How to start and stop bisphosphonates

A new tool can help internists determine when to start bisphosphonates in their patients, Susan L. Greenspan, MD, FACP, told an audience of hundreds of Internal Medicine 2013 attendees in San Francisco in April. She also offered some simple advice on the effects of different bisphosphonates, as well as when to consider a drug holiday.

Bisphosphonates are the mainstay of therapy for osteoporosis, said Dr. Greenspan, a professor of medicine at the University of Pittsburgh. In 2008, guidelines from the National Osteoporosis Foundation stated that if a T-score was −1 or higher, patients had normal bone mass and didn't require treatment. A score of −2.5 or worse indicated osteoporosis, which did require treatment. The patients in between were classified as having osteopenia or low bone mass. “They are often the ones that you see the most of,” she said.

This year, the National Osteoporosis Foundation updated its “Clinician's Guide to Prevention and Treatment of Osteoporosis,” available online. In the new paradigm, a patient should receive bisphosphonates even without getting a bone density test if he or she had a vertebral or hip fracture. Patients also qualify for bisphosphonate therapy if they have a 3% or greater risk of hip fracture or a 20% or greater risk of any major osteoporotic fracture in the next 10 years.

“Patients don't have to have both,” Dr. Greenspan said. “It's one or the other. These are suggested guidelines. If you decide you want to treat the patient and they don't quite meet the guidelines, that's up to you. If you don't want to treat your patients and they meet the guidelines, again, that is up to you.”

In addition, the FRAX tool, readily available online and as an app, can provide internists with helpful information on osteopenic (low bone mass) patients, Dr. Greenspan said.

She described FRAX as a “handy algorithm” that gives doctors the 10-year probability of a major fracture, based on highly individualized criteria. The algorithm takes into account age, gender, country, race, smoking and alcohol use, use of corticosteroids, rheumatoid arthritis, and bone mineral density.

Dr. Greenspan said, “The nice thing is that it's individualized for your patient ... her height, her age, her risk factors, her medications. It gives you the individual risk.”

There are differences among the bisphosphonates, Dr. Greenspan continued. All drugs in the class work by binding to bone and also by interrupting an important cholesterol-building pathway in the osteoclast, the cell that reabsorbs bone. But no two drugs have the same efficacy for either mechanism.

“This accounts for some of the differences we see in the fracture reduction, but also the ability we see to reduce bone turnover markers or improve bone density in the clinical trials,” Dr. Greenspan said.

For example, she continued, zoledronic acid binds most tightly to bone, followed by alendronate, ibandronate and risedronate. For blocking cholesterol formation during reabsorption, alendronate has the strongest effect, followed by ibandronate, risedronate and zoledronic acid. This results in a range of bone density improvements and a range of hip fracture reductions. Other differences in clinical trial results are due to differences in the inclusion and exclusion criteria of the patients enrolled.

On average, in a three-year time frame, bisphosphonates increased spine bone density about 5% to 8%, increased hip bone density 3% to 6%, and reduced vertebral fractures by 40% to 70%. Alendronate, risedronate and zoledronic acid reduced nonvertebral fractures and hip fractures, but it is very important to know that ibandronate generally does not, Dr. Greenspan said. However, a post-hoc analysis found nonvertebral fracture reduction with ibandronate within a high-risk subgroup that included women who had a T-score less than −3.0 at baseline, she added.

A variety of side effects have become important, Dr. Greenspan said. While randomized, controlled trials during bisphosphonates' clinical approval processes did not reveal any increase in upper gastrointestinal events or complaints, real-world results produced a significant number of side effects, including heartburn.

Eventually, the FDA issued a class warning that arthralgias, myalgias, and bone and joint pain can occur at any point during treatment. Bisphosphonates can exacerbate patients' hip and knee arthritis. There's also an influenza-like symptom that occurs after the first monthly oral dose or after the first IV doses, Dr. Greenspan noted.

“And there's a class warning about jaw osteonecrosis and atypical fractures of the femoral shaft. Those two seem to be of the greatest concern for physicians and certainly for our patients,” said Dr. Greenspan. It is worrisome enough (and reported commonly enough on the Internet) to lead patients to ask for a drug holiday. And that's OK to consider, she said.

For low-risk patients, if bone mineral density is stable or increasing, consider a drug holiday of one to two years after five years of treatment, and restart the drugs if bone mineral density declines or a fracture occurs. In high-risk patients (those with fractures, those taking glucocorticoids, or those with very low bone mineral density), consider a drug holiday at 10 years and then restart the drugs even if bone mineral density is stable.

Patients can take teriparatide or raloxifene during the drug holiday. Alternatively, high-risk patients may continue on bisphosphonate therapy. But, Dr. Greenspan added, drug holidays are a “a data-free zone. We don't have a lot of hard data on what we're doing with these holidays.”

She did cite a few studies that offer some insight on the effects of bisphosphonates. Analysis of a very large database of 90 million U.S. inpatient hospital records from 1997 and 2007 found that hip fracture rates decreased about 32% during that time. Meanwhile, in a large-scale national household survey, bisphosphonate use increased from 3.5% to 16.6% in noninstitutionalized women. When researchers looked at atypical fractures, they suggested that for every 100 hip fractures prevented, there was one atypical fracture observed.

A large study in Canada found that among nearly 2,000 women age 68 and older taking bisphosphonates between 2002 and 2008, atypical fractures occurred in only 71 patients after one year and 117 patients after two years. Researchers calculated that patients taking bisphosphonates for more than five years had a 2.7 times higher risk of an atypical fracture but a 25% decrease in their risk of a typical fracture, Dr. Greenspan said. Many other studies have suggested similar results, she added.

Dr. Greenspan also pointed out that jaw osteonecrosis is extremely rare, ranging from 1 case in every 1,000 patients to 1 in 100,000. Most cases occur in patients who have had cancer, who were on a high-dose IV bisphosphonate or who had an invasive procedure for their jaw such as an implant. It does not generally occur after getting teeth cleaned, having a filling fixed, or getting dentures repaired, Dr. Greenspan said.

“Originally dentists and oral surgeons were treating it very aggressively,” she said. “Now, most of the time it heals on its own just with conservative management. Antibiotics help if an exposed area becomes infected, she added.

“What do we do when the patient comes to you and says, ‘My dentist will not work on my teeth, will not put that implant in, will not pull that tooth, unless I stop the bisphosphonate?’ What do you do? You stop it so the patient can have the dental work done,” Dr. Greenspan said. Bisphosphonates stay in bone for years—they recycle themselves, in a way—and the benefit of the drug continues even if the patient stops it for the three or six months that the dentist requests. Dr. Greenspan said the American Dental Association now states in its guidelines that continuing or halting a bisphosphonate should be based on skeletal health, not dental health.

Often, patients ask how often side effects might occur before deciding to take a drug holiday from bisphosphonates. “And it turns out that their risk of a fracture is much, much more common than either of these other two events,” she said.

Depending on individual risk factors, a patient might have the same chance of being in a fatal motor vehicle accident as she does of experiencing an atypical fracture, Dr. Greenspan noted. And while her chances of being murdered in the next 10 years could be around 0.06%, chances for osteonecrosis of the jaw might be 0.007%. “This is really not something for her to worry about,” Dr. Greenspan said.