than that in the general elderly population in Taiwan. In addition, patients ≥65 years old and on dialysis had
13 times the risk of a hip fracture than did younger patients on dialysis. We also found that female patients had a higher incidence of hip fractures than did the male patients, which is consistent with a previous study on the general population [26]. The higher incidence rate in females might be attributable to postmenopausal osteoporosis [27]. Different dialysis modalities were associated with different incidence rates of hip fractures. The incidence rate of hip fracture in patients on HD was twice that in patients on PD. Patients on PD are younger than patients on HD, and more patients on HD have DM compared to those patients on PD [28]. Both age and DM were risk factors for hip fractures in the current study. After multivariate adjustment for gender, dialysis modality, prior transplantation, prior hip fracture, osteoporosis, and other comorbidities, the patients on HD still had a 31% higher risk for hip fractures than did those on PD. This may be explained by hemodynamic instability [29] and orthostatic hypotension [30,31] in patients on HD. Comorbidities, including prior hip fracture and osteoporosis, were identical risk factors for hip fractures in the current study, which is consistent with other studies [2,32]. Chen et al. [33] also reported that the risks for hip fractures are higher both in men (HR: 1.28; 95% CI: 1.21– 1.34) and in women (HR 1.72, 95% CI: 1.66–1.78) with DM than without DM in the general population. We found that DM was a statistically significant risk factor for hip fracture (HR: 1.66; 95% CI: 1.51–1.83) in patients with ESRD and on dialysis, which is consistent with a previous report [32]. The mechanism of the association between DM and hip fracture is not yet clear. It might be that people with DM are much more likely to fall while suffering hypoglycemia, and to have peripheral neuropathy, stroke, and impaired bone formation [33]. In addition to renal failure, liver dysfunction is a risk factor for hip fracture. In the current study, liver cirrhosis was associated with a 37% increase in hip fracture in patients with ESRD. This might be due to their inability to convert vitamin D into the active form and because of the bone loss seen in cirrhosis [34–38]. Hip fracture have been reported to be associated with subsequent mortality, including in-hospital and long-term mortality [5,33,39]. Chie et al. [25] reported an in-hospital mortality rate of 0.97% in the general population ≥65 years old with hip fracture. Hannan et al. [40] reported an in-hospital mortality rate of 1.6% in patients ≥50 years old with hip fracture. The in-hospital mortality rate in the current study was much higher: 3.2%. Other studies have reported one-year mortality rates of 15–20% after a hip fracture in the general US population [41]. In our study, the one-year cumulative survival rate was only 64.6%. Furthermore, the cumulative survival rate in our study was 50.6% at three years. Both long-term and in hospital mortality rates after hip fractures were much higher than those in the general population. This might be because patients with ESRD have more comorbidities than the general population [28]. There are several limitations to this study. First, the comorbidities relied solely on ICD-9-CM diagnosis codes and no other clinical criteria, which may have resulted in misclassification of some disease. Second, the NHIRD does not indicate the severity of the diseases. Third, there was a lack of specific data on dialysis adequacy, patient compliance, nutritional status, biochemical data, socioeconomic characteristics, causes of death, sarcopenia, and falls. Fourth, whether the female patients had reached menopause was not included in the database. In conclusion, the incidence rate of hip fracture in patients with ESRD was high. Being on HD, old age, female gender, a prior hip fracture, osteoporosis, DM and liver cirrhosis were risk factors for hip fracture. Subsequent mortality rates were high. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.bone.2014.04.017. Acknowledgments The study was supported by grants CMFHR10073 and CMFHR10266 from Chi-Mei Medical Center and grant NHRI-NHIRD-99182 from the National Health Research Institutes in Taiwan.
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