Abstract
Background and objectives Patients on hemodialysis have a high rate of hip fractures. In this study, we performed a contemporary analysis of mineral and bone parameters and their relationship to hip and femur fracture risk.
Design, setting, participants, & measurements Patients on hemodialysis treated between 2000 and 2013 in Fresenius Medical Care North America facilities were included. Predictors were on the basis of data as of December 31 of each baseline year and time-averaged values of selected laboratory parameters and medication doses throughout the year. Four period cohorts were constructed from baseline years: 2000, 2003, 2006, and 2009. Follow-up for each cohort was ≤3 years.
Results The incidence of hip and femur fractures remained generally unchanged (P=0.40), except among patients who were white and >65 years of age, in whom the rate decreased significantly over the 14-year period (P<0.01). Results from combined multivariable models indicated that the lowest quartiles of time–averaged intact parathyroid hormone were independently associated with higher hip fracture risk (intact parathyroid hormone =181–272 pg/ml: hazard ratio, 1.20; 95% confidence interval [95% CI], 1.03 to 1.41 and intact parathyroid hormone <181 pg/ml: hazard ratio, 1.20; 95% CI, 1.01 to 1.44; referent third quartile, 273 to <433 pg/ml). The lowest quartile of time–averaged serum calcium was also associated with higher risk (calcium <8.7 mg/dl; hazard ratio, 1.17; 95% CI, 1.00 to 1.37) compared with the referent third quartile of 9.1 to <9.5 mg/dl.
Conclusions We found an association between lower levels of intact parathyroid hormone and serum calcium and greater risk for hip and femur fractures among patients on hemodialysis. These findings support additional research toward elucidating long-term safety of treatment approaches for hyperparathyroidism in patients with ESRD.
- parathyroid hormone
- hemodialysis
- calcium
- Bone and Bones
- Follow-Up Studies
- Hip Fractures
- Humans
- hyperparathyroidism
- Incidence
- Kidney Failure, Chronic
Introduction
Patients on hemodialysis (HD) have a greater incidence of hip fractures than the general population. Alem et al. (1) found the rate of hip fractures to be 4.4 times higher among patients on dialysis. Nair et al. (2) reported the incidence of hip fractures in patients on dialysis to be 29.3/1000 person-years. Outcomes postfracture are poor, with 17.4% of patients dying within 30 days (2), a mean of 55.9 skilled nursing facility days per year (3), and a posthospital discharge death rate of 0.82 per patient-year (3).
Studies have found that the rate of hip fractures in the general population has significantly declined in the United States (4,5). In contrast, among patients on dialysis, recent studies have documented an increase in fractures beginning in 1992 and continuing until at least 2000–2005, with a leveling off by the mid-2000s (2,6,7). The reasons for these changes in fracture rates are not clear but suggest the possibility that certain treatment practices could have had unanticipated effects.
In light of the importance of hip fractures, this study was designed to address the following questions. First, did the trends in the rate of hip fractures in patients on dialysis continue up to 2013? The objective was to provide a more contemporary view than other recent studies. Second, how did the corresponding trends in mineral and bone parameters move over the same time period? Third, what is the relationship between these parameters and observed fracture rates? Most previous studies used a single laboratory value to assess exposure risk; we elected to use ≤1 year of time-averaged observation. Furthermore, we studied whether any identified relationship between risk factors and hip fracture rates behaves differently among older, white individuals, a group often displaying a phenotype consistent with bone fragility.
Materials and Methods
Study Population
All adult (age ≥18 years old) permanent patients on HD treated for ≥90 days without a prior history of hip fracture between January 1, 2000 and December 31, 2013 in eligible Fresenius Medical Care North America outpatient dialysis facilities were included. For analysis of annual data, all patients over the 14-year period were studied. In total, 687 of 785 eligible facilities that continuously contributed patient information into the Knowledge Center Data Warehouse (8) during the study period were eligible after excluding those with incomplete hospitalization data (>10% missing). Data on the patients treated at the 98 excluded dialysis facilities are provided in Supplemental Table 1.
The following demographic, clinical, and laboratory information was obtained for each period prevalent patient annually: age, sex, race, dialysis vintage, and presence or absence of diabetes. Age was categorized into <40, 41–50, 51–59, 60–65, 66–70, 71–75, 76–80, 81–85, or >85 years old, and dialysis vintage was categorized into <1, 1 to <3, 3 to <5, and >5 years. All laboratory results were performed by a central laboratory (Spectra Laboratories, Rockleigh, NJ), and patients had to have at least one albumin test result reported (reflecting the opportunity for blood testing) to be eligible for the study. Albumin was measured using the bromcresol green method. During the period from October 28, 2002 to June 30, 2005, parathyroid hormone (PTH) concentrations were measured using the Nichols Bio-Intact Parathyroid Hormone 1–84 (Bio-PTH) Nichols Advantage method. Bio-PTH results were converted to intact parathyroid hormone (iPTH) equivalent values using the formula (9) . For laboratory parameters with multiple values throughout the base year, the mean of all available values during the year was used, representing a time–averaged annual value. The natural quartile value was used for the cutoff for laboratory value. Time trend values were calculated annually for iPTH, phosphorus, calcium, albumin, and albumin-corrected calcium using the formula
Drug doses for intravenous medications, such as vitamin D and iron, were summarized to reflect mean monthly doses after converting different drug preparations into equivalent calcitriol and elemental iron units, respectively. No information was available on oral drugs, such as vitamin D, phosphate binders, and cinacalcet.
Primary Outcome
Hip fractures were ascertained using International Classification of Diseases, Ninth Revision diagnosis codes for the following fractures: 820, neck of femur; 820.0 and 820.1, transcervical; 820.2, pertrochanteric; 820.8 and 820.9, unspecified part of neck of femur; 821, other and unspecified parts of femur; 821.0, shaft or unspecified part; 821.1, shaft or unspecified part; and 821.2 and 821.3, lower end or distal end. These events were identified from the Knowledge Center Data Warehouse of Fresenius Medical Care North America. The primary outcome was a patient’s first hip fracture recorded as a new comorbid illness or a discharge diagnosis posthospitalization. For patients with more than one hip fracture in a year, only the first fracture was included. A time trend for hip fracture rates calculated from the annual incidence of new hip fractures per person-time exposure during each year from 2000 to 2013 was tracked. Additionally, as a subgroup of interest a priori, hip fracture rates for only the subset of white patients ages >65 years old were also calculated.
Study Cohorts and Follow-up
Four distinct period cohorts were constructed from baseline years 2000, 2003, 2006, and 2009, allowing for sufficient separation between them to minimize overlap while selecting patients who were deemed to be representative of the time period of the study. The predictors for each patient from these cohorts were on the basis of demographic (e.g., age) data determined as of December 31 of each baseline year and time–averaged mean values of selected laboratory parameters and medication dose during the baseline year (e.g., intravenous vitamin D). The patients were included if they were alive and without an existing hip fracture as of January 1 of the year immediately after the baseline year. Follow-up time for each time period cohort was ≤3 years (e.g., from January 1, 2001 to December 31, 2003 for the 2000 period cohort; from January 1, 2004 to December 31, 2006 for the 2003 period cohort; and so forth). Data from all patients who were part of all four cohorts were combined for analysis of risk relationships. Primary analyses included a compilation of all subcohorts, but a sensitivity analysis, which included the cohort year as a variable, evaluated differences by subcohort time period.
Statistical Analyses
Time trends were tested for statistical significance using Poisson regression models. Cohort patient characteristics were presented as means, medians, or percentages, and statistical significance was determined using chi-squared tests, general linear models, and nonparametric Wilcoxon tests as appropriate. Cox proportional hazard models were used to determine the association between baseline predictors and time to initial hip fracture. Proportionality assumptions were verified using Kaplan–Meier curves and log rank tests. Models were constructed in four forms: model 1 (univariable) for each predictor variable of interest; model 2, which adjusted for case mix (age, sex, race, dialysis vintage, and diabetic status); model 3, which included all adjusters in model 2 with the addition of laboratory parameters; and model 4, which included all adjustments in model 3 with the addition of intravenous iron and/or vitamin D dose. Primary analyses included a compilation of all subcohorts, but a sensitivity analysis evaluated differences by subcohort time period. All analyses were performed using SAS, version 9.3 (SAS Institute Inc., Cary, NC). This study was deemed exempt by the Hofstra North Shore–Long Island Jewish Health System Institutional Review Board.
Results
Trends over Time
We studied 955,341 patients from 687 dialysis facilities treated between 2000 and 2013. In Table 1, we display results for key mineral and bone parameters over the study period. Medians of iPTH levels initially increased from 2000 to 2005 and then, remained stable over time. Mean serum calcium concentrations remained stable. Serum phosphorus levels declined significantly (P<0.001) over time.
Overall trends of laboratory values from 2000 to 2013
The incidence rates of hip and femur fractures were 6.4/1000 patient-years in 2000 and 7.9/1000 patient-years in 2013 (P=0.40 for trend). Because previous studies had found that there had been an increasing (over time) rate of fractures in older, white patients, we display their results separately. Among these patients, the rate decreased over time (12.7/1000 patient-years in 2000), decreasing until rising slightly to 12.5/1000 patient-years in 2013 (P<0.01 for the trend). For context, data are also displayed for nonwhite individuals <65 years of age (Figure 1).
Longitudinal trends in hip and femur fracture in dialysis patients. Rates of hip and femur fracture with 95% confidence intervals from 2000 to 2013 for the overall study population. For white patients ≥65 years old and nonwhite patients <65 years old, the numbers of patients in each group are shown below. Overall trend test: overall, P=0.40; white patients ages ≥65 years old, P<0.01; nonwhite patients ages <65 years old, P=0.90.
Cohort Outcomes
For analysis of cohort outcomes, there were four exposure periods (Materials and Methods) with 142,407 patients studied. Patient characteristics are depicted in Table 2. It can be seen that the percentage of patients >80 years of age significantly increased over this time period (P<0.001). Similarly, there was a significant increase in the percentage of patients with diabetes (P<0.001). There was a slightly higher proportion of black patients in the study sample relative to the prevalent national United States HD population: 38.4% in 2000, 38.0% in 2003, 37.5% in 2006, and 37.5% in 2009 (10).
Demographic and clinical characteristics of the population at risk for fractures in 2000, 2003, 2006, and 2009
After combining the four patient cohorts, risk relationships for hip and femur fracture were studied. In unadjusted analyses, lower time–averaged concentrations of iPTH, serum calcium, and serum phosphorus and lower mean monthly active vitamin D doses were associated with a higher risk of hip fracture. There was no relationship for intravenous iron treatment. In multivariable models that adjusted for case mix, laboratory results, and medications, the lowest two quartiles of time–averaged iPTH concentration were independently associated with a higher risk of hip fracture (iPTH=181–272 pg/ml: hazard ratio [HR], 1.20; 95% confidence interval [95% CI], 1.03 to 1.41; iPTH<181 pg/ml: HR, 1.2; 95% CI, 1.01 to 1.44) (Figure 2). The lowest quartile of time–averaged serum calcium was also associated with higher hip fracture risk (calcium <8.7 mg/dl: HR, 1.17; 95% CI, 1.00 to 1.37) (Figure 3). Neither serum phosphorus nor monthly active intravenous vitamin D dose was associated with hip fracture risk in the adjusted models (Figures 4 and 5⇓). Similarly, there was no association found for intravenous iron (data not shown). As part of the sensitivity analyses, adjusted models indicated that the year of entry into the cohort was not a significant factor determining fracture risk. Additional subgroup analyses revealed that, although risk trends for iPTH were consistent within each of the 4 baseline years of entry, most subgroups lost statistical significance in adjusted models.
Hazard ratios for hip and femur fracture in relation to intact parathyroid hormone (iPTH) levels categorized by quartiles. IV, intravenous; Phos, phosphorus.
Hazard ratios for hip and femur fracture in relation to serum calcium concentration categorized by quartiles. iPTH, intact parathyroid hormone; IV, intravenous; Phos, phosphorus.
Hazard ratios for hip and femur fracture in relation to serum phosphorus concentration categorized by quartiles. iPTH, intact parathyroid hormone; IV, intravenous.
Hazard ratios for hip and femur fracture in relation to intravenous (IV) vitamin D monthly doses categorized by quartiles. iPTH, intact parathyroid hormone; Phos, phosphorus.
In Figure 6, time-averaged iPTH and serum calcium and time–averaged vitamin D doses are related to the risk for hip and femur fractures. It can be seen that risk generally increases in categories with lower mean iPTH and vitamin D doses.
As planned a priori, because of the greater risk of hip fractures in patients on dialysis who were white and >65 years of age, a phenotype consistent with bone fragility, the relationship of risk exposures and hip fracture outcomes was explored in this population (n=37,508). In contrast to the whole dialysis population, among these patients, there was no straightforward discernible relationship between risk exposures and hip fracture outcomes. For example, only the second quartile of iPTH (147–221 pg/ml; HR, 1.30; 95% CI, 1.05 to 1.62) was significantly associated with a higher risk of hip fractures (Figure 7), and it is not clear if a larger sample size could have maintained a significantly higher fracture risk in the lowest iPTH quartile. There was no significant relationship between serum calcium, phosphorus, or active vitamin D dose and risk for hip fractures among >65-year-old white patients (data not shown).
Hazard ratios (HRs) for fracture in relation to tertile categories of parathyroid hormone (PTH) and calcium (Ca) levels and mean vitamin D doses. The reference group is the median levels of intact PTH (212–355 pg/ml) and Ca (8.9–9.4 mg/dl) and mean intravenous (IV) vitamin D doses (16.7–43.5 mg/mo). Whiskers depict the 95% confidence intervals (95% CIs).
Hazard ratios for hip and femur fracture in relation to intact parathyroid hormone (iPTH) levels categorized by quartiles in the population of white patients ≥65 years of age. IV, intravenous; Phos, phosphorus.
Discussion
We detected several findings with respect to hip fractures in this large national period prevalent cohort of patients on HD. First, we found that the rate of hip fractures did not change significantly in patients on HD from 2000 to 2013. Second, there was a secular trend toward increasing iPTH from 2000 to 2005 and a progressive trend from 2000 to 2013 toward lower serum phosphorus. Third, lower time–averaged concentrations of iPTH (particularly <273 pg/ml) and lower levels of serum calcium (<8.7 mg/dl) were associated with higher risk for hip fractures. Fourth, among elderly white patients, there were no clear relationships between the risk factors studied and risk for hip fractures, with the possible exception of low iPTH.
The finding of stability in the incidence of hip fractures between 2000 and 2013 is important in that it updates published data that found a substantial increase in the rate of fractures in patients on HD from the 1990s to approximately the mid-2000s (2,6,7). Although it remains unclear why the incidence of hip fractures had previously increased, it is reassuring to note that the rate has stabilized. Moreover, because the proportion of patients >80 years of age has increased and because age is a determinant of hip fracture risk, it is possible that the age-adjusted incidence of hip fracture might have decreased over time.
The trend toward higher serum concentrations of iPTH from 2000 to approximately 2005 seems consistent with a decreasing focus during that time period on intense iPTH suppression (11). This trend became more standardized with the 2009 Kidney Disease Improving Global Outcomes guidelines (12), which liberalized iPTH targets. The previous Kidney Disease Outcomes Quality Initiative PTH target of 150–300 ng/ml (13) was raised to two to nine times the upper limit of the PTH assay (12). It should be noted that PTH assays have changed over time, and at least some of the secular change could be explained by these changes. The decreasing trend in serum phosphorus during the period of observation may reflect a greater level of attention that had been placed on phosphate management, perhaps reflecting studies indicating harmful effects associated with higher phosphorus levels (14–16).
We found that patients who had time-averaged iPTH <273 pg/ml had a greater risk for hip fractures, even after adjustment for clinical factors, medications, and laboratory tests. This relationship might help explain the longitudinal trend in hip fractures, which increased substantially from 1992 to the early 2000s (2,6,7) and then, stabilized up to 2013, which we showed in this study. We found the mean iPTH to be 197.5 pg/ml in 2000. To the extent that 2000 was representative of iPTH values over the preceding decade, the relative suppression of iPTH during that period could explain the increasing rates of fractures. From the relatively low mean iPTH value in 2000, we found that mean iPTH values increased to approximately 300 pg/ml by 2004 and that, in parallel, the rate of hip fractures stabilized during this time period. The stabilization in fracture rate might reflect the relatively large increase in mean iPTH values to above the higher risk threshold of 273 pg/ml.
One possible explanation for greater fracture risk with lower levels of iPTH could be low–turnover bone disease, which may be found with lower iPTH values (17) and might predispose to bone fragility. Although studies relating PTH values and bone morphology have yielded inconsistent results, most studies have found a fairly high positive predictive value for lower PTH levels and low–bone turnover morphology; Barreto et al. (17) found that iPTH<150 pg/ml had an 83% positive predictive value for predicting low bone turnover. The relationship between bone histomorphology and fracture risk is less clear, because the literature is generally composed of studies too small in sample size to detect sufficient events of hip fracture. A recent study evaluated bone quality as assessed by material and mechanical properties. The primary finding was that “bone with low turnover had microstructural abnormalities such as lower cancellous bone volume and reduced trabecular thickness” (18). We did not have access to tests, such as bone alkaline phosphatase, vitamin D levels, or fibroblast growth factor-23, that might have provided information on bone health.
It might be expected that lower time–averaged iPTH values would be related to treatment with active vitamin D (or more recently, cinacalcet) and that, therefore, the association of lower iPTH with higher fracture risk should extend to higher doses of active vitamin D being a risk factor as well. However, accounting for intravenous vitamin D, we did not find this to be true. After adjustment, there was no relationship between active intravenous vitamin D dose and fracture risk. This divergence is a surprising finding that might suggest a hypothesis that patients with spontaneously low to normal iPTH levels (rather than those suppressed with treatment) may be a subset with greater bone fragility. One reason for lower unsuppressed iPTH concentrations could be reduced sensitivity to lower serum calcium levels. Our finding that lower serum calcium, like lower iPTH, was an independent risk factor for hip fractures may lend some support to this hypothesis. Indeed, in Figure 7, we show a general trend toward greater fracture risk when lower iPTH, vitamin D, and serum calcium are combined. However, absence of information regarding the use of oral calcimimetics or postsurgical parathyroidectomy leaves the potential for iatrogenic low calcium and low iPTH to be contributory.
Our findings with respect to lower iPTH being associated with hip fracture risk are externally consistent with a study by Coco and Rush (19), which found that lower PTH concentrations (<195 pg/ml) predicted hip fracture risk in patients on HD. In contrast, other studies failed to find PTH to be a predictor of fractures (20–22). Previous studies of bone parameters and fracture risk generally studied periods before 2000, were usually on the basis of single laboratory values, and were of much smaller sample sizes. Our study may have benefitted from a more contemporary view, a 1-year time-averaged view on risk exposure given the known variability of PTH (23), and a large sample size, although we also recognize limitations of our study below.
In previous studies, we and others found a secular trend toward increased hip fractures in patients on dialysis from 1992 to approximately 2005, which with additional analyses, occurred in patients of white race or those >65 years of age (6). Furthermore, there seemed to be less correlation between histomorphic bone turnover and iPTH in black patients (24). Taken together, this knowledge led to a hypothesis that, in this subgroup of patients, who often are of a phenotype representative of osteoporosis or bone fragility, oversuppression of iPTH could be particularly harmful (6). However, we found no consistent significant relationship between lower iPTH and higher hip fracture risk in this subgroup.
Our study has certain strengths, including large sample size, the contemporary dataset, and the use of time–averaged risk exposures. However, there are certain limitations as well. First, the observational design prevents understanding of causality in relationships. Second, although the dataset used was a clinical repository, we cannot assure absolute capture of all fracture events. Third, although the cohort seems to be representative of typical dialysis populations, the results are not necessarily generalizable to all United States dialysis populations. Fourth, for the year 2000 cohort, duration of dialysis was unknown in 53.1% of patients (Table 2). Fifth, we did not have information on parathyroidectomy.
A more important limitation is that we lack information on oral medications for bone and mineral metabolism management, particularly cinacalcet. This agent, US Food and Drug Administration approved in 2004, is used in treatment in approximately 20% of patients on dialysis (25). Because it is an effective treatment for hyperparathyroidism and has been shown to reduce fracture risk (26), it could be an important exposure variable. Future studies should seek to incorporate information on cinacalcet treatment where information on treatment is available.
In conclusion, there seemed to be a stabilization of hip fracture rates at the end of the first decade of this millennium. Furthermore, we affirm an association between lower levels of iPTH and serum calcium and greater risk for hip fractures among patients on HD. We suggest a hypothesis that patients with lower levels of iPTH in the absence of high–intravenous vitamin D doses may be at higher risk for hip fracture; this hypothesis requires additional evaluation, particularly with differentiation for patients with spontaneous low iPTH levels versus iatrogenic nonvitamin D parathyroid suppression therapy (e.g., calcimimetics or postparathyroidectomy). These findings support evaluating long-term safety of therapeutic strategies for hyperparathyroidism in patients with ESRD.
Disclosures
S.F. has been engaged in research with Amgen, Inc. (Thousand Oaks, CA) that involved treatment for hyperparathyroidism. L.M. is an employee of Fresenius Medical Care North America. During the planning and initiation of the study, E.L. was an employee of Fresenius Medical Care North America.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.09280915/-/DCSupplemental.
- Received September 1, 2015.
- Accepted February 23, 2016.
- Copyright © 2016 by the American Society of Nephrology