A Review of Bisphosphonates for Osteoporosis

This is a review of bisphosphonates by two endocrinologists who agree with the editors of their British journal on the importance of two principles: evidence-based medicine and patient input.  The landscape of treatment for osteoporosis and bone fracture is populated by a few high-quality randomized, controlled trials (some of them contradictory), with many gaps in the evidence, most significantly the lack of head-to-head comparisons between different bisphosphonates. Hip fractures cause significant mortality, and bisphosphonates can definitely reduce mortality in some patients, but it’s not clear exactly who those patients are. Some studies use an endpoint of bone mineral density, while others use an endpoint of clinical fractures. It’s reasonable to assume that increasing bone mineral density will reduce fractures, but that hasn’t been rigorously proven. Meta-analyses and systematic reviews try to fill in the gaps in data, but also don’t always agree with each other. Treatment is controversial. [[{"type":"media","view_mode":"media_crop","fid":"41166","attributes":{"alt":"©donskarpo/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_8559781033545","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4306","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":" ","typeof":"foaf:Image"}}]] In terms of rheumatoid arthritis, other studies have found an increased risk of bone loss and fracture in people with rheumatoid arthritis who are at increased risk for osteoporosis for a number of reasons. Glucocorticoid medications are associated with bone loss, but also, inactivity due to pain can lead to bone loss. Some studies have also shown that bone loss in rheumatoid arthritis (primarily around affected joints) can occur directly as a result of RA. In addition, women, who are at increased risk for osteoporosis, are two to three times more likely than men to have rheumatoid arthritis. â€‹Some doctors believe that osteoporosis is undertreated, and that we should be more aggressive in diagnosing and treating it, while others believe that it is overtreated, and argue provocatively that smoking cessation, fall prevention and exercise training would have a better return.  This review, in the Sept. 2, 2015 issue of the BMJ, attempts to navigate that evidence, and is generally consistent with other reviews reported in Rheumatology Network, with a few updates and a few details of interest particularly to rheumatologists.  Bisphosphonates currently approved by the Food and Drug Administration for the prevention or treatment (or both) of osteoporosis include alendronate, ibandronate, risedronate and zoledronic acid. Bisphosphonates Use in Rheumatic Diseases The role of bisphosphonates in preventing fractures and preserving bone mass in rheumatic patients remains unclear, wrote the authors of the PLoS review which found that in both short-term and middle-term, bisphosphonates can preserve bone mass and reduce the incidence of vertebral fractures in rheumatic patients, but mainly for patients on glucocorticoids. The efficacy of bisphosphonates is better for prevention rather than for the treatment of osteoporosis in rheumatic patients, the researchers concluded. A 2013 PLoS study is based on a review of 20 clinical trials with a time limit of Jan. 6, 2012. It included randomized clinical trials of bisphosphonates for adults with rheumatic disease with a follow-up of six months or more. The relative risk in rheumatic patients treated with bisphosphonates was 0.61 (95%CI [0.44, 0.83], P = 0.002) for vertebral fractures, and 0.49 (95%CI [0.23, 1.02], P = 0.06) for non-vertebral fractures. The difference and change in the lumbar spine was 3.72% (95%CI [2.72, 4.72], P<0.001) at 6 months, 3.67% (95%CI [2.84, 4.50], P<0.001) at 12 months, 3.64% (95%CI [2.59, 4.69], P<0.001) at 24 months, and 5.87% (95%CI [4.59, 7.15], P<0.001) at 36 months in patients using bisphosphonates, as compared with those treated with calcium, vitamin D or calcitonin. In subgroup analyses, rheumatic patients using BPs for osteoporosis prevention had greater WMD than those using bisphosphonates for treating osteoporosis at 6 months (4.53% vs. 2.73%, P = 0.05) and 12 months (4.93% vs. 2.91%, P = 0.01). “BPs can prevent bone loss at both lumbar spine and hip, and can further reduce the risk of vertebral fractures,” the researchers wrote. “There is, however, no robust evidence to suggest that BPs can prevent non-vertebral fractures and that continuous therapy is better than intermittent therapy.” The optimal usage of bisphosphonates in managing osteoporosis in patients with rheumatic diseases remains to be seen, they wrote. Glucocorticoid-Induced Osteopenia “Bisphosphonates are approved by the FDA for preventing osteoporosis in menopausal women, but it is not known whether their use decreases the risk of fractures,” write the authors, Spyridoula Maraka and Kurt Kennel, from the Mayo Clinic, Rochester, Minn. Patients with osteopenia who require drugs that could induce bone loss - such as glucocorticoids, aromatase inhibitors, and androgen deprivation therapy - could potentially benefit from bisphosphonates,” they write.  “A meta-analysis published in 2014 reported high quality evidence that bisphosphonates (alendronate, ibandronate, risedronate and zoledronic acid) reduce fractures compared with placebo in postmenopausal women, with relative risks in the range of 0.4 to 0.6 for vertebral fractures and 0.6 to 0.8 for non-vertebral fractures,” the authors of the review wrote.  A network meta-analysis of eight randomized controlled trials also assessed the relative effectiveness of alendronate, ibandronate, risedronate, and zoledronic acid on fracture outcomes and concluded that zoledronic acid was more likely to reduce fracture by a greater amount, but this analysis was sponsored by the manufacturer of zoledronic acid, they note. Zolendronic acid has the benefit of requiring only one intravenous infusion a year.  Patients Recommend Shared Decision-Making Two patients reviewed the BMJ manuscript. As a result of their input the authors expanded the discussion of bisphosphonate therapy for osteopenia. They also put more emphasis on the importance of communication between patients and providers, shared decision making and care coordination. This is particularly important with osteoporosis treatment, since the evidence is so incomplete that decisions are not straightforward, and depend in large part on a dialog between the provider’s clinical judgment and patient preference, including cost.  Non-adherence is a major problem with bisphosphonate treatment. One review found that half the patients prescribed oral bisphosphonates discontinued treatment within one year. However, other studies found that patient education and decision aids can improve the quality of decisions and may have improved adherence. The Mayo Clinic has developed an online decision aid that will calculate the individual risks of fracture without treatment, the risks of a fracture with treatment, and the costs and adverse effects of the treatment. 

References:

Maraka S, Kennel KA.

State of the Art Review: Bisphosphonates for the prevention and treatment of osteoporosis. the BMJ

2015;351:h3783. doi: 10.1136/bmj.h3783. September 2, 2015 Feng Z., Zeng S., et al.

Bisphosphonates for the Prevention and Treatment of Osteoporosis in Patients with Rheumatic Diseases: A Systematic Review and Meta-Analysis. PLoS One.

Dec. 6, 2013. doi:  10.1371/journal.pone.0080890