Nancy A Melville

September 09, 2017

( Updated Osteoporosis drugs including oral bisphosphonates show efficacy and safety in the treatment of bone loss in patients with chronic kidney disease (CKD) in several observational studies. However, caution is still urged, particularly with oral bisphosphonates, say the authors of the research, presented here at the American Society of Bone and Mineral Research (ASBMR) 2017 Annual Meeting.

"The take-home message...is that oral bisphosphonates seem to be safe and effective, at least in terms of bone-density improvement, in patients with chronic kidney disease," coauthor Daniel Prieto-Alhambra, MD, an associate professor at the University of Oxford, in the United Kingdom, told Medscape Medical News.

But he advised that "these data are…observational, and we must replicate these analyses in external data before we can recommend any changes to existing clinical practice and/or recommendations.

"In the meantime, oral bisphosphonates continue to be contraindicated in patients with severe chronic kidney failure."

Bone loss and resulting fractures are highly common in CKD, presenting a clinical challenge in terms of pharmacological treatment, particularly with oral bisphosphonates, which are eliminated through the kidneys and therefore are of concern in the setting of renal insufficiency.

However, evidence detailing drug effects is lacking because patients with severe CKD are often excluded from clinical trials.

In commenting on the research, Michael Econs, MD, a professor in the Indiana University School of Medicine, in Indianapolis, and incoming ASBMR president, said this work offers important insight to add to knowledge of osteoporosis drugs in CKD.

"The most notable finding...is that these drugs work in people with impaired kidney function," he told Medscape Medical News.

"Surprising" Findings

In an effort to better understand the effects, Dr Prieto-Alhambra and his colleagues conducted several analyses looking at mortality, adverse events, and bone improvement among moderate- to severe-CKD patients treated with oral bisphosphonates.

In the first of three abstracts presented at the meeting, they evaluated the efficacy of bisphosphonate in patients with moderate or severe CKD [estimated glomerular filtration rate [eGFR] of <45 mL/min), looking at bone-mineral density (BMD) changes in a Danish population between 1999 and 2016. The study excluded patients who had previously used oral bisphosphonates

The review included data from a regional database of all DXA-based routine measurements in Funen, Denmark, in which the use of oral bisphosphonates in moderate to severe CKD was expectedly rare, with only 81 patients identified.

However, compared with 282 bisphosphonate nonusers, also with stage 3B CKD, the bisphosphonate users showed gains of an average of 0.59% total hip BMD per year, whereas the nonusers lost an average of 1.98% annually.

After adjustment for factors including age, sex, body mass index (BMI), baseline eGFR, fracture history, and other comorbidities, the mean difference was +1.81% and, in the propensity score–adjusted analysis, the difference was +2.44% in favor of oral bisphosphonate use.

"The finding of an improved BMD is good news, as this suggests these drugs could be effective at improving bone strength," Dr Prieto-Alhambra said.

In the second study, the authors evaluated all-cause mortality rates among a population of patients in UK primary-care records with eGFR <45 (CKD 3B), aged 40 and older.

They found that among 18,904 oral bisphosphonate users with CKD 3B, compared with 190,850 nonusers also with CKD 3B, the bisphosphonate users had significantly lower all-cause mortality, with an adjusted HR of 0.85 (95% CI 0.82–0.88).

Greater reductions in mortality linked to bisphosphonate use were seen in women (HR, 0.82) ,han men (HR, 0.96); in those with previous fracture (HR, 0.78) compared with no previous fracture (HR, 0.90); and in those with more severe CKD (stage 4 or higher; HR, 0.71) compared with stage 3B (HR, 0.88; all P < .0001).

"[The findings] are surprising given that bisphosphonates are contraindicated in patients with severe kidney disease," Dr Prieto-Alhambra said.

"We hypothesize that residual confounding, such as unobserved differences between users and nonusers of these drugs, might at least partially explain this finding. Indeed, sensitivity analyses completed more recently suggest this," he explained.

"It is in any case reassuring that bisphosphonates are, despite being contraindicated in some of these patients, not associated with increased mortality in actual users of the drug."

And in their third analysis, Dr Prieto-Alhambra's team evaluated the risk of acute kidney injury (AKI), gastrointestinal events, and hypocalcemia leading to hospital admission in the same UK population of patients with stage 3B or higher CKD, with an eGFR < 45 mL/min, but at age 50 or older. Among those patients, 19,315 were oral bisphosphonate users who were compared with 210,568 bisphosphonate nonusers.

Overall, 8846 patients developed acute kidney injury, 499 had gastrointestinal events, and 682 developed hypocalcemia.

In comparing the incidence rates of events between oral bisphosphonate users and nonusers, the hazard ratios (HR) were not significant for acute kidney injury (HR, 0.95; 95% CI, 0.8–1.07), gastrointestinal events (HR, 0.85; 95% CI, 0.48–1.52) or hypocalcemia (HR, 1.11; 95% CI, 0.77–1.62).

"Bisphosphonate use is not associated with acute kidney injury, gastrointestinal events, or hypocalcemia among patients with moderate to severe (stage 3B+) CKD," the authors report.

No Safety Signal with Denosumab in CKD, Either

Still another study presented at the meeting examined the effects of osteoporosis drug denosumab in patients with mild to moderate CKD.

Unlike bisphosphonates, denosumab is not metabolized through the kidneys and is not contraindicated in patients with severe CKD; however, research is nevertheless lacking on the drug's effects on renal insufficiency.

For that study, the researchers analyzed data on patients who were enrolled in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every Six Months (FREEDOM) Extension study, which was the extension of the phase 3 FREEDOM trial, evaluating denosumab treatment for up to 10 years.

Patients included those who received long-term denosumab treatment for up to 10 years, as well as those in a crossover arm with up to 7 years of treatment.

Patients, who had a mean age of 72 to 74, were categorized according to their baseline eGFR, and assessments were made according to the change in the rate at the last visit during the study.

The rates of mild or moderate renal insufficiency (stage 2 or 3 CKD) prior to denosumab treatment were high, including 1969 (84%) of 2343 in the long-term (10-year) treatment group and 1781 (81%) of 2206 in the crossover (7-year) group.

Of those with CKD, 67% of patients in the long-term treatment group and 68% in the crossover group retained stable renal function from baseline to the last visit, suggesting no worsening of their CKD in relation to denosumab treatment.

Approximately 7% in both arms progressed to CKD stage 2, and 15.4% in the long-term arm and 13.1% in the crossover arm progressed to CKD stage 3.

Progression from CKD stage 2 or 3 to stage 4 was rare, occurring in less than 1% of subjects, and none of the patients required renal replacement therapy.

The incidence of new vertebral as well as nonvertebral fractures was similar between those with CKD stage 2 or 3, including those in the long-term and crossover arms, compared with those with normal renal function.

There were no significant differences in the groups in terms of serious adverse events, which occurred in 52% of those with CKD stage 2, 57% of those with CKD stage 3 in the long-term group, and 54% of those with normal eGFR.

In the crossover group, the rates of serious adverse events were lower, including 42% in stage 2 CKD, 45% in CKD stage 3, and 43% in those with normal eGFR.

In response to several questions from the audience, presenter Aaron Broadwell, MD, noted that parathyroid-hormone levels were not measured over time for the study.

Coauthor Paul D Miller, MD, a metabolic bone disease specialist, with the Colorado Center for Bone Research at Panorama Orthopedics & Spine Center, in Golden, noted that among patients who did have reductions in GFR, the changes were not believed to be associated with the treatment drug.

"All of the reductions in GFR were age-related, with no known intrinsic kidney disease or proteinuria," he told Medscape Medical News.

He added that an important limitation was the lack of patients with more serious CKD.

"The findings were very reassuring — in this largest study of its kind, we found consistent results of no negative effects of denosumab use on GFR," he said.

"However, we did not study stage 4 to 5 CKD (GFR less than 30 or 15 mL/min), where hypocalcemia is more prevalent, though still rare."

Dr Prieto-Alhambra's studies were funded by National Institute for Health Research (NIHR) Health Technology Assessment, United Kingdom. His research group has received funding from Amgen, Servier, and UCB Pharma.  Dr Miller's study was funded by Amgen and he has received research funding from Amgen and Radius Health. Dr Econs is on the data safety and monitoring board for Amgen's studies with denosumab and romozosomab.

American Society of Bone and Mineral Research 2017 Annual Meeting. September 8–11, 2017, Denver, Colorado. Abstracts FR0242, LB SA0388, SU 0226, and 1070.

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