Abstract
Background
Patients with chronic kidney disease, especially those undergoing hemodialysis (HD), have a higher risk of fragility fractures. However, the magnitude of the problem and risk factors associated with fracture incidence have not been well studied in the Kingdom of Saudi Arabia.
Methods
This multicenter retrospective study involved HD centers in Jeddah from 2015 to 2021. This study included all adult HD patients. Patient demographics, medication usage, and clinical and biochemical parameters were collected from the registry records.
Results
The study included 328 patients on HD, with a mean age of 53 years. The median duration of HD was 47 months. Osteoporosis was found in 9% of the patients, and 8% had a previous parathyroidectomy. Over the observation period, fractures occurred in 32 patients, with an incidence rate of 20 case/1000 end stage kidney disease patients-year. Patients with fractures had a higher rate of osteoporosis, underwent more parathyroidectomy, had longer HD vintage, and higher bone-specific alkaline phosphatase (BSAP) levels. BSAP was the most significant predictor of fracture incidence in the regression analysis. Using a BSAP cutoff value of 96.6 µg/L, the sensitivity and specificity to predict fractures were 81.8% and 49%, respectively.
Conclusion
The main risk factors for incident fractures were osteoporosis, previous parathyroidectomy, longer HD vintage, and higher BSAP level. A higher BSAP score was the most significant predictor of incident fractures. This may highlight the importance of monitoring bone turnover markers and the negative impact of high bone turnover on patient health.
Introduction
The burden of chronic kidney disease (CKD) has significantly increased worldwide with the global rise in hypertension and diabetes. In the Kingdom of Saudi Arabia (KSA), there has been a drastic increase in the number of dialysis centers in the recent decades which illustrates the high prevalence of end-stage chronic kidney disease (ESKD) [Citation1–3].
Osteoporosis is an imbalance between bone resorption and formation. In patients with CKD, it might be presented as low or high bone turnover disease. To select the appropriate intervention, it is crucial to comprehend the etiology of bone loss [Citation4]. In patients with CKD, the pathogenesis of osteoporosis is complex and multi-factorial. Many factors lead to bone loss in patients with kidney disease. Renal osteodystrophy is determined by an imbalance in bone remodeling, parathyroid hormone changes, bone mineral and vitamin D abnormalities. Furthermore, the uremic milieu, medication usage, disrupted gonadal hormones, and premature aging contribute to the increased prevalence of osteoporotic fractures among patients with ESKD [Citation5]. Moreover, patients with CKD has not only a bone quantity but also a bone quality problem [Citation6].
Compared with the general population, patients with CKD have at least a double risk of bone loss and a 4- to 5-fold risk of fragility fractures [Citation4]. The risk of fractures increased with worsening of kidney function, with patients in advanced CKD stages having the highest fracture risk [Citation7–9]. Patients with ESKD on dialysis have up to a 100-fold higher risk of developing hip fractures compared with age-matched persons in the general population [Citation10].
Patients with CKD have impaired quality of life, increased morbidity, and mortality due to the high incidence of fractures. The mortality rate in the first year following hip fracture in a patient on dialysis can reach 64% [Citation11]. However, the true magnitude of this problem and the impact of biochemical markers on fracture risk in patients on chronic hemodialysis (HD) have not been well studied. Accordingly, this study aimed to investigate the incidence of fractures among patients on chronic hemodialysis in KSA and the risk factors associated with the occurrence of these fractures.
Study Objectives:
To calculate the incidence of bone fractures among adults with CKD undergoing HD.
To identify the significant risk factors for bone fractures among those patients.
To determine whether there is a relationship between the risk of bone fractures and surrogate biochemical markers of CKD.
Methods
This multicenter retrospective study involved the Ministry of Health hemodialysis centers in Jeddah from to 2015–2021. The study was conducted at DaVita East Jeddah Hospital Dialysis Center and DaVita King Abdulaziz Hospital Dialysis Center. The study was conducted in accordance with the Declaration of Helsinki and was approved by the IRB Committee (IRB Number: H-02-K-076-0320-270 AFFAIRS OFFICE).
Participants
All HD patients over the age of 18 years had received hemodialysis for > 90 days. Convenience and non-probability sampling procedures were used. With a margin of error of 5% and confidence level of 1.962, the target sample size was 377.
Inclusion criteria
The participants in the study were all HD patients aged > 18 years who had received hemodialysis for more than 90 days.
Exclusion criteria
Patients younger than 18 years old.
Patients who refuse to sign the consent.
Non-communicable patients/established advanced dementia.
Patients who have received hemodialysis for less than 90 days.
Data collection
There are two primary sources of data. The patient data was collected from the Ministry of Health (MOH) Registry. These records were used to collect demographic, clinical, and biochemical data. The history of osteoporosis was dependent upon dual x-ray absorptiometry (DXA) results. DAVITA is an outsource hemodialysis clinic in Saudi Arabia and it has the final diagnosis of osteoporosis based on DXA scans from MOH data system. However, we do not have the reports of DXA scans. Regarding parathyroidectomy, all patients with history of parathyroidectomy were subjected to subtotal parathyroidectomy. Quaternary readings per year of biochemical parameters were obtained from the study follow-up, starting from December 2015 to December 2021. Then, we took the averages of the readings and used them for statistical analysis. The follow-up period started in 2015, depending on each patient’s first HD in the center, and continued until the date of the last recorded serum laboratory results in December 2019. All the lab results were collected before the incidence of fracture.
Efforts were made to minimize possible biases in the data and data analysis. Selection bias was minimized by enrolling all qualified patients in the sample. Misclassification or information bias was controlled using validated data collection instruments. Recall bias was mitigated using a face-to-face interview approach to collect questionnaire data. This approach enabled patients to seek clarification on any issue that they did not understand.
Serum bone-specific alkaline phosphatase (BSAP) was determined on the COBAS c 501 system. The colorimetric assay was in accordance with a standardized method. In the presence of magnesium and zinc ions, p-nitrophenyl phosphate is cleaved by phosphatases into phosphate and p-nitrophenol. The reference ranges for BSAP in adult males, premenopausal, and postmenopausal females were < 20.1, 14.3, and 22.4 µg/L, respectively. The Alinity intact parathyroid hormone (iPTH) assay is a chemiluminescent microparticle immunoassay (CMIA) used for the quantitative determination of iPTH in human serum and plasma on the Alinity i analyzer. This assay is a two-step immunoassay for the quantitative determination of iPTH in human serum and plasma using chemiluminescent CMIA technology. The sample, anti-PTH-coated paramagnetic microparticles, and assay diluent are combined and incubated. The iPTH present in the sample binds to the anti-PTH-coated microparticles. The mixture is washed. Anti-PTH acridinium-labeled conjugate is added to create a reaction mixture and incubated. Following a wash cycle, Pre-Trigger and Trigger Solutions are added. The resulting chemiluminescent reaction is measured in relative light units (RLUs). There is a direct relationship between the amount of iPTH in the sample and the RLUs detected by the system optics. The reference range for iPTH was 15–65 pg/mL. All assays were performed on their dedicated automated analyzers according to the manufacturers’ instructions.
Data analysis
The collected data were coded and analyzed using the Statistical Package for Social Science (SPSS) version 25 for Windows on personal computers. Qualitative data were described as numbers and percentages, while quantitative data were expressed as mean ± SD or median (minimum–maximum) for parametric and non-parametric data, respectively. The Kolmogorov–Smirnov test was used to test the normality of the continuous variables. Independent samples t-tests and Mann–Whitney U-tests were used to compare parametric and non-parametric variables between the two groups. The chi-square test was used to compare the qualitative variables between the two groups. Binominal logistic regression analysis was used to identify significant predictors of fracture incidence. Receiver operating characteristic (ROC) curve analysis was performed to detect the cutoff value of BSAP to predict the incidence of fracture, depending on the sensitivity and specificity. The level of significance was set at 5% (p < 0.05).
Results
The study included 328 patients on maintenance HD (55.8% males), with a mean age of 53.4 years. The median HD was 46.5 months. Most patients were obese (mean BMI, 35.9 kg/m2). Hypertension was prevalent in 92% of the patients, while diabetes mellitus (DM) was found in 44.5%. Calcium channel blockers were the most commonly used antihypertensive medications, followed by beta-blockers and renin angiotensin aldosterone system (RAAS) inhibitors. Osteoporosis was found in 9.1% of the patients, and 8.2% had a previous parathyroidectomy. The demographic and clinical data of the patients are shown in .
Table 1. Demographic and clinical parameters of the studied patients.
Average values of the laboratory data of the patients over the last six years are shown in . The median iPTH level was 577 pg/ml, whereas the median 25(OH) vitamin D level was 15 ng/mL. Vitamin D deficiency (<20 ng/mL) was found in 35.9% of patients.
Table 2. Laboratory data of the studied patients.
Over the observation period, fractures occurred in 32 patients (9.75%), with an incidence rate of 19.5 case/1000 ESKD patients per year. The fracture sites were as follows: hip, 34.3% (n = 11); leg, 21.8% (n = 7); arm, 15.6% (n = 5); forearm, 6.3% (n = 2); ribs, 6.3% (n = 2); shoulder, 6.3% (n = 2); femur, 6.3% (n = 2), and spine, 3.1% (n = 1).
There was no increase in fracture incidence among patients with vitamin D deficiency (p = 0.9). Patients within the highest PTH quartile had more fractures than the patients with the lowest quartile (18.7% vs. 7.5%, p = 0.035).
Compared to patients who did not experience fractures, patients with fractures had a higher frequency of osteoporosis (7.8% vs. 21.9%), underwent a higher rate of parathyroidectomy (7.1% vs. 18.8%), and had a statistically significantly longer duration of HD (44 vs. 64 months) and higher bone-specific alkaline phosphatase (BSAP) levels (97.5 vs 131.25 µg/L) ( and ).
Table 3. Demographic and clinical parameters of the patients with and without fractures.
Table 4. Laboratory data of the patients with and without fractures.
Bone-specific alkaline phosphatase was the most significant predictor of fracture incidence in HD patients in the binary logistic regression analysis (odds ratio = 1.004, p = 0.013) (). By constructing a ROC analysis to test BSAP for the prediction of fracture, the area under the curve for the occurrence of fracture using BSAP was 0.665. Using a cutoff value of 96.6 µg/L, the sensitivity and specificity were 81.8% and 49%, respectively ().
Figure 1. ROC curve of BSAP as a predictor of risk of fracture.
Table 5. Independent predictors of fractures.
Discussion
In this cohort of patients with ESKD on HD, the incidence of fractures was 10% during the observation period. The main risk factors for incident fractures were osteoporosis, previous parathyroidectomy, longer HD duration, and higher BSAP levels. In the regression analysis, a higher BSAP was the most significant predictor of incident fractures with good sensitivity and average specificity.
The mean age of the patients was 53 years, and the median HD duration was 47 months. HTN and DM were the most common comorbidities. This reflects the expected characteristics of ESKD [Citation12].
Osteoporosis was prevalent in 9% of patients, depending on their medical records. CKD is an independent risk factor for osteoporosis. Moreover, the incidence of osteoporosis increases with loss of kidney function, reaching its highest prevalence in ESKD patients on maintenance HD [Citation4].
In our study, the median iPTH level was 577 pg/ml, and 8% of patients had previous parathyroidectomy. In a recent study by Mathur et al. the rate of parathyroidectomy was 1.1% in the United States; however, it was among patients with secondary hyperparathyroidism [Citation13]. According to a recent study by Danese et al. the rate of parathyroidectomy per 1,000 person-years decreased from 6.5 in 2016 to 5.3 in 2018 according to a recent study by Danese and colleagues [Citation14]. Schneider et al. reported that 15% of ESKD patients may require parathyroidectomy after 10 years of dialysis [Citation15]. This rate is expected to decrease with the current use of calcimimetics.
The low median vitamin D level among our patients with 36% of patients had vitamin D deficiency indicates the need for close observation and correction of vitamin D deficiency among our dialysis patients. However, we did not find an increase in fracture risk in patients with vitamin D deficiency. Moreover, the use of a vitamin D receptor analog (calcitriol) did not differ according to the occurrence of fractures. Ambrus et al. suggested that vitamin D insufficiency is associated with a higher risk of fracture in dialysis patients [Citation16]. Similarly, in general population, Swanson et al. reported a possible protective role for higher vitamin D level [Citation17]. The association between use of calcitriol and lower vertebral fractures was reported in a cross-sectional study in CKD patients [Citation18]. However, there is no consensus about the effect of vitamin D deficiency on fracture risk among the general population and patients with ESKD.
The incidence rate of fractures was 19.5 case/1000 ESKD patients-year. Ten percent of our patients developed fragility fractures during the observation period, with the hip being the most common fracture site. The incidence of fractures in our patients was similar to that reported by Matias et al. [Citation19] and was lower than that reported by Fusaro et al. [Citation20] for patients undergoing dialysis. Instead of depending on patients’ history and documented fractures, the latter study used quantitative vertebral morphometry to screen fractures. Moreover, the patients were older patients with a high prevalence of vascular calcification. It is well known that patients with ESKD have multiple fractures compared to the general population [Citation21].
As expected, our patients with a longer HD duration and those with osteoporosis had a higher incidence of fragility fractures. A longer HD vintage predisposes the patient to a higher load of uremic toxins and is associated with increased renal osteodystrophy, among other factors that predispose the patient to fractures [Citation22,Citation23].
Interestingly, the incidence of fractures was higher in patients with a history of parathyroidectomy. Many studies have reported that parathyroidectomy is associated with a lower risk of incident fractures in control subjects [Citation24,Citation25]. However, after parathyroidectomy, patients have persistent bone microarchitecture changes with an ongoing decline in trabecular and cortical thickness [Citation26]. It is conceivable that these patients had markedly elevated PTH levels and, hence, higher bone resorption rates before parathyroidectomy; however, because of the observational nature of the study, it was not feasible to study the sole effect of parathyroidectomy. It is reasonable to assume that both extremes of PTH would have a higher incidence of fractures.
In the regression analysis, a higher BSAP level was the most significant predictor of fracture incidence among dialysis patients. BSAP is a bone turnover marker with its higher value indicating a higher rate of bone formation, mainly, but also a higher resorption [Citation6]. The association between higher BSAP levels and fracture risk may indicate that the bone resorption rate was higher than the formation rate in our patients. Park et al. reported that serum alkaline phosphatase levels were negatively associated with bone mineral density in patients undergoing HD [Citation27]. BSAP is more specific and does not accumulate in ESKD patients. Our finding that a higher BSAP is associated with a higher incidence of fractures in HD patients is in concordance with that reported by other investigators [Citation19,Citation28,Citation29]. The cutoff value for BSAP for predicting fractures among our patients was 96.6 µg/L; which is clearly higher than the normal BSAP levels and indicates the prevalence of high bone osteodystrophy among our patients [Citation30].
Our study has some limitations, including its retrospective observational nature, unavailability of DXA scan results, and other bone turnover biomarkers. However, this adds to the scarce available data on the prevalence and risk factors of fractures among dialysis patients, especially in the Middle East.
Conclusion
In conclusion, 10% of our patients on HD had fragility fractures during the observation period. The main risk factors for incident fractures are osteoporosis, previous parathyroidectomy, longer HD vintage, and higher BSAP levels. A higher BSAP score was the most significant predictor of incident fractures. This may highlight the importance of monitoring bone turnover markers and the negative impact of high bone turnover on patient health.
Ethical approval
The study was conducted in accordance with the Declaration of Helsinki and was approved by the IRB Committee (IRB Number: H-02-K-076-0320-270 AFFAIRS OFFICE).
Author contributions
Conceptualization, A.K.; methodology, M.A.; software, F.A.O. and N.A.A.; resources, A.K.; data curation, N.H.A, B.A.A, and A.F.A.; writing—original draft preparation, M.A.; writing—review and editing, E.N.; supervision, A.K and M.A. All authors have read and agreed to the published version of the manuscript.
Acknowledgments
The authors acknowledge the contributions of Falwah Abdulrahman Fatani and Talah Khalid Magadmi from the Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Disclosure statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.
Data availability statement
The dataset for this study is available upon request from the corresponding author.
Additional information
Funding
References
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