New Guidance: Bisphosphonate Holidays for Low-Risk Patients

Nancy A Melville

February 03, 2016

New guidance from an American Society for Bone and Mineral Research (ASBMR) task force on the long-term use of bisphosphonates in those with osteoporosis endorses consideration of drug holidays after several years of treatment, but primarily only for patients at a low risk of fracture.

"The task force report attempts to help the osteoporosis nonexpert decide which patients to continue therapy beyond 3 to 5 years and which ones to stop," lead author Robert A Adler, MD, from McGuire Veterans Affairs Medical Center and Virginia Commonwealth University School of Medicine, Richmond, told Medscape Medical News.

While drug holidays are common in the long-term treatment of chronic conditions, the issue is of particular importance with bisphosphonates in osteoporosis, due to evidence of rare but nevertheless troubling side effects, including atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ).

The risk of AFF, which has been estimated to double with bisphosphonate treatment longer than 3 years, appears to decline with discontinuation of the drug, while the drug's antiresorptive effects remain persistent, hence the potential benefit of a "drug holiday."

But because the beneficial effects of bisphosphonates eventually wane — and with some agents in the class at a faster pace than others — the interruption should indeed only be a "holiday," and not full discontinuation.

Furthermore, although such side effects are rare, patients who are at a higher risk of fracture are better advised not to interrupt treatment at all, according to the task force, which published its report January 4 in the Journal of Bone and Mineral Research.

"The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with bisphosphonate-therapy duration, but such rare events are outweighed by vertebral-fracture risk reduction in high-risk patients," Dr Adler and coauthors conclude.

Assess Patients After a Few Years of Bisphosphonates

The task force guidance specifies that all patients be reassessed after 5 years of oral bisphosphonates or 3 years of intravenous bisphosphonates, and a drug holiday can be considered for those not at high risk for fracture.

Higher-risk patients and those with previous major osteoporotic fractures should continue on the medications for up to 10 years if using oral bisphosphonates, and 6 years if intravenous, with periodic evaluation approximately every 2 years.

The task force meanwhile recommends discussing risks and benefits of the treatment with patients.

"The clinician caring for the patient with the chronic disorder of osteoporosis will need to use the art in addition to the science of medicine," the doctors conclude.

Lack of Evidence Hampers International Consensus

Dr Adler explained to Medscape Medical News that international guidelines on this issue vary, with efforts to provide definitive advice and consensus on long-term treatment with bisphosphonates hampered by a simple lack of evidence.

"Only two placebo-controlled studies have gone beyond the 3 years necessary to get FDA approval for osteoporosis treatment," he said.

Those include the Fracture Intervention Trial Long-term Extension (FLEX) trial, in which postmenopausal women treated with the bisphosphonate alendronate for 10 years showed greater reductions in vertebral fractures compared with those switched to placebo after 5 years; and the HORIZON extension, in which women treated with six annual infusions of zoledronic acid had greater reductions in morphometric vertebral fractures compared with those switched to placebo after 3 years.

Patients showing the strongest response to the continued therapy included women with a low hip T score, between –2 and –2.5 in the FLEX trial and below –2.5 in HORIZON extension.

The trials also revealed the side effects more clearly — with ONJ showing a risk of approximately one in 10,000 to one in 100,000 osteoporosis patients and AFF in one in 10,000 for first 5 years and likely higher after that, Dr Adler added.

"The latter is a big problem, requiring surgery and long-term rehabilitation. We can't predict yet who is at highest risk for atypical fractures."

Meanwhile, the severity of the potential side effects, much more than the (rare) frequency, have brought substantial negative attention to bisphosphonates.

"Because of the reports of the side effects, the lawyer ads on TV, and the internet, many patients are unwilling to take these medications," Dr Adler noted.

Misconceptions in the Medical Community

That fear has meanwhile been compounded by misconceptions even in the medical community, particularly regarding the need for drug holidays, according to another editorial recently published by the International Osteoporosis Foundation Working Group (Osteoporos Int. 2015; DOI:10.1007/s00198-015-3453-y).

"It has been our observation that some physicians (and even entire health-authority regions) are automatically stopping bisphosphonates in patients who are taking osteoporosis medication without consideration for the patient's risk of fracture," wrote the authors, led by Stuart L Silverman, MD, medical director of the OMC Clinical Research Center in Beverly Hills, California.

"In addition, some physicians have mistakenly extended this concept to other antiresorptives such as raloxifene and denosumab, where bone-density gains are quickly lost with discontinuation."

The editorial's title, "Bisphosphonate Holidays: We Reap What We Sow," sums up the problematic public interpretation that can result when proposing a drug holiday — particularly when side effects are a factor, Dr Silverman told Medscape Medical News.

"I think patients perceive that if a medicine is recommended to be stopped after 3 to 5 years, then it's probably dangerous and therefore they shouldn't take it at all," he said.

"We sowed this by being honest and transparent about the fact that there are these side effects, even though they are rare, and we therefore created an atmosphere where people don't trust these medications — when they get a fracture they don't take them, and as soon as they go on the drug holiday, they say 'thank god I'm off of that dangerous medicine.' "

Dr Silverman referred to particularly troubling data showing that osteoporosis medication use among people who have already sustained hip fractures — and are therefore at a very high risk of refracture — has in fact declined significantly, from 40% in 2002 to only 21% in 2011 (J Bone Miner Res. 2014;29:1929-1937).

"There is strong evidence that fear of these drugs' side effects is a leading reason for this decline," he observed.

Despite the rarity of ONJ, reports of the condition tend to resonate with patients and generate more fear than reports of the potential risk of a fracture that can occur with discontinuation of the drugs, he added.

"The bottom line is that physicians and staff, including nursing and dental assistants, as well as patients, need to be educated on this, and we really need to have a conversation about the risks and benefits."

Overwhelming Evidence Bisphosphonates Are Effective

Dr Adler seconds the need to better inform medical professionals of appropriate treatment after an osteoporotic fracture.

"After a fracture, people don't realize that the reason they broke a hip after a fall from a standing position was underlying osteoporosis — and their doctors may not as well," he said.

"[Therefore,] only about a quarter of older women who suffer a low-trauma fracture have any attention paid to the underlying disorder [and] for men, the proportion is even lower."

Meanwhile, the potential benefits of treatment are substantial, he added.

"After one fracture, the chance of another in a year may be as high as 20%, so treatment can save a lot of fractures, and — as has been shown after hip fracture — a lot of lives. Medications are usually covered and are not expensive now that most bisphosphonates are generic."

This point was further underscored in a recent case vignette by Dennis M Black, PhD, of, University of California, San Francisco, and Clifford J Rosen, MD, of the Maine Medical Research Center (N Engl J Med. 2016;374:254-262).

This article summarized the extensive research supporting the effectiveness of bisphosphonates in increasing bone mass and reducing future fractures in osteoporosis patients.

President of the ASBMR and a professor of medicine at Harvard Medical School, Douglas P Kiel, MD, MPH, said in a press statement: "It's critical that doctors and patients understand that there is overwhelming evidence that these drugs are extremely effective in preventing future fractures."

Dr Kiel cited data from the Centers for Disease Control and Prevention (CDC) showing that nearly 65% of people in the US who are 65 or older have either osteoporosis or low bone mass and therefore are at risk for a fracture.

"We must close the treatment gap and prevent millions of people from suffering needlessly," he concludes.

Dr Adler's reports receiving consulting fees from Amgen and research grants from Genentech, Merck, Novartis, and Eli Lilly; disclosures for the coauthors are listed in the article. Dr Silverman has received grant/research support from Roche diagnostics and is a consultant to Lilly, Amgen, and Pfizer and is a member of the speaker's bureau for Lilly, Pfizer, and Amgen; disclosures for the coauthors are listed in the article. Dr Black reports receiving fees for serving on a data and safety monitoring board from Eli Lilly, fees for a presentation and for serving on an advisory board from Amgen, consulting fees from Radius Health, lecture fees and travel support from Merck and Novartis, and grant support from Alexion. Dr Rosen reports receiving grant support from Alexion.

J Bone Miner Res. Published online January 4, 2016. Article

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