Value of Osteoporosis Drugs Uncertain in Patients With CKD

Pam Harrison

April 18, 2017

The benefits and harms of treating patients with chronic kidney disease (CKD) with any of the drugs used to prevent bone loss and subsequent fracture remain uncertain, according to a systematic review and meta-analysis of the published literature.

"Patients with CKD, particularly those with end-stage renal disease and those requiring kidney transplantation, have a higher risk for fractures than the general population. Fractures are associated with reduced quality of life and higher mortality," the researchers write.

Lisa Wilson, ScM, from the Johns Hopkins University Bloomberg School of Public Health in Baltimore, Maryland, and colleagues report their findings in an article published online April 10 in the Annals of Internal Medicine.

The authors analyzed 13 studies in which the safety and efficacy of the bisphosphonates, teriparatide, raloxifene, and denosumab were evaluated in patients with CKD as well as transplant recipients. All were judged to have either moderate or high risk for bias. Six studies compared a bisphosphonate against placebo, with the primary endpoint being the effect that bisphosphonates had on bone mineral density (BMD) at 12 and 36 months of follow-up.

Bisphosphonates

Three of four studies involving transplant recipients found statistically significant differences in absolute BMD changes in the lumbar spine at study endpoint, and one study detected a significant difference in BMD scores at the femoral neck. In contrast, the two studies that evaluated bisphosphonates in patients with stage 3 and 4 CKD had mixed results. "We stratified our analysis comparing bisphosphonates with placebo in terms of vertebral fractures by kidney transplant recipients and those with CKD," the authors observe.

When they pooled the four trials involving kidney transplant patients, the risk for vertebral fracture was lower for patients who had received a bisphosphonate compared with placebo, but not significantly so. Results were similar in the two studies involving patients with stage 3 or 4 CKD. Researchers thus could not conclude that treatment with a bisphosphonate is better at preventing vertebral fracture than placebo.

Too few nonvertebral fractures occurred in the studies reviewed for researchers to arrive at any conclusion regarding the effectiveness of the bisphosphonates against nonvertebral fracture.

Other Osteoporosis Medications

Three studies evaluated the ability of raloxifene to improve BMD compared with placebo. "None of the studies reported statistically significant differences between raloxifene and placebo in lumbar spine BMD," researchers note. One study did report a significantly higher annual rate of change in femoral neck BMD in favor of raloxifene, but two others did not.

As for fracture prevention, two studies in postmenopausal women stratified for glomerular filtration rate evaluated raloxifene vs placebo to prevent vertebral fracture. "Pooling the 2 studies resulted in a lower risk for vertebral fractures among patients treated with raloxifene versus placebo," the investigators acknowledge. "However, these results were strongly influenced by the subgroup of patients with a [glomerular filtration rate] of 45 to 59 mL/min/1.73 m2. With the removal of this subgroup, the results were no longer statistically significant," they point out.

One study in postmenopausal women with stage 2 or 3 CKD evaluated the effect of teriparatide on BMD vs placebo. At the end of 21 months, BMD at the lumbar spine had increased to a greater extent among teriparatide recipients, but results were not consistent for femoral neck BMD. Vertebral and nonvertebral fracture rates were also lower in teriparatide recipients compared with placebo.

However, because findings from this single study were so limited, the authors again could not endorse the use of teriparatide to improve BMD or to prevent fractures in patients with CKD. Two studies compared denosumab against placebo; the larger one of the two again involved postmenopausal women with osteoporosis stratified by CKD status. The other included men and women who had received a kidney transplant.

"The effects of denosumab on lumbar spine, femoral neck, and total hip BMD were not consistent across the studies," the researchers write. They again could not conclude that denosumab favorably affects BMD in patients with CKD. As for fracture risk, the one study carried out in postmenopausal women found that women with stage 3 CKD, although not stage 4 CKD, treated with denosumab had significantly fewer vertebral fractures than placebo controls, but there was no difference in nonvertebral fracture rates between the two groups.

The strength of evidence supporting the use of denosumab to prevent fractures in patients with CKD was thus judged to be "very low," as the authors observe. Last, a single study compared ibandronate with risedronate in kidney transplant patients. In this study, investigators found no real differences in lumbar spine or femoral neck T-scores between the two groups, and they were again unable to reach any conclusion about the effect ibandronate had on BMD, relative to risedronate. The comparative fracture risk afforded by these two agents has not been studied.

The investigators also found some evidence that denosumab might increase infection risk, diarrhea, and hypocalcemia, whereas teriparatide might increase the risk for hypercalcemia. "Our results may have limited applicability to the general population of patients with CKD," the study authors caution.

This is because only the bisphosphonates and denosumab have been studied in men, and almost all of the studies exploring the effect of raloxifene, teriparatide, and denosumab involved postmenopausal women, some of whom were excluded from the study if they had elevated creatinine levels. Investigators also point out that it was difficult to ascertain whether patients evaluated in these studies had comorbid diabetes, which could have altered outcomes as well.

Thus, the researchers conclude, "[m]ore research is needed to determine the best options for patients across the spectrum of CKD to improve BMD and prevent fractures with minimal risk for adverse outcomes."

This study was supported by Kidney Disease: Improving Global Outcomes. The authors have disclosed no relevant financial relationships.

Ann Intern Med. Published online April 10, 2017. Abstract

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