Bisphosphonate Therapy, Death, and Cardiovascular Events Among Female Patients With CKD: A Retrospective Cohort Study

doi:10.1053/j.ajkd.2011.11.037

American Journal of Kidney Diseases

Volume 59, Issue 5, May 2012, Pages 636-644

https://doi.org/10.1053/j.ajkd.2011.11.037 Get rights and content

Background

Accelerated vascular calcification contributes to cardiovascular disease burden in patients with chronic kidney disease (CKD). We hypothesized that bisphosphonate therapy would reduce the risk of mortality and cardiovascular events in this population.

Study Design

Retrospective cohort study.

Setting & Participants

Adult women with stage 3 or 4 CKD receiving primary care in a large rural integrated health care system in 2004-2010.

Exposure

Time-dependent exposure status based on outpatient prescription for any medication within the bisphosphonate class, obtained from electronic health records.

Outcomes

Time to death and first cardiovascular event (composite of myocardial infarction, heart failure, or stroke).

Results

Data from 9,604 eligible female patients with CKD were analyzed; 3,234 were treated with bisphosphonate therapy. During a median follow-up of 3.9 (25th-75th percentile, 2.3-5.4) years, there were 286 versus 881 deaths and 206 versus 571 cardiovascular events (treated vs not-treated groups, respectively). In a multivariate Cox proportional hazard model, the adjusted HR for death (treated vs not treated) was 0.78 (95% CI, 0.67-0.91; P = 0.003). In Cox modeling adjusted for similar baseline covariates, treatment with bisphosphonates was not associated with a lower risk of the composite cardiovascular outcome (adjusted HR, 1.14; 95% CI, 0.94-1.39; P = 0.2).

Limitations

Residual confounding by unidentified factors, exclusion of male patients, and lack of information about longitudinal drug adherence.

Conclusions

For female patients with CKD, treatment with bisphosphonates is associated with a lower risk of death, but not cardiovascular events. Confirmatory studies and investigations of potential causal mechanisms are warranted.

Section snippets

Study Design

This retrospective cohort study was reviewed and approved under exempt status by the Geisinger Medical Center Institutional Review Board. The data source was EpicCare, Geisinger Medical Center's electronic health record, which contains detailed demographic, lifestyle (eg, smoking), procedural, laboratory, radiographic, vital, and other clinical data for more than 3.5 million patients receiving care at any of the more than 40 outpatient clinics and 3 inpatient facilities in Central Pennsylvania.

Results

A total of 12,412 adult female patients with CKD receiving primary care at Geisinger on or after January 1, 2004, were eligible for the study. Of these, 135 were excluded for prior end-stage renal disease or solid organ transplant; 11, for pregnancy; 131, for metastatic cancer; 34, for hospital-acquired acute kidney injury; and 2,497, for a history of heart failure, myocardial infarction, stroke, or amputation before cohort entry. Of the remaining 9,604 patients, 3,234 were treated with

Discussion

In this analysis of older female patients with moderate to advanced CKD, bisphosphonate treatment was associated with a 22% lower mortality risk in models adjusted for factors influencing survival. No cardioprotective association was observed.

Results were robust in a propensity score–based sensitivity analysis, providing some degree of confidence regarding the internal validity of the results. The sensitivity analysis would not account for unidentified or confounders; as is true of all

Acknowledgements

This study was presented in modified form at the National Kidney Foundation's Spring Clinical Meeting, April 26-30, 2011, in Las Vegas, NV.

The authors thank Ms Amanda Bengier and Mr Raymond Menapace for assistance with data extraction and programming.

Support: None.

Financial Disclosure: Drs Perkins and Kirchner have received research support unrelated to this project and within the past 2 years from American Regent and Amgen, Inc. The remaining authors declare that they have no relevant

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Cited by (37)

The impact of bisphosphonates on mortality and cardiovascular risk among osteoporosis patients after cardiovascular disease
2021, Journal of the Formosan Medical Association
Citation Excerpt :
Trials designed to study the cardiovascular safety of BPs are limited. Nevertheless, some epidemiologic studies, which provided support for the protective effects of BPs treatment against cardiovascular diseases, excluded patients who had previously suffered from cardiovascular disease before.11,25 Therefore, our cohort study can help fill the gap of evidence in these special populations who were at very high risk of further cardiovascular events.
Bisphosphonates (BPs) impact on the survival and cardiovascular safety of osteoporosis patients after acute coronary syndrome (ACS) or acute ischemic stroke (AIS) was evaluated.
A nationwide epidemiological study was conducted using the Taiwan National Health Insurance Research Database from 2000 to 2010. From the 1456 osteoporosis patients with previous ACS or AIS, mortality and cardiovascular safety was compared between 464 patients who used BPs and 464 patients who did not. Primary outcomes included all-cause mortality, and major adverse cardiovascular events.
The BPs group had a lower risk of all-cause mortality than the control group after the 8-year follow-up (HR, 0.64; 95% CI, 0.46–0.88; P = 0.006). The risks of myocardial infarction, ischemic stroke, cardiovascular death, hospitalization for heart failure or other causes of mortality were similar across groups. However, there was a higher risk of hospitalization for atrial fibrillation in the BPs group than the control group (HR, 1.76; 95% CI, 1.26–2.46; P = 0.001).
Among osteoporosis patients after ACS or AIS, BPs use was associated with a reduced risk of all-cause mortality. However, patients with previous cardiovascular disease who received BP treatment should be careful about the risk of atrial fibrillation.
Is there a role for bisphosphonates in vascular calcification in chronic kidney disease?
2021, Bone
Citation Excerpt :
Recipients were older with more hypertension, more coronary artery disease, a higher Charlson co-morbidity index score, more osteopenia but less diabetes. The findings of the study showed that there was a reduced death rate in the treatment group, with a hazard ratio (HR) of 0.78 (p = 0.003) but no difference in cardiovascular event rate (HR = 1.14, p = 0.02) [76]. These findings of lack of protective function of latter generation bisphosphonate on vasculature echo the post hoc findings of the HORIZON pivotal fracture study within the postmenopausal population.
Theoretically bisphosphonates could accelerate or retard vascular calcification. In subjects with low GFR, the position is further confounded by a combination of uncertain pharmacokinetics (GI absorption is poor and inconsistent at all levels of renal function and the effect of low GFR generally is to increase bioavailability) and a highly variable skeletal substrate with extremes of turnover that increase unpredictably further. Although bisphosphonates reduce bone formation by 70–90% in subjects with normal GFR and reduce the ability of bone to buffer exogenous calcium fluxes, in bisphosphonate treated postmenopausal women accelerated vascular calcification has not been documented. The kidneys assist with this buffering, but the capacity to modulate calcium excretion declines as GFR falls, increasing the risk of hypercalcaemia in the event of high calcium influx. In the ESRD patient, decreased buffering capacity substantially increases the risk of transient hypercalcaemia, especially in the setting of dialysis, and as such may promote vascular calcification which is highly prevalent in the CKD population. Low bone turnover may thus be less of a vascular problem in patients with preserved renal function and a bigger problem when the GFR is low. In patients with stage 4 and 5 CKD, adynamic bone disease associates with the severity and progression of arterial calcification, including coronary artery calcification, and further suppression of bone turnover by a bisphosphonate might exacerbate an already high predisposition to vascular calcification. No convincing signal of harm has emerged from clinical studies thus far. For example 51 individuals with CKD stage 3–4 treated with either alendronate 70 mg per week or placebo for 18 months showed no difference in the rate of vascular calcifications. Conversely an observational study of women with stage 3–4 CKD with pre-existing cardiovascular disease found an increased risk of mortality with a hazard ratio of 1.22 (1.04–1.42) in those given bisphosphonates. Direct suppression of vascular calcification by bisphosphonates is probably confined to etidronate – treatment of soft tissue calcification was a recognized indication for this drug and etidronate markedly reduced progression of vascular calcification in CKD patients. Bisphosphonates are analogues of pyrophosphate, a potent calcification inhibitor in bone and soft tissue. Thus the efficacy of etidronate as treatment for soft tissue calcification brought with it a problematic tendency to cause osteomalacia. In contrast, conventional doses of nitrogen-containing bisphosphonates fail to yield circulating concentrations sufficient to exert direct anti-calcifying effects, at least in patients with good renal function and studies using alendronate and ibandronate have yielded inconsistent vascular outcomes.
Association between the cumulative exposure to bisphosphonates and hospitalization for atherosclerotic cardiovascular events: A population-based study
2020, Atherosclerosis
Citation Excerpt :
So far, observational studies investigating the effect of bisphosphonate treatment on CV morbidity and mortality yielded conflicting results. The discrepancies in results may have arisen from having sampled different populations [29], representing different subgroups treated with bisphosphonates, and from having adopted different study designs [30]. It has been suggested that the decreasing risk of CV hospitalization observed with increasing adherence to bisphosphonate therapy might be partly due to a “healthy adherer” effect: patients with higher adherence are likely to have healthier lifestyle habits [24].
Although bisphosphonates have been suggested to protect against atherosclerotic cardiovascular (CV) events, evidence is still conflicting. We aimed at investigating the effect of bisphosphonates on hospitalizations for atherosclerotic CV events.
We carried out a retrospective cohort study selecting subjects aged>40 years, incident users of bisphosphonates. Exposure to bisphosphonates was characterized based on cumulative doses (proportion of days covered, PDC). Treatment's adherence was classified as low (PDC≤40%), intermediate (PDC 41%–80%), or high (PDC>80%). A multivariate Cox model was fitted to estimate the association between cumulative time-dependent exposure to bisphosphonates and hospitalization for atherosclerotic CV events (hazard ratio [HR] and 95% confidence interval).
Among 82,704 new bisphosphonates users (females 87.0%, mean age 70.7 ± 10.6 years), 16.1% had a CV hospitalization during a mean follow-up of 6.5 + 2.6 years. Compared with individuals with PDC ≤40%, those exposed for 41–80% or more than 80% showed HRs of CV hospitalization of 0.95 [0.91–0.99] and 0.75 [0.71–0.81], respectively. In the sub-analysis by type of event, a PDC >80% was associated with a reduced incidence for both coronary and cerebrovascular events (HRs 0.75 [0.68–0.83] and 0.76 [0.70–0.83], respectively). The protective effect was confirmed in stratified analyses by sex and age classes, and in those performed at 1 and 3 years of follow-up.
Strict adherence to bisphosphonate treatment was associated with a better CV outcome. Although further studies to investigate possible mechanisms are warranted, bisphosphonates could be considered as having a potential CV benefit beyond the effect on bones.
Osteoporosis associated with chronic kidney disease
2020, Marcus and Feldman’s Osteoporosis
Chronic kidney disease (CKD) is associated with high rates of fracture, cardiovascular events, and mortality. The pathophysiology is complex, including reduced levels of Klotho and active vitamin D, and markedly elevated levels of fibroblastic growth factor 23 and parathyroid hormone. Abnormal Wnt and activin signaling pathways influence the maturation of bone and vascular smooth muscle cells. These changes play important roles in the early development of the bone disorders and heightened cardiovascular risk of patients with CKD. Bones are also impacted by acidosis, abnormalities in circulating hormones, accumulation of toxic substances, and poor muscle strength. In addition to fractures, patients manifest bone pain and extraskeletal calcifications that are related to the bone disease in complex ways. Diagnostic tests such as bone density, histology, radiology, and biochemical markers are useful but all have limitations. There is inadequate data from clinical trials to guide treatment of the fragile bones in CKD patients. Treatments to attain normal turnover and improve bone mineralization may be beneficial. Standard therapies used for osteoporosis must be carefully targeted because inappropriate use of these treatments may be unsafe or ineffective.
Bisphosphonates pharmacology and use in the treatment of osteoporosis
2020, Marcus and Feldman’s Osteoporosis
Bisphosphonates that have been widely used in the treatment of osteoporosis are popular and effective agents with robust evidence for fracture risk reduction. Bisphosphonates bind avidly to bone and reduce osteoclastic bone resorption. These agents are generally safe and well-tolerated, although concerns about long-term use have emerged. For most patients with osteoporosis, the benefits of treatment outweigh the risks. Because these agents accumulate in bone with some persistent antifracture efficacy after therapy is stopped, it is reasonable to consider a bisphosphonate “holiday.” The duration of treatment and the length of the holiday should be based on individual assessments of risk and benefit.
Adverse cardiovascular effects of nitrogen-containing bisphosphonates in patients with osteoporosis: A nationwide population-based retrospective study
2016, International Journal of Cardiology
Citation Excerpt :
Risk factors for vascular disease, such as dyslipidemia, systemic arterial hypertension, diabetes mellitus, and hyperhomocysteinemia, have been associated with a higher incidence of low-bone mineral density [39,40]. Previous studies have suggested that treatment with BPs is associated with a reduction in aortic plaques and with a lower risk of death in female patients with chronic kidney disease [10,41]. In contrast, we found that N-BP treated osteoporotic patients had a higher rate of composed cardiovascular events with increased all-cause mortality.
Bisphosphonates (BPs) are a class of medications used for the treatment of osteoporosis. Nitrogen-containing BPs (N-BPs) are more potent than non-nitrogenous BPs in terms of their effects on osteoporosis. We examined the effects of N-BPs on osteoporosis in patients included in a large population-based cohort study.
Based on the National Health Insurance Research Database of Taiwan, we identified 1258 patients with osteoporosis who had received N-BP treatment from 2005 through 2010.
During the retrospective observation period, N-BP users had significantly higher incidence rates of hypertension, acute ischemic stroke, atrial fibrillation (Af), and congestive heart failure (CHF), and lower rates of hyperlipidemia than patients who did not use N-BPs. Overall, N-BP users had a higher incidence of cardiovascular events at the end of the follow-up period. After adjustment for age, sex, and comorbidities, the risk of developing cardiovascular events was significantly high for patients using N-BPs. Patients who received N-BP therapy also had a higher risk of Af and CHF than those who did not during the five-year follow-up period.
We provide evidence that patients with osteoporosis using N-BP therapy have an increased risk of CHF and Af. This potential risk should be weighed against the reduction in the risk of osteoporotic fractures.

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: Originally published online January 16, 2012.

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Original InvestigationPathogenesis and Treatment of Kidney DiseaseBisphosphonate Therapy, Death, and Cardiovascular Events Among Female Patients With CKD: A Retrospective Cohort Study

Background

Study Design

Setting & Participants

Exposure

Outcomes

Results

Limitations

Conclusions

Section snippets

Study Design

Results

Discussion

Acknowledgements

Am J Kidney Dis

Kidney Int

Kidney Int

Am J Kidney Dis

Kidney Int

Acad Radiol

Gen Pharmacol

Am J Kidney Dis

USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States

Am J Kidney Dis

Pathophysiology of vascular calcification in chronic kidney disease

Circ Res

Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality

Nephrol Dial Transplant

The mechanism of phosphorous as a cardiovascular risk factor in CKD

J Am Soc Nephol

Original Investigation
Pathogenesis and Treatment of Kidney Disease
Bisphosphonate Therapy, Death, and Cardiovascular Events Among Female Patients With CKD: A Retrospective Cohort Study