Risk of Hip Fracture Among Dialysis and Renal Transplant Recipients FREE

Hip fractures are a common cause of morbidity and mortality.^{1 - 2} Relative to persons without kidney disease, those with impaired renal function, including persons undergoing dialysis or those who have received a renal transplant, have been observed to be at increased risk of hip fracture.^{3 - 6} Although the results of one study⁷ suggest that the risk among dialysis and transplant recipients is similar, the follow-up after transplantation was relatively short. Furthermore, that study was not able to separate the possible adverse effects of type of treatment modality from patient characteristics associated with preferential receipt of a particular treatment modality. Using data from the US Renal Data System (USRDS), we conducted a cohort study of patients placed on the renal transplant waiting list to determine if persons who have undergone renal transplantation have a different risk of hip fracture relative to those who continue to undergo dialysis.

The USRDS database contains demographic and clinical information on all US patients with end-stage renal disease (ESRD) who qualify for Medicare and who have survived more than 90 days with renal replacement therapy. Briefly, data from the USRDS are generated from various sources, including Medicare billing records, United Network for Organ Services transplant records, and ESRD medical evidence reports (Centers for Medicare and Medicaid Services form 2728), network census reports, and death notification reports. The structure of the USRDS is described in greater detail elsewhere.⁸

To obtain roughly comparable health status between patients receiving a renal transplant and those undergoing dialysis, only patients listed on the transplant waiting list were included in the dialysis group.⁹ Thus, data were extracted for those patients who had not undergone transplantation before January 1, 1990, and who were placed on the transplant waiting list between January 1, 1990, and December 31, 1999. Patients older than 70 years were excluded, since less than 1% of these patients had received a renal transplant. After implementing these inclusion and exclusion criteria, data on 101 039 patients were available for the current analysis. Dialysis modality included both peritoneal dialysis and hemodialysis, and transplant modality included both kidney and kidney-pancreas transplantation.

Covariates that we identified a priori as potential risk factors for hip fracture included age at time of placement on the transplant waiting list, sex, race (African American, white, other), diabetes (as listed on the Centers for Medicare and Medicaid Services medical evidence form), and length of time undergoing dialysis before being placed on the transplant waiting list. Date of transplantation was abstracted from the USRDS treatment history file, which contains information regarding the history of modalities prescribed for each patient in the database.

The number of hip fractures occurring during follow-up was determined using information contained in the USRDS hospitalization file. Data contained in the hospitalization file are derived from the Health Care Financing Administration's standard analytical files, which contain data on inpatient hospital stays. For the current analysis, hospitalization data were considered for January 1, 1990, through December 31, 1999. Hip fractures were identified using International Classification of Diseases, Ninth Revision codes indicating cervical, intertrochanteric, or subtrochanteric hip fractures. Because patients younger than 65 years who have maintained a successful renal transplant for at least 3 years are no longer considered eligible for Medicare, the USRDS hospitalization file does not identify fractures that occur in these individuals. Thus, in our analyses, patients younger than 65 years were censored if they had maintained a successful renal transplant for more than 3 years.

Hip fracture incidence rates were calculated as the observed number of hip fractures per total patient time at risk, where patients were considered at risk from the time of initial placement on the transplant waiting list until the occurrence of a hip fracture, death, termination of Medicare coverage, loss to follow-up, or December 31, 1999. In the event that no Medicare payments for renal replacement therapy were recorded for 1 year, patients were considered lost to follow-up from the date of the last known payment.

Survival analysis was used to model time from initial placement on the waiting list until hip fracture. To account for changes in ESRD treatment modality between the start and end of the study, treatment modality was modeled as a time-dependent covariate. Transplantation was analyzed according to intention to treat, ie, once patients underwent transplantation they were entered into and remained in the transplant group regardless of the status of the graft. Preliminary diagnostics revealed the presence of nonproportional hazards with respect to the association between transplantation and the risk of hip fracture, suggesting that the relative risk (RR) of hip fracture associated with transplant varied with time. To model this association, a time-dependent covariate that indicated the total time each patient had been a member of the transplant group was also entered into the regression model. Adjustment covariates were included in the multivariate analysis if they were considered a priori to be potential confounders or independent risk factors for fracture. To further investigate the possible burden of dialysis on the risk of fracture before undergoing renal transplantation, a subanalysis was conducted within patients who actually received a transplant before December 31, 1999. A Cox proportional hazards model was used to model the relationship between time undergoing dialysis before transplantation and the risk of hip fracture after adjustment for potential confounders and independent predictors of fracture. For this subanalysis, patients were considered at risk from the day of transplantation until the time of fracture, death, termination of Medicare coverage, loss to follow-up, or December 31, 1999. All statistical analyses were performed using SAS v8.2 (SAS Institute Inc, Cary, NC) and S-Plus v6.1 (Insightful Inc, Seattle, Wash).

Of the 101 039 patients on the renal transplant waiting list, 41 095 (40.7%) never received a transplant during follow-up, whereas 59 944 (59.3%) underwent transplantation at some point before fracture, death, termination of Medicare coverage, loss to follow-up, or December 31, 1999. Patients who received a renal transplant during follow-up tended to be younger, male, white, and free of diabetes, and spent a shorter time undergoing dialysis before being placed on the transplant waiting list (Table 1). Median time undergoing dialysis before placement on the transplant waiting list was 196 days (range, 0 days-9.10 years), with 22 766 patients being listed before initiating dialysis. The median follow-up time after being placed on the transplant waiting list was 2.98 years (range, 1 day-10 years). With respect to patients who received a transplant, median time from being placed on the waiting list to the time of transplantation was 200 days (range, 0 days-8.56 years), with 9349 patients undergoing transplantation on the day of their first recorded dialysis session.

Hip fracture rates observed in the study are displayed in Table 2. A total of 971 patients experienced an incident hip fracture during the total follow-up time of 314 767 person-years. Increasing age, female sex, white race, diabetic nephropathy, increasing length of time undergoing dialysis before being listed for transplantation, and receiving a renal transplant were all associated with increased estimates of the incidence of hip fracture. The observed incidence rate of hip fracture in patients who did not undergo transplantation was 2.9 fractures per 1000 person-years compared with 3.3 fractures per 1000 person-years for patients who underwent transplantation.

Cox regression estimates are presented in Table 3. After adjustment for other factors in the table, age was a strong risk factor for fracture. For each decade of life, the risk of hip fracture was estimated to be 55% higher (95% confidence interval [CI], 1.47-1.64; P<.001). Patients aged 56 to 70 years experienced a 3.27-fold greater risk of hip fracture compared with patients younger than 40 years (95% CI, 2.77-3.87; P<.001). Women were estimated to have a 64% greater risk of hip fracture compared with men (95% CI, 1.44-1.86; P<.001). After adjustment for other covariates of interest, black patients were estimated to have experienced a 62% lower risk of hip fracture compared with white patients (95% CI, 0.32-0.45; P<.001). Patients with diabetic nephropathy were estimated to have a nearly 3-fold greater risk of hip fracture compared with those without diabetic nephropathy (adjusted RR, 2.96; 95% CI, 2.61-3.36; P<.001). For each month of dialysis before being placed on the transplant waiting list, the risk of hip fracture was estimated to be 2% higher (95% CI, 1.02-1.03; P<.001). Patients who underwent dialysis for more than 12 months before placement on the transplant waiting list were estimated to have a risk of hip fracture 91% higher than patients undergoing dialysis treatment only 0 to 3 months before being listed (95% CI, 1.60-2.26; P<.001).

After adjustment for age, sex, race, diabetic nephropathy, and time undergoing dialysis before being placed on the transplant waiting list, patients who underwent transplantation were estimated to have an initial 34% higher risk of hip fracture compared with patients continuing with dialysis (95% CI, 1.12-1.61; P = .002). However, this relative risk was estimated to decrease 1% each month following transplantation (95% CI, 0.98-0.99; P<.001). Figure 1 depicts the risk of hip fracture associated with transplantation as a function of time. It was estimated that the risk of fracture among patients who underwent transplantation became equal to that of dialysis patients approximately 630 days after transplantation, although pointwise CIs suggest that the risks may become equal anywhere between the first and third years after transplantation.

The burden of dialysis before the time of transplantation on the risk of hip fracture was further investigated among a subgroup of patients on the transplant waiting list who eventually underwent transplantation during follow-up. After adjustment for age, sex, race, and diabetic nephropathy, patients who received dialysis treatment 3 to 12 months before transplantation were estimated to have a 67% greater risk of hip fracture than patients whose duration of dialysis had been fewer than 3 months (95% CI, 1.22-2.29). Patients on the transplant waiting list who received dialysis for more than 12 months before transplantation were estimated to have a 2.2-fold greater risk of hip fracture than those who had undergone dialysis for fewer than 3 months (95% CI, 1.68-2.95).

We observed that, relative to patients continuing dialysis, renal transplantation was associated with a 34% greater risk of hip fracture soon after transplant. However, the magnitude of the increased risk waned with increasing time since transplantation. It was estimated that after approximately 630 days the risk of hip fracture was greater among patients who continued with dialysis. In addition, among persons who underwent renal transplantation, the risk of hip fracture was greater among those with longer length of time spent undergoing dialysis before transplantation.

In contrast to our previous report,⁷ we found a higher risk of hip fracture associated with renal transplantation compared with dialysis during the first 630 days after transplantation. However, our previous study may have underestimated the relative risk of hip fracture because we included all ESRD patients, including less-healthy dialysis patients who were not eligible for transplantation. Although we adjusted for age and sources of comorbidities in our previous study, it is likely that we were unable to fully account for differences in health status between dialysis patients both eligible and ineligible for transplantation. The current study included only those patients placed on the waiting list for renal transplantation, resulting in a cohort of relatively more uniform health status. In addition, our previous study used data from a smaller number of patients included in a USRDS special study, resulting in less power to detect differences.

The particularly high RR of hip fracture that we observed soon after renal transplantation is likely attributable to rapid bone loss during the first 6 months after renal transplantation.^{10 - 14} Potential mechanisms that might explain this rapid bone loss include high doses of steroids used during induction therapy and initially after transplantation, and postoperative immobility followed by increased physical activity due to improved health status.^{15 - 19}

Our observation that the excess RR of hip fracture associated with renal transplantation gradually diminishes during the first 1 to 3 years following transplantation, after which the risk is less than that for persons who continue with dialysis, is consistent with reports²⁰ demonstrating increases in bone density with time since renal transplantation. Resolution of pretransplantation conditions deleterious to bone architecture and decreases in immunosuppressive therapy are likely explanations for this improvement. In addition, a variety of factors specific to dialysis could increase the incidence of hip fracture among those patients with longer exposure to dialysis, including low bone mineral density due to poor nutritional status, debilitation, hypogonadism, multiple comorbidities, chronic acidosis, inactivity, heparin use, pretransplantation use of steroids, aluminum intoxication, hyperparathyroidism, and abnormal calcium metabolism.^{3 ,11 ,21 - 25} This hypothesis is supported by our data, which suggest that a longer time undergoing dialysis before renal transplantation is associated with a greater risk of hip fracture after transplantation. Therefore, the diminishing RR of hip fracture over time associated with renal transplantation likely results from a combination of decreasing risks in transplant patients and increasing risks in dialysis patients.

This study has limitations. If patients were not hospitalized for their fractures, we would have underestimated the incidence of hip fracture. However, prior studies have shown that most hip fractures require hospitalization for treatment.²⁶ Also, given the observational nature of the data, it is possible that there were unmeasured characteristics associated with receipt of a particular type of treatment modality that may have also been relevant to the risk of hip fracture. We tried to minimize bias from this source by identifying only patients eligible for transplantation and by adjusting for factors that were associated both with type of treatment modality and the incidence of hip fracture.

The data suggest that, in the short term, recipients of kidney transplants are at greater risk of hip fracture compared with those with renal failure who continue with dialysis. However, after 1 to 3 years, the risk among transplant recipients appears to be lower. Additionally, we found that among transplant recipients, the longer the time undergoing dialysis before transplantation, the greater the risk of hip fracture after transplantation.