Amid Osteoporosis Treatment Crisis, Experts Suggest Addressing Patients’ Bisphosphonate Concerns | JAMA

JAMA. Published online June 6, 2018. doi:10.1001/jama.2018.7097

Several times a month, orthopedic surgeon Anna N. Miller, MD, repairs an unusual type of thigh bone break that can afflict elderly patients being treated for osteoporosis. Known as atypical femur fractures, these breaks occur not after a fall or other trauma, but during routine activities, like walking, twisting at the waist, or even just standing still. The injuries are devastating, Miller says, often requiring multiple surgeries, a stay at a rehabilitation facility, and months to walk normally again.

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Worse yet, many atypical femur fractures can feel like a too-cruel joke to patients because they aren’t directly caused by their bone disease. Rather, they may be an adverse effect of bisphosphonates—the very medications that treat osteoporosis.

That’s one side of the story, the one that strikes fear into the hearts of patients. But the other side is this: Bisphosphonates are tremendously effective drugs, reducing the risk of spine fractures by up to 70% and hip fractures by up to 50%.

Miller, who is chief of orthopedic trauma at Barnes Jewish Hospital and Washington University in St Louis, sees so many atypical femur fractures because she’s known in the region for performing the surgeries. She and other specialists emphasize that the absolute risk of this albeit awful injury is low, ranging on average from 3.2 to 50 cases per 100 000 patients in a given year. Another adverse effect of bisphosphonates, osteonecrosis of the jaw, is rarer still, with a risk somewhere between fewer than 1 in 100 000 and 1 in 10 000 patients per year on average.

In contrast, an estimated 866 of 100 000 women with osteoporosis who aren’t treated will have a hip or femur fracture in a given year, according to data from a trial of the bisphosphonate zoledronic acid.

“There is a very small percentage of these patients on these drugs who get these horrible side effects, but overall bisphosphonates do a great deal for the population,” Miller says.

It’s not clear why the adverse effects occur. Bisphosphonates and the monoclonal antibody denosumab are the first-line drugs prescribed for osteoporosis. They inhibit bone resorption and turnover, reducing the disease’s hallmark bone loss. Some believe the drugs slow the remodeling process needed to repair tiny cracks that occur in bones. According to Miller, the thigh bone is one of the skeleton’s highest stressed regions, making it particularly vulnerable to these microcracks. Over years of use, antiresorptive drugs essentially freeze bone repair in place, she says. Occasionally, minuscule cracks may progress, giving rise to atypical femur fractures.

Osteonecrosis of the jaw usually occurs only in people taking high doses to prevent chemotherapy-related bone loss or to treat cancer that has spread to the bone, often after they’ve had a tooth extracted or other oral surgery.

According to some estimates, treating 1000 women with osteoporosis with bisphosphonates for 3 years might cause up to 1.25 atypical femur fractures, while preventing approximately 100 osteoporotic fractures.

Yet for many patients who have heard about the snapped femurs and crumbling jaws—both have been the subject of news reports and lawsuits—the statistics aren’t reassuring. “I think the patient mindset is, ‘Yeah, the risk is low, but what if it happens to me?’” says Sundeep Khosla, MD, an osteoporosis clinician and researcher at the Mayo Clinic.

Physicians report that fearful patients are turning down prescriptions they need to prevent life-limiting fractures. Qualms about bisphosphonates, and by extension all osteoporosis drugs, could be adding to what some experts are calling a treatment crisis.

Patient Fears Take a Toll

Although the crisis has many causes, including less bone density testing in recent years, experts say that patients’ fears about the medications and how physicians respond to those concerns are important contributors.

In a National Institutes of Health (NIH) study, a more than 50% decline in oral bisphosphonate use in women aged 55 years and older between 2008 and 2012 coincided with media reports of safety concerns and spikes in Google searches for the brand-name bisphosphonate Fosamax.

The NIH researchers noted that some of the decline could be the result of more judicious prescribing in patients with osteopenia—low bone mass that isn’t low enough to be osteoporosis—using the Fracture Risk Assessment Tool (FRAX) released in 2008.

But studies of older women with fragility fractures suggest that many high-risk patients who should be getting pharmacological treatment aren’t. In an international study published in 2012, more than 80% of postmenopausal women with fragility fractures were not treated with osteoporosis medications.

Having a fracture doubles the risk of breaking another bone, and bisphosphonates and other medications can reduce the risk of a second fracture and death. Yet a 2014 study found that between 2002 and 2011, the use of osteoporosis medications in the year following a hip fracture hospitalization among women aged 50 years or older decreased from 40% to 21%.

“That’s abominable, and I think that’s on the PCPs [primary care physicians],” says Carolyn Crandall, MD, an internist at the University of California Los Angeles Medical Center who specializes in osteoporosis and menopause.

However, some physicians may not realize that a fracture in an older person can be a sign of osteoporosis and should trigger a clinical evaluation, says Meryl Susan LeBoff, MD, who directs the Skeletal Health and Osteoporosis Center at Brigham and Women’s Hospital in Boston.

Crandall suspects that many physicians don’t know the incidence of rare adverse effects associated with bisphosphonates and therefore don’t feel confident weighing the benefits and risks with patients who balk at taking osteoporosis drugs. “I think they actually give up too easily,” she says.

In other cases, patients discontinue the medications too soon. A 2015 study by Fosamax manufacturer Merck & Co found that 60% of women who started taking oral osteoporosis medications stopped within a year.

There’s some evidence that the treatment decline may already be taking a toll. According to a new analysis of Medicare claims data from women aged 65 years and older, age-adjusted hip fracture rates in the years 2013 through 2015 were greater than projected, resulting in more than 11 000 additional hip fractures than predicted by earlier estimates.

A rise in hip fractures raises red flags because of their terrible outcomes: More than half of patients don’t fully regain the level of function they had before the injury, and around a fifth require nursing home care. Most sobering, a hip fracture at least doubles the risk of death in the first year after the injury.

Beyond Benefits and Risks

With the potential fallout looming from an aging population declining treatment en masse, osteoporosis specialists are looking for solutions to meaningfully address patients’ bisphosphonate concerns.

Crandall puts things into perspective for patients. She explains the rarity of adverse effects and clarifies what a 50% hip fracture risk reduction from bisphosphonates means for an individual’s own risk based on a calculator like FRAX. A patient with a 2% risk of fracture in the next 10 years may not want to chance a serious side effect to bring that risk down to 1%. But for a patient with a 20% fracture risk, getting it down to 10% may seem worth it, she says.

Khosla encourages physicians to go one step further. “[One of] the things that I’ve started to do over the past several years is point out that had we known back 5, 10 years ago what we know now, it’s likely that there would be far fewer, if any, atypical femur fractures.”

Patients may appreciate knowing that the drugs are now reserved for those at high fracture risk—reducing overtreatment that may have occurred in the past—and that they’re no longer prescribed indefinitely.

“[N]ow, we’re treating patients for 5 or 10 years on an oral bisphosphonate or 3 to 6 years on an intravenous bisphosphonate, and we’re really making clinical judgements about continuing long-term care,” LeBoff says.

A 2016 report from the American Society for Bone Mineral Research suggests considering bisphosphonate drug holidays for patients who have been treated for at least 3 to 5 years and are no longer at high risk of fracture. Bisphosphonates accumulate in bone, and the risk of adverse effects increases with longer-term use. “The idea is by getting off the drug you continue to benefit from its antifracture effects and at the same time the risk of some rare possible adverse effects may be decreased,” says E. Michael Lewiecki, MD, director of the New Mexico Clinical Research & Osteoporosis Center in Albuquerque.

Lewiecki, however, emphasizes that drug holidays are just that: a holiday and not a retirement. Patients must be monitored while they’re not taking bisphosphonates because “sooner or later, the therapeutic effects of the medication are going to wear off and probably treatment needs to be restarted,” he says.

Although not everyone agrees with this approach, many physicians are continuing to monitor bone density during osteoporosis treatment, bucking controversial new guidance from the American College of Physicians (ACP).

The ACP argues that in clinical trials, women treated with bisphosphonates benefited from reduced fractures even if bone mineral density did not increase.

“These medicines are improving your bone strength and reducing fracture risk in ways that are not necessarily visible on a bone density test,” Crandall says.

However, proponents of monitoring say that it identifies nonresponders who continue to lose bone on the therapy and may benefit from switching to an intravenous bisphosphonate or denosumab. Plus, patients want their bone density retested. “Who on earth would want to take any medication for 5 years without having any feedback if it’s working or not?” Lewiecki says.

More Techniques on the Way

Another insight has emerged: atypical femur fractures are often preceded by thigh or groin pain. Knowing that a warning sign exists and could help prevent a break may be reassuring for patients, Khosla says.

According to guidance from the International Osteoporosis Foundation, physicians should proactively ask patients who are taking bisphosphonates about thigh or groin pain. The organization recommends that patients who report this pain should get x-rays of both femurs followed by magnetic resonance imaging or a radionuclide bone scan if there’s high suspicion that an atypical femur fracture is present. Although some patients need a rod placed to prevent a complete break, others can do so by discontinuing bisphosphonates and possibly switching to a drug that stimulates bone formation.

There’s also a new tool to help prevent atypical femur fractures. The two most widely used dual-energy x-ray absorptiometry machines for bone mineral density testing now come with software to image the entire femur and identify bone abnormalities that precede the breaks. Although most physicians don’t yet routinely employ the technique, Khosla is already using it to monitor patients who have been taking bisphosphonates for a few years.

In the future, it may be possible to know which patients are at higher risk of an atypical femur fracture and may benefit from shorter treatment and closer monitoring. Femur geometry appears to be a factor, for example, as does Asian ethnicity. Early research suggests there could be a genetic predisposition to atypical femur fractures, which if verified could lead to pharmacogenomic-guided prescribing down the line.

For now, Khosla says, addressing patients’ fears about drug treatment is paramount, despite the rarity of adverse effects: “If the patient has a sense that the physician is really attuned to their concerns about it and is going to be as proactive as possible to address those concerns, I think that goes a long way towards trust building.”

Categories: School of Medicine, UNM Hospitals, Research

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