Young Eun Kwon and Hyung Yun Choi contributed equally to this study.
Edited by Sang Ho Lee, Kyung Hee University, Seoul, Korea
Chronic kidney disease (CKD)-mineral and bone disorder (MBD) and fracture risk are both closely related to declining renal function. Controlling hyperphosphatemia with phosphate binders is a basic principle of CKD-MBD treatment. The aim of this study was to identify differences in fracture risk between pre-dialysis CKD patients and end-stage renal disease (ESRD) on dialysis, and to evaluate the effects of phosphate binders on fracture risk in ESRD patients.
Data from a total of 89,533 CKD patients comprising CKD diagnosis, dialysis, fracture history, and phosphate binder prescription history from 2012 to 2016 were retrieved from the Health Insurance Review and Assessment Service Database. Multivariate Cox regression analyses were performed to identify whether dialysis or phosphate binders were associated with an increased fracture risk.
Overall, the rate of fractures in pre-dialysis CKD patients was 74 per 1,000 patient-years, while that in dialysis patients was 84 per 1,000 patient-years. The risk of fracture in ESRD patients was higher than pre-dialysis CKD patients (hazard ratio, 1.16; 95% confidence interval, 1.12–1.21;
Fractures were more prevalent in ESRD patients on dialysis than pre-dialysis CKD patients. Use of phosphate binders was associated with a lower fracture risk in ESRD patients.
Chronic kidney disease (CKD) is a momentous issue both for individuals and society as a whole. The prevalence of CKD has been steadily increasing along with the size of the elderly population and the increasing prevalence of other chronic diseases such as diabetes mellitus and hypertension, and is associated with a tremendous increase in medical expenditures [
CKD patients are susceptible to fractures, especially hip fractures that can lead to prolonged immobilization and subsequent fatal complications such as thromboembolism, pneumonia, and pressure sores [
At the center of CKD-MBD is phosphorus, which has an important role as an essential mineral to control our body. Eighty to ninety percent of the body’s phosphorus content is stored in the bones and teeth, while the remainder resides in cells, body fluids, and the blood to control cell metabolism and energy generation [
Here, we studied the impact of renal function decline on fracture risk in non-dialysis and dialysis-dependent CKD patients. In addition, we investigated the difference in fracture risk according to use of phosphate binders in dialysis-dependent CKD patients using data obtained from the Health Insurance Review and Assessment Service Database.
Our study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of Ewha Womans University College of Medicine (IRB number: EUMC 2017-08-028-001). Data was obtained from the Health Insurance Review and Assessment Service Database after anonymization. The IRB committee waived the requirement for informed consent due to the nature of the data and study design.
We analyzed data from the Health Insurance Review & Assessment Service Database from 2012 to 2016. First, patients diagnosed with CKD or end-stage renal disease (ESRD) (coded as N18.1 to N18.5, and N18.9) were enrolled. Next, patients were classified into pre-dialysis CKD patient or dialysis patient groups. Specifically, if a patient’s record included a hemodialysis treatment code (O7010 or O7020), peritoneal dialysis operation code (O7070), or peritoneal dialysate prescription code, they were classified into the dialysis patient group. Conversely, patients who did not fit the criteria for an ESRD patient on dialysis were classified into the pre-dialysis CKD group. To include incident pre-dialysis CKD or ESRD on dialysis patients only during the study period (2013–2016), we selected and excluded patients who already had CKD diagnosis codes or dialysis codes in 2012 (wash-out period). We were not focused on renal allograft patients in this study, so patients who underwent a renal allograft in 2012 were excluded.
Data on major and minor fracture diagnoses were obtained using fracture diagnosis codes for the spine (S32-), hip (S72-), upper extremities (S42-, S42.2, S42.4, S52-, S62-), lower extremities (S92-, S82-, S72.3, S72.4), skull (S02), thorax (S22), or other (S82-). Fracture data was collected from the time of CKD or ESRD diagnosis up to 2016 for all patients. We attempted to identify differences in fracture risk between age groups under 65 years and 65 years and over. We also performed analyses to identify the risk of fracture between the pre-dialysis CKD and ESRD patients on dialysis groups. Lastly, we analyzed the association between fracture risk and use of phosphate binders in patients on dialysis.
Categorical variables including dialysis status, age, sex, and fracture occurrence were expressed as frequencies (percentages). The number of fractures were counted, and the person-years of the study population were calculated by multiplying the number of patients and the follow-up period (years) or the period until the time of fracture. The total number of fractures was first divided by total person-years in the respective CKD and ESRD groups, and logistic regression analysis was conducted to find the statistical significance of fracture risk. Kaplan–Meier plot analyses were performed to evaluate differences in fracture risk according to dialysis status, female sex, and age over 65 years. A multivariate Cox proportional hazard regression analysis was then conducted to identify the fracture risk of dialysis patients.
Lastly, Kaplan–Meier analysis was carried out to verify whether there was any difference in the time from dialysis initiation to fracture diagnosis between those who were and were not taking phosphate binders. In addition, multivariate Cox proportional hazard regression analysis was performed to determine the effect of phosphate binders on fracture risk.
Statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, USA).
Of the 89,533 CKD patients, 76,106 (85.0%) were pre-dialysis CKD patients. Among the 13,427 dialysis patients, 12,098 patients (90.1%) were receiving hemodialysis and 1,329 patients (9.9%) were undergoing peritoneal dialysis treatment. A total of 37,610 (42.0%) of the patients were female, and 51,723 (57.8%) of the study patients were over the age of 65 years. A total of 25,771 (28.8%) patients had between 0 and 5 points on the Charlson Comorbidity Index (CCI) scoring system, 35,840 (40.0%) had between 6 and 8 points, and 27,922 (31.2%) had between 9 and 27 points (
In
We next compared the risk of fractures using Kaplan–Meier curves depending on dialysis status, gender, and age (cutoff 65 years).
Cox proportional hazard regression analysis was performed to determine the risk of fracture in dialysis patients compared to pre-dialysis patients after adjusting for confounding variables. Univariate analysis showed the hazard ratio (HR) for fracture risk in dialysis patients was 1.11 (95% CI 1.07–1.16,
We next investigated the incidence of fracture according to the use of phosphate binders in dialysis patients. Of the 13,427 dialysis patients, 9,918 were taking phosphate binders. Among those taking phosphate binders, 1,935 patients (19.5%) experienced fractures. Among the patients who were not taking phosphate binders (n = 3,509), 671 (19.1%) experienced a fracture (
We also investigated fracture risk according to the use of phosphate binders in dialysis patients using Cox proportional hazard regression analysis. The crude HR for sustaining a fracture in the group not taking phosphate binders was 1.33 (95% CI 1.22–1.45,
This large-scaled, nationwide, observational study showed that the fracture risk of dialysis patients was 16.0% higher than that of pre-dialysis CKD patients. In addition, dialysis patients who were not taking phosphate binders had a 20.0% higher risk of fracture compared to those who were taking phosphate binders.
Fractures can be a fatal complication in patients with CKD, and these patients have a higher fracture risk for a number of reasons. First, bones of CKD patients are fragile. Increasing age over 65 years as well as increased steroid exposure, alterations in vitamin D metabolism, and parathyroid hormone abnormalities all have an impact on bone quantity and strength in CKD patients. To date, most of the therapeutic modalities aimed at reducing fracture risk have targeted the general population, and not CKD patients. Bisphosphonates, which are representative osteoporosis medications, cannot be prescribed to advanced CKD patients with a creatinine clearance under 30 mL/min/1.73 m2. Therefore, despite a higher prevalence of osteoporosis in patients with advanced CKD and ESRD, they cannot be treated appropriately. Next, ESRD patients are more likely to experience dizziness, and thus have a higher risk of falling. Multiple other factors including anemia, intradialytic hypotension, and autonomic neuropathy due to diabetes, all common manifestations in ESRD patients, can also influence dizziness and falls [
Controversy persists as to whether decreased renal function is associated with osteoporosis and increased fracture risk, and the statistical significance of the relationship between renal function and fracture risk varies according to fracture site and study population, especially in patients with mild to moderate renal dysfunction [
In this study, dialysis patients who were not taking phosphate binders had a higher risk of fracture compared to patients taking phosphate binders. There are several explanations for this finding. First, control of secondary hyperparathyroidism by treating hyperphosphatemia using phosphate binders may, at least in part, contribute to a decreased fracture risk. A reduction in fracture risk in patients taking phosphate binders has not been identified in randomized controlled trials; however, phosphate binders may nevertheless impact fracture risk. For example, one study showed that treatment of secondary hyperparathyroidism with cinacalcet was associated with a reduced risk of fracture (relative risk 0.46, 95% CI 0.22–0.95) [
A second explanation for the difference in fracture risk according to phosphate binder treatment is that calcium-based phosphate binders may specifically lead to reduced fracture risk. One study showed a clear association between use of calcium-based phosphate binders and reduced fracture risk in child patients (HR 0.37, 95% CI 0.15–0.91,
Lastly, protein-energy wasting (PEW) in dialysis patients might be associated with differences in fracture risk. PEW refers to decreased protein and energy in the body and is common among ESRD patients [
There were some limitations to our study. First, we did not have data regarding the specific diagnosis of osteoporosis and CKD stages among study patients. In particular, we could not verify the estimated glomerular filtration rate for individual patients because we only used CKD diagnostic codes to extract CKD patients from the Health Insurance Review and Assessment Service Database. As a result, we tended to recruit advanced CKD patients rather than early stage CKD patients. This bias may have underestimated the incidence of CKD and caused sampling error. In addition, the proportion of patients over 65 years was statistically higher in the pre-dialysis CKD patient group than in the dialysis-dependent ESRD patient group (
Taken together, the results of this study demonstrated that fracture was more prevalent in dialysis patients compared to pre-dialysis CKD patients, and ESRD patients on dialysis taking phosphate binders experienced less fractures compared to patients not taking phosphate binders. This study confirmed that decreased renal function might be associated with a higher fracture risk, and suggests the possibility of an association between phosphate binders and fracture risk. Additional studies, including randomized controlled trials, will be needed to verify our results.
This work was supported by Kyowa Hakko Kirin Korea Co., Ltd.
All authors have no conflicts of interest to declare.
Young Eun Kwon wrote the manuscript. Hyung Yun Choi participated in the study design and performed the statistical analysis. Sol Kim helped to draft the manuscript and provided technical support. Dong-Ryeol Ryu provided intellectual content of critical importance to the work. Hyung Jung Oh participated in the conception, analysis, and interpretation of data. All authors read and approved the final manuscript.
Kaplan–Meier plot of fracture incidence in pre-dialysis chronic kidney disease and end-stage renal disease patients.
Kaplan–Meier plot of fracture incidence in patients with pre-dialysis and dialysis chronic kidney disease according to (A) sex and (B) age group.
CCI, Charlson Comorbidity Index; HR, hazard ratio.
CCI, Charlson Comorbidity Index; HR, hazard ratio.
Baseline characteristics of the study population
Variable | Total (n = 89,533) | Pre-dialysis (n = 76,106) | Dialysis (n = 13,427) | |
---|---|---|---|---|
Age group (yr) | < 0.001 | |||
< 65 | 37,810 (42.2) | 30,594 (40.2) | 7,216 (53.7) | |
≥ 65 | 51,723 (57.8) | 45,512 (59.8) | 6,211 (46.3) | |
Sex, male | 51,923 (58.0) | 43,925 (57.7) | 7,998 (59.6) | < 0.001 |
Charlson Comorbidity Index | < 0.001 | |||
0–5 | 25,771 (28.8) | 23,140 (30.4) | 2,631 (19.6) | |
6–8 | 35,840 (40.0) | 30,382 (39.9) | 5,458 (40.6) | |
9–27 | 27,922 (31.2) | 22,584 (29.7) | 5,338 (39.8) | |
Phosphate binder use | ||||
Calcium-based | NA | NA | 7,456 (55.5) | |
Non-calcium-based | NA | NA | 2,462 (18.3) |
Data are presented as number (%).
NA, not available.
Fracture risks in the dialysis group according to the fracture site
Total | Spine | Hip | Others | |||||||||
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OR | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | |||||
Pre-dialysis | Reference | Reference | Reference | Reference | ||||||||
Dialysis | 1.10 | 1.05–1.16 | < 0.001 | 0.98 | 0.90–1.08 | 0.694 | 1.66 | 1.54–1.82 | < 0.001 | 1.04 | 0.99–1.10 | 0.133 |
Odds ratio (OR) and 95% confidence interval (CI) were attained by multivariate logistic regression analysis adjusted for age group and sex.
Cox regression analysis for fracture risk of ESRD patients compared to pre-dialysis CKD patients
Variable | Univariate | Multivariate | ||||
---|---|---|---|---|---|---|
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HR | 95% CI | HR | 95% CI | |||
Dialysis | ||||||
Pre-dialysis CKD | Reference | Reference | ||||
ESRD | 1.11 | 1.07–1.16 | < 0.001 | 1.16 | 1.12–1.21 | < 0.001 |
Age (yr) | ||||||
< 65 | Reference | Reference | ||||
≥ 65 | 2.07 | 2.01–2.14 | < 0.001 | 1.80 | 1.74–1.86 | < 0.001 |
Sex | ||||||
Male | Reference | Reference | ||||
Female | 1.71 | 1.66–1.76 | < 0.001 | 1.69 | 1.64–1.74 | < 0.001 |
Charlson Comorbidity Index | ||||||
0–5 | Reference | Reference | ||||
6–8 | 1.61 | 1.55–1.68 | < 0.001 | 1.41 | 1.35–1.47 | < 0.001 |
9–27 | 2.35 | 2.25–2.45 | < 0.001 | 1.92 | 1.84–2.01 | < 0.001 |
CI, confidence interval; CKD, chronic kidney disease; ESRD, end-stage renal disease; HR, hazard ratio.
Baseline demographic and fracture incidence data according to phosphate binder prescription in end-stage renal disease patients
Variable | Taking phosphate binders (n = 9,918) | Not taking phosphate binders (n = 3,509) |
---|---|---|
Fracture | ||
Yes | 1,935 (19.5) | 671 (19.1) |
No | 7,983 (80.5) | 2,838 (80.9) |
Age (yr) | ||
< 65 | 5,878 (59.3) | 1,338 (38.1) |
≥ 65 | 4,040 (40.7) | 2,171 (61.9) |
Sex | ||
Male | 5,945 (59.9) | 2,053 (58.5) |
Female | 3,973 (40.1) | 1,456 (41.5) |
Charlson Comorbidity Index | ||
0–5 | 1,972 (19.9) | 659 (18.8) |
6–8 | 4,090 (41.2) | 1,368 (39.0) |
9–27 | 3,856 (38.9) | 1,482 (42.2) |
Data are presented as number (%).
Cox regression analysis for fracture risk in patients who did and did not take phosphate binders in end-stage renal disease
Variable | Univariate | Multivariate | |||||||
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HR | 95% CI | Model 1 | Model 2 | ||||||
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HR | 95% CI | HR | 95% CI | ||||||
Phosphate binders | |||||||||
Users | Reference | Reference | Reference | ||||||
Non-users | 1.33 | 1.22–1.45 | < 0.001 | 1.19 | 1.09–1.30 | < 0.001 | 1.20 | 1.09–1.31 | < 0.001 |
Age (yr) | |||||||||
< 65 | Reference | Reference | Reference | ||||||
≥ 65 | 2.04 | 1.89–2.21 | < 0.001 | 1.95 | 1.80–2.11 | < 0.001 | 1.70 | 1.57–1.84 | < 0.001 |
Sex | |||||||||
Male | Reference | Reference | Reference | ||||||
Female | 1.47 | 1.36–1.59 | < 0.001 | 1.39 | 1.29–1.50 | < 0.001 | 1.45 | 1.34–1.56 | < 0.001 |
Charlson Comorbidity Index | |||||||||
0–5 | Reference | Reference | |||||||
6–8 | 1.63 | 1.43–1.85 | < 0.001 | 1.51 | 1.33–1.72 | < 0.001 | |||
9–27 | 2.43 | 2.15–2.75 | < 0.001 | 2.05 | 1.81–2.33 | < 0.001 |
Model 1: phosphate binder prescription, age, sex; model 2: model 1 + Charlson Comorbidity Index.
CI, confidence interval; HR, hazard ratio.