Hip fracture in patients with non-dialysis chronic kidney disease stage 5

Hip fracture is a significant health problem and is associated with increased mortality. Patients with chronic kidney disease (CKD) are more at risk of hip fracture than the general population, but the hip fracture risk is not evident among non-dialysis CKD stage 5 patients. This study aims to assess the risk of hip fracture in patients with non-dialysis CKD stage 5 comparing to those with CKD stages 1–4. Patients with non-dialysis CKD stage 5 and CKD stages 1–4 were retrieved from Taiwan longitudinal health insurance database 2011–2014. All patients were followed to the end of 2018 for the development of hip fractures. We analyze the risk of hip fracture of propensity score-matched patients with CKD stage 5 compared to patients with CKD stages 1–4 using stepwise Cox regression and competing risks regression. We analyzed 5649 propensity score-matched non-dialysis CKD 1–4 patients and non-dialysis CKD 5 patients between 2011 and 2014. All patients were followed to the end of 2018, 229 (4.1%) of CKD 1–4 patients in 21,899 patient-year, and 290 (5.1%) of CKD 5 patients had hip fractures in 18,137 patient-year. CKD 5 patients had a higher risk of hip fracture than patients with CKD stages 1–4. The adjusted HR was 1.53 (95% CI 1.08–1.54) in the Cox regression with adjustments for age, gender, comorbidity, and history of fracture. In the competing risks regression, the subdistribution hazard ratio was 1.29 (95% CI 1.08–1.54). Female gender, age, history of fractures, and Charlson–Deyo comorbidity index were independently associated with increased hip fracture risks. Non-dialysis CKD 5 patients had a higher risk of hip fracture than patients with CKD stages 1–4. This association is independent of patients’ age, female gender, history of fractures, and comorbidities.

www.nature.com/scientificreports/ Study subjects. Inclusion criteria were patients with at least three outpatient visits or one hospitalization for CKD from 2011 to 2014 (Fig. 1). The ICD-9-CM code for CKD includes 581.9, 582.9, 584.9, 585, and 586. The date of the CKD stage 1-4 diagnosis was defined as the index date. CKD 5 ND patients were identified using the prescription of erythropoiesis-stimulating agents (ATC code B03XA01 and B03XA02) because these medications were only prescribed to patients with an estimated glomerular filtration rate less than 15 ml/min/1.73 m 2 . The date of the first erythropoiesis-stimulating agent prescription was defined as the index date. Patients who met the following criteria were excluded: (1) younger than 18 years old; (2)   Statistical analysis. Patient characteristics were expressed as number (percentage) or mean (standard deviation) where appropriate. Chi-square tests and t test was used to test the differences of variables between the two groups. The sensitivity analysis was performed using the propensity score matching with sex, age, history of fractures, medications, and CCI with a ratio of 1:1. The risk of hip fracture was analyzed Cox regression, and the variables with a p < 0.05 were further analyzed using stepwise Cox regression with adjustments for age, gender, comorbidity, history of fractures, and CCI. Hazard ratios (HRs) and 95% confidence interval (CIs) of HRs were calculated. The results of Cox regression were further analyzed using competing risk regression 6 . Death and dialysis were considered as competing events. Subgroup analysis was performed for age, comorbidities, and www.nature.com/scientificreports/ CCI. All statistical analyses were carried out using SAS statistical package, version 9.3 (SAS, Inc., NC, USA). All comparison tests were two-sided, and a p value of less than 0.05 was considered statistically significant.

Ethics approval and consent to participate. This study was approved by the internal review board of
Taipei Medical University (TMU-JIRB No.: N201903124).

Discussion
The increased risks of hip fracture in patients with CKD are also supported by previous studies 7, 8 . We further demonstrate a high hip fracture in non-dialysis CKD 5 patients compared to patients with CKD stages 1-4 in Cox regression. The application of Cox regression in this study was supported by test for the proportional hazard assumption (ESM Appendix Table 1). The association between CKD and hip fracture may be explained by CKDrelated mineral and bone disorders 9,10 and CKD-associated frailty 11 . Parathyroid hormone, calcium, phosphate are the critical component of mineral and bone disorders. Calcium-based phosphate binders are prescribed to patients with hyperphosphatemia. Vitamin D was prescribed to hyperparathyroidism patients. Patients with hyperphosphatemia and hyperparathyroidism had a high risk of hip fracture. We analyzed medications, including calcium-based phosphate binders, vitamin D, and denosumab. However, none of these medications were significantly associated with hip fracture. Denosumab is covered by Taiwan health insurance in patients with  www.nature.com/scientificreports/ compression fractures and a less than − 2.4 SD bone density. These patients had a very high risk of hip fracture. A limited number of patients had denosumab treatment and the time of follow-up is not long. As homocysteine predicts hip fracture risk 12 , homocysteine-lowering medications such as folic acid and vitamin B12 might reduce hip fracture risks 13 . However, treatment with folic acid plus vitamin B12 did not decrease hip fracture risk in the previous studies 14 . When the interaction of CKD 5 and folic acid is considered, folic acid is associated with reduced hip fracture risks in this study before the propensity score matching. However, magnesium oxide, folic acid, vitamin B were associated with an increased risk of hip fracture after propensity score matching. We also identify other hip fracture risk factors, including female gender, age, and the number of comorbidities. These findings were also supported by previous studies [15][16][17][18] .
There were some limitations to the study. First, laboratory data is not available in Taiwan's longitudinal health insurance database, and we can not identify patients' CKD stages 1-4 using an individual's renal function. We cannot analyze the association of parathyroid hormone, calcium, phosphate, and hip fracture. Second, cinacalcet and non-calcium-containing phosphate binders on hip fractures are not examined because health insurance does not cover these medications and therefore are not recorded. Third, immortal bias may be present in the effect of folic acid on hip fractures as patients who died during follow-up were censored in the analysis. Fourth, erythropoiesis-stimulating agents may not be prescribed in CKD 5 patients with a hemoglobin of more than 11 g/dl. 12.6% of CKD 5 patients 19 may be classified as CKD stages 1-4 patients in the analysis because we use erythropoiesis-stimulating agents to identify CKD 5 patients.

Conclusion
Nondialysis CKD stage 5 patients had increased hip fracture risks compared to CKD stages 1-4. Female gender, patients' age, history of fractures, diabetes, and Charlson-Deyo comorbidity index are independently associated with increased hip fracture risks.

Data availability
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.