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Observational Study

Serum phosphate is associated with increased risk of bone fragility fractures in haemodialysis patients

Pedro Barrera-Baena et al. Nephrol Dial Transplant. .

Abstract

Background: Bone fragility fractures are associated with high morbidity and mortality. This study analysed the association between the current biochemical parameters of chronic kidney disease-mineral and bone disorders (CKD-MBD) and bone fragility fractures in the COSMOS (Current management Of Secondary hyperparathyroidism: a Multicentre Observational Study) project.

Methods: COSMOS is a 3-year, multicentre, open cohort, prospective, observational study carried out in 6797 haemodialysis patients (227 centres from 20 European countries). The association of bone fragility fractures (outcome) with serum calcium, phosphate and parathyroid hormone (PTH) (exposure), was assessed using standard Cox proportional hazards regression and Cox proportional hazards regression for recurrent events. Additional analyses were performed considering all-cause mortality as a competitive event for bone fragility fracture occurrence. Multivariable models were used in all strategies, with the fully adjusted model including a total of 24 variables.

Results: During a median follow-up of 24 months, 252 (4%) patients experienced at least one bone fragility fracture (incident bone fragility fracture rate 28.5 per 1000 patient-years). In the fractured and non-fractured patients, the percentage of men was 43.7% and 61.4%, mean age 68.1 and 63.8 years and a haemodialysis vintage of 55.9 and 38.3 months, respectively. Baseline serum phosphate >6.1 mg/dL (reference value 4.3-6.1 mg/dL) was significantly associated with a higher bone fragility fracture risk in both regression models {hazard ratio (HR) 1.53 [95% confidence interval (CI) 1.10-2.13] and HR 1.44 (95% CI 1.02-2.05)}. The significant association persisted after competitive risk analysis [subHR 1.42 (95% CI 1.02-1.98)] but the finding was not confirmed when serum phosphate was considered as a continuous variable. Baseline serum calcium showed no association with bone fragility fracture risk in any regression model. Baseline serum PTH >800 pg/mL was significantly associated with a higher bone fragility fracture risk in both regression models, but the association disappeared after a competitive risk analysis.

Conclusions: Hyperphosphatemia was independently and consistently associated with an increased bone fracture risk, suggesting serum phosphate could be a novel risk factor for bone fractures in haemodialysis patients.

Keywords: CKD, chronic kidney disease–mineral and bone disorders (CKD-MBD); bone fragility fractures; haemodialysis; serum phosphate.

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Conflict of interest statement

F.L. is a member of an advisory board and speaker at meetings supported by Amgen. A.O. has received grants from Sanofi and consultancy or speaker fees or travel support from Advicciene, Astellas, AstraZeneca, Amicus, Amgen, Fresenius Medical Care, GSK, Bayer, Sanofi-Genzyme, Menarini, Mundipharma, Kyowa Kirin, Alexion, Freeline, Idorsia, Chiesi, Otsuka, Novo-Nordisk, Sysmex and Vifor Fresenius Medical Care Renal Pharma, and is Director of the Catedra Mundipharma-UAM of diabetic kidney disease and the Catedra Astrazeneca-UAM of chronic kidney disease and electrolytes. J.F. has received honoraria from Amgen, AstraZeneca, Bayer, Boehringer, Fresenius, Novartis and Vifor, and serves on the data safety monitoring board of Novo Nordisk and Visterra. J.B.C.-A. has received grants or consultancy, speaker fees and travel support from Amgen, Kyowa Kirin and Vifor Fresenius Medical Care Renal Pharma. The remaining authors declare no conflict of interest concerning the work. The results presented in this paper have not been published previously in whole or part, except in abstract format. The authors are not aware of any additional relationships, funding or financial holdings that might be perceived as affecting the objectivity of this study.

Figures

Figure 1:
Figure 1:
Association between serum calcium and the incidence of bone fractures. Multivariate adjustments; Model 1: age, sex, body mass index, aetiology of CKD, time on haemodialysis, smoking habit, diabetes, cardiovascular disease history, bone fracture history in the previous 12 months, vascular or valvular calcification, and parathyroidectomy. Model 2: Model 1 plus dialysis type, calcium concentration in the dialysate, hours of haemodialysis per week, treatment with erythropoietin-stimulating agents (ESAs), prescription of vitamin D metabolites/analogues, native vitamin D or calcidiol, phosphate-binding agents. Model 3: Model 2 plus haemoglobin, albumin, phosphate and PTH.
Figure 2:
Figure 2:
Association between serum PTH and the incidence of bone fractures. Multivariate adjustments; Model 1: age, sex, body mass index, aetiology of CKD, time on haemodialysis, smoking habit, diabetes, cardiovascular disease history, bone fracture history in the previous 12 months, vascular or valvular calcification, and parathyroidectomy. Model 2: Model 1 plus dialysis type, calcium concentration in the dialysate, hours of haemodialysis per week, treatment with erythropoietin-stimulating agents (ESAs), prescription of vitamin D metabolites/analogues, native vitamin D or calcidol, phosphate-binding agents. Model 3: Model 2 plus haemoglobin, albumin, phosphate and calcium.
Figure 3:
Figure 3:
Association between serum phosphate and the incidence of bone fractures. Multivariate adjustments; Model 1: age, sex, body mass index, aetiology of CKD, time on haemodialysis, smoking habit, diabetes, cardiovascular disease history, bone fracture history in the previous 12 months, vascular or valvular calcification, and parathyroidectomy. Model 2: Model 1 plus dialysis type, calcium concentration in the dialysate, hours of haemodialysis per week, treatment with erythropoietin-stimulating agents (ESAs), prescription of vitamin D metabolites/analogues, native vitamin D or calcidiol, phosphate-binding agents. Model 3: Model 2 plus haemoglobin, albumin, PTH and calcium.
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