Bisphosphonate use safe for adults with CKD
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Adults with moderate to severe chronic kidney disease at high risk for fracture were no more likely to die of any cause when prescribed bisphosphonate therapy compared with adults with CKD who were not prescribed a bisphosphonate, according to findings from a population-based study published in the Journal of Bone and Mineral Research.
Bisphosphonates are cleared by the kidneys and therefore may worsen kidney function and exacerbate other adverse events common for adults with CKD on renal replacement therapy, such as hypocalcemia, hypophosphatemia and gastrointestinal events, Dunia Alarkawi, MBBS, MPH, MHM, a doctoral student at the Garvan Institute of Medical Research, University of New South Wales, Sydney, and colleagues wrote.
“This study shows that oral bisphosphonates are safe for people with moderate to severe CKD, at least in relation to mortality outcomes,” Alarkawi told Healio. “This provides reassurance to clinicians in regard to using oral bisphosphonates, the most commonly used osteoporosis treatment, for this population, which are at high risk for fracture and have limited options to fracture prevention.”
In a population-based study, Alarkawi and colleagues analyzed data from 230,305 adults aged at least 40 years with an estimated glomerular filtration rate less than 45 mL/min/1.73 m2 and at least 1 year of follow-up data available from the U.K. Clinical Practice Research Datalink (CPRD; 19,351 using oral bisphosphonates) and 90,273 adults from the Catalan Information System for Research in Primary Care database (SIDIAP; 4,146 using oral bisphosphonates). Use of oral bisphosphonates including alendronate, risedronate and ibandronate was identified from prescriptions (CPRD cohort) and pharmacy dispensations (SIDIAP cohort); researchers excluded previous and current users of other osteoporosis therapies. Primary outcome was all-cause mortality. For both cohorts, researchers used Cox regression models fitted to calculate mortality risk according to oral bisphosphonate use, and used logistic regression models to calculate propensity scores using prespecified predictors of mortality including age, sex, baseline eGFR, socioeconomic status, comorbidities, previous fracture, comedications and number of hospital admissions in the previous year.
In the CPRD cohort, researchers observed 5,234 deaths among bisphosphonate users (27%) during 45,690 person-years of follow-up, and 85,105 deaths among nonusers (40%) during 915,867 person-years of follow-up. An 8% lower mortality observed among bisphosphonate users vs. nonusers did not persist after propensity score trimming.
In the SIDIAP cohort, researchers observed 1,330 deaths among bisphosphonate users (32%) during 14,374 person-years of follow-up and 36,513 deaths among nonusers (42%) during 344,389 person-years of follow-up. Oral bisphosphonate use was not associated with mortality after propensity score adjustment and trimming.
The researchers noted that the median follow-up time of bisphosphonate users vs. nonusers was shorter for the CPRD cohort (median, 1.5 vs. 3.5 years) compared with the SIDIAP cohort (median, 3 vs. 3.6 years). Additionally, bisphosphonate users in the CPRD cohort were older, had a higher prevalence of comorbidities and a higher absolute mortality rate vs. nonusers.
“More research is needed about the other effects of oral bisphosphonates, including their effects on adverse events and fracture risk in people with moderate to severe CKD, especially those with grade 5 and 5D, as they were underrepresented in this study,” Alarkawi said. – by Regina Schaffer
For more information:
Dunia Alarkawi, MBBS, MPH, MHM, can be reached at the Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia; email: dunia.ark@gmail.com.
Disclosures: The authors report no relevant financial disclosures.
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David B. Karpf, MD
Although not randomized, this is an interesting study that provides some level of reassurance about the overall safety of oral bisphosphonate use among people with moderate-severe chronic kidney disease. To me, these results are not too surprising, for several reasons.
With oral dosing of bisphosphonates, less than 1% is absorbed; for alendronate it is about 0.6% in terms of oral bioavailability after a 2-hour fast, falling to about 0.4% with a 1-hour fast. Of that small amount absorbed, about 50% binds to the exposed bone surface at a remodeling site below an osteoclast, based on radiolabeled studies in rats, and the other about 50% is fairly rapidly excreted by the kidneys. So, an anephric patient would be expected to be exposed to roughly twice the serum concentration of an oral bisphosphonate, such as alendronate, compared with a patient with normal renal function.
In the pivotal phase 3 studies for alendronate, 200 of the 600 participants took 20 mg per day for 2 years before switching to 5 mg per day for the third year, whereas 200 participants each took either 10 mg per day or 5 mg per day for all 3 years. Safety was similar between groups, despite exposure for some that was twofold or fourfold higher.
During the most "real-world" clinical trial in the alendronate program, the FIT study, several dozen participants had eGFR values less than 35 mL/min/1.73m2, and neither efficacy, in terms of bone turnover and BMD effects, nor safety appeared to differ for this small subset. It is due to the lack of comprehensive data in the population with severe CKD that the label cautions against use in this population.
Even more telling, patients who receive IV bisphosphonates experience serum levels that are orders of magnitude higher than patients dosed with oral bisphosphonates, with no apparent difference in safety other than a risk of renal tubular irritation, which can be prevented by administering the bisphosphonate in a more dilute formulation and more slowly.
This is why for all of the patients I have treated with zoledronic acid, the 5 mg in 100 mL formulation is diluted into 500 mL of normal saline and the diluted 600 mL volume is infused over 60 minutes. This has allowed me to treat patients with an eGFR as low as 36 mL/min/1.73m2 with IV zoledronic acid without seeing any bumps in serum creatinine.
However, in general, I prefer to treat my patients with both osteoporosis and CKD with oral alendronate, although denosumab is another option, as long as the patient is a candidate for bisphosphonate treatment if they discontinue the denosumab.
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