Systematic Review of the Evidence Underlying the Association Between Mineral Metabolism Disturbances and Risk of Fracture and Need for Parathyroidectomy in CKD

doi:10.1053/j.ajkd.2009.02.010

American Journal of Kidney Diseases

Volume 53, Issue 6, June 2009, Pages 1002-1013

https://doi.org/10.1053/j.ajkd.2009.02.010 Get rights and content

Background

Chronic kidney disease (CKD) is associated with such complications as fractures and the need for parathyroidectomy. Mineral metabolism control in patients with CKD has been poor. Studies have assessed fractures and parathyroidectomy risk with mineral disturbances, but with considerable diversity in methods. Thus, a systematic review was conducted to assess method or clinical heterogeneity by comparing the design, analytical techniques, and results of studies.

Study Design

Systematic review of the MEDLINE, EMBASE, and Cochrane databases between 1980 and December 2007.

Setting & Population

Patients with CKD or dialysis patients.

Selection Criteria for Studies

Observational and clinical trials investigating the risk of fractures or parathyroidectomy with mineral disturbances.

Predictor

Mineral metabolism variables (phosphorus, calcium, and parathyroid hormone [PTH] levels).

Outcomes

Fractures, need for parathyroidectomy.

Results

9 studies were identified that assessed fractures (n = 6) or need for parathyroidectomy (n = 3). Data for fractures or parathyroidectomy risk in predialysis patients are absent. Diversity across studies was observed in populations, methods of exposure assessment, adjusted covariates, and reference mineral levels used in risk estimation. A significant fracture risk was observed with increasing PTH levels. However, additional data are required to understand fracture risk with changes in phosphorus or calcium levels. Data supported greater parathyroidectomy risk with increasing PTH, phosphorus, or calcium levels.

Limitations

Clinical and method heterogeneity across studies precluding the quantitative synthesis of data.

Conclusions

Serious limitations were observed in the number, quality, and method rigor of studies. Despite heterogeneity across studies, data suggest a significant parathyroidectomy risk with mineral disturbances and a fracture risk with increasing PTH levels in dialysis patients. Additional high-quality data for risk of fractures or parathyroidectomy with changes in phosphorus, calcium, or PTH levels is required to highlight the importance of managing such common, but subclinical, conditions as mineral metabolism disturbances.

Section snippets

Literature Review

The MEDLINE, EMBASE, and Cochrane databases were systematically searched for English-language articles published from January 1980 to December 2007. The search strategy was composed of the following medical subject headings and key words from 3 categories: population (renal dialysis, kidney failure chronic, dialysis, kidney failure, end-stage renal disease, chronic kidney disease, hemodialysis, peritoneal dialysis), mineral metabolism parameters (phosphorus, calcium, parathyroid hormone), and

Literature Review

The search strategy identified 1,162 references, of which 235 abstracts were selected for full-text review. Nine of these met the criteria for inclusion in the review. The majority of rejected articles failed to assess the outcomes of interest (Fig 1). All 9 studies were observational in nature and assessed fractures (n = 6) or parathyroidectomy (n = 3).

Fractures

Data for fracture risk with mineral disturbances are limited (n = 6). Furthermore, much diversity was observed in study populations, methods,

Discussion

Our review is the first systematic appraisal of the evidence for risks of fractures and parathyroidectomy associated with mineral disturbances in patients with CKD. The quality of evidence relating mineral parameters and clinical outcomes poses serious limitations. Very few studies have focused on fractures (n = 6) and parathyroidectomy (n = 3) in dialysis patients. Assessments of predialysis patients for risk of these outcomes are absent, which raises concern in view of the role of CKD in

Acknowledgements

Antonia Panayi of Amgen Europe provided editing assistance. Previously presented in abstract form at the European Renal Association-European Dialysis Transplant Association (ERA-EDTA) conference in Sweden, May 10-18, 2008.

Support: Information on funding sources is listed in the Financial Disclosure.

Financial Disclosure: This study was funded by Amgen (Europe) GmbH. Dr Goldsmith has served as a speaker or member of an advisory board for Amgen, Genzyme, and Shire Pharmaceuticals. Drs Kothawala,

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Citation Excerpt :
In 24 case reports involving 44 dialysis patients (35 on hemodialysis and 9 on peritoneal dialysis therapy), baclofen use was associated with adverse outcomes including altered mental status, ataxia, abnormal muscle tone, and falls.13,15,18-28 Altered mental status may predispose to fall and fracture,47 and our results are also consistent with the increased susceptibility of hemodialysis patients to fall and fracture due to factors such as peridialysis hypotension,10 frailty,11 impaired muscle strength,48 and mineral bone disorder.12 In addition, a large proportion of hemodialysis patients are elderly, a population in which muscle relaxant use has been associated with increased risk for altered mental status, fall, and fracture.6-8
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140,899 Medicare-covered adults receiving hemodialysis in 2011, identified in the US Renal Data System.
Time-varying muscle relaxant exposure.
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Multivariable Cox regression analysis.
10% of patients received muscle relaxants in 2011. 11%, 6%, 3%, and 13% had an episode of altered mental status, fall, fracture, and death, respectively. Muscle relaxant use was associated with higher risk for altered mental status (HR, 1.39; 95% CI, 1.29-1.51) and fall (HR, 1.18; 95% CI, 1.05-1.33) compared to no use. Muscle relaxant use was not statistically significantly associated with higher risk for fracture (HR, 1.17; 95% CI, 0.98-1.39). Muscle relaxant use was associated with lower hazard of death (HR, 0.85; 95% CI, 0.76-0.94). However, hazards were higher for altered mental status or death (HR, 1.17; 95% CI, 1.10-1.25), fall or death (HR, 1.14; 95% CI, 1.06-1.22), and fracture or death (HR, 1.10; 95% CI, 1.01-1.20).
A causal association between muscle relaxant use and outcomes cannot be inferred, and residual confounding cannot be excluded. Exposure and outcomes were ascertained using administrative claims.
Muscle relaxant use was common in hemodialysis patients and associated with altered mental status and falls. We could not rule out a clinically meaningful association between muscle relaxant use and fracture. The lower risk for death with muscle relaxants may have been the result of residual confounding. Future research to define the appropriate use of muscle relaxants in this population is warranted.
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It remains unclear whether total or subtotal parathyroidectomy for secondary hyperparathyroidism yields the best outcomes. We investigated mortality, cardiovascular events, hip fracture, and recurrent parathyroidectomy after total versus subtotal parathyroidectomy in patients on renal replacement therapy.
Using the Swedish Renal Registry, the surgical registry for thyroid and parathyroid surgery, and the National Inpatient Registry, we identified patients who underwent parathyroidectomy between 1991 and 2013. We calculated the risk of outcome after total versus subtotal parathyroidectomy using COX's regression, adjusting for age, sex, cause of renal disease, time with a functioning graft before and after parathyroidectomy, Charlson comorbidity index, year of surgery, prevalent cardiovascular disease, time on dialysis, renal transplantation at parathyroidectomy, and treatment with calcimimetics before parathyroidectomy.
There were 824 patients who underwent parathyroidectomy, 388 total and 436 subtotal. There was no difference in mortality or risk of incident hip fracture between groups. Comparing the subtotal with the total parathyroidectomy, the adjusted hazard ratio (95% confidence interval) for cardiovascular events was 0.43 (0.25–0.72) and for recurrent parathyroidectomy 3.33 (1.33–8.32).
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Modified Creatinine Index and the Risk of Bone Fracture in Patients Undergoing Hemodialysis: The Q-Cohort Study
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Modified creatinine index was correlated with skeletal muscle mass measured by BIA. Lower modified creatinine index was associated with increased risk for bone fracture in male and female hemodialysis patients.
Comparison of the effects of novel vitamin D receptor analog VS-105 and paricalcitol on chronic kidney disease-mineral bone disorder in an experimental model of chronic kidney disease
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Citation Excerpt :
In patients with chronic kidney disease (CKD), various abnormalities of mineral and bone metabolism frequently emerge, and together, these are known as chronic kidney disease-mineral bone disorder (CKD-MBD) [1]. It has recently become well known that these abnormalities lead not only to osteopenia or fracture but also to cardiovascular disease (CVD) and mortality [2,3]. Therefore, the control of CKD-MBD is crucial and strategies for managing it are necessary.
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Original InvestigationPathogenesis and Treatment of Kidney DiseaseSystematic Review of the Evidence Underlying the Association Between Mineral Metabolism Disturbances and Risk of Fracture and Need for Parathyroidectomy in CKD

Background

Study Design

Setting & Population

Selection Criteria for Studies

Predictor

Outcomes

Results

Limitations

Conclusions

Section snippets

Literature Review

Literature Review

Fractures

Discussion

Acknowledgements

Kidney Int

Am J Kidney Dis

Am J Kidney Dis

Am J Kidney Dis

Am J Kidney Dis

Kidney Int

Am J Kidney Dis

Am J Kidney Dis

Kidney Int

Am J Kidney Dis

Kidney Int

Kidney Int

Am J Kidney Dis

Am J Kidney Dis

Kidney Int

Prevalence of chronic kidney disease in the United States

JAMA

USRDS 2007 Annual Data Report

2005 Annual Data Report Paris, France, European Renal Association-European Dialysis Transplant Association

Original Investigation
Pathogenesis and Treatment of Kidney Disease
Systematic Review of the Evidence Underlying the Association Between Mineral Metabolism Disturbances and Risk of Fracture and Need for Parathyroidectomy in CKD