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Warning on bone drugs: stop after 5 years

Posted by medconsumers on September 23, 2011

First, a trip down memory lane on the use of bone drugs for the prevention of hip fractures. It is now 16 years since Merck’s widely prescribed Fosamax went on the market. In time, it was prescribed inappropriately to women with so-called “pre-osteoporosis” or osteopenia (yet-another drug maker invented “disease”). It was also prescribed inappropriately to women in their early 50s, thanks to Merck’s marketing strategies that made us think we would start crumbling inside right after menopause. Then came the reports of osteonecrosis of the jaw and spontaneous thighbone fractures in some women on Fosamax. And now, the latest bulletin on Fosamax and its knock-offs like Actonel, Reclast, and Boniva: If you have been on one of these drugs for five years, stop taking it.

What has happened to send out word that five years is enough and longer would be too risky? Two things: a paper by bone physiologist Susan Ott, MD, in the Cleveland Clinic Medical Journal published this month and the recent announcement that two FDA advisory panels will conduct a comprehensive safety review of the research supporting the use of these drugs called bisphosphonates.  As noted often on this website: drug makers conduct the FDA-required studies of their own products; a new drug’s effectiveness is carefully studied to determine whether it is better than nothing, i.e., a placebo; and the full story on a new drug’s adverse reactions comes many years later, if at all.

Members of the FDA advisory committee that met early this month agreed that a time limit should be put on the duration of bisphosphonate therapy, but they could not agree on what that time limit should be. Anyone currently on a bisphosphonate drug should not wait for the FDA; and instead, go with Dr. Ott’s advice to stop taking the drug after five years. Her newly published paper entitled, “What is the optimal duration of bisphosphonate therapy?” is an in-depth assessment of all studies in which one of these bone drugs was compared with a placebo, as well as observational studies. Here is her conclusion:

Almost all the data about the safety and efficacy of bisphosphonate drugs for treating osteoporosis are from patients who took them for less than 5 years. Reports of adverse effects with prolonged use have caused concern about the long-term safety of this class of drugs. This is particularly important because these drugs are retained in the skeleton longer than 10 years, because there are physiologic reasons why excessive bisphosphonate-induced inhibition of bone turnover could be damaging, and because many healthy postmenopausal women have been prescribed bisphosphonates in the hope of preventing fractures that are not expected to occur for 20 to 30 years.

As someone who regularly visits Dr. Ott’s website (see below), I know that she has long been a supporter of appropriate use of bisphosphonates. The reason was given in her newly published paper: These drugs “reduce the incidence of devastating hip fractures”

I’ll stop quoting Dr. Ott right here to explain the operative words in her statement: reduce the incidence. This careful choice of words that is unlikely to be explained by many prescribing doctors. Consequently, many women go on bisphosphonate therapy mistakenly thinking they will not a have hip fracture. In truth and at best, only a small percentage of women who go on three to five years of bisphosphonate therapy will avoid a fracture.

One of the first important clinical trials to compare Fosamax with a placebo is the FLEX trial.  After four years the FLEX trial found that 1.1% of the women in the placebo group had a hip fracture and 0.9% of the women taking Fosamax. Yes, that tiny fraction of a difference between taking Fosamax and going without treatment is what osteoporosis researchers get excited about. (If this described a woman’s chance of developing a serious drug side effect, it would be characterized as “rare.”)

The drugs always look better in osteoporosis studies when the authors throw all types of fracture (hip, forearm, spine, etc.) together. Again, using data from the FLEX trial:   21.3% of women on placebo had any type of fracture, compared with 19.9% of the women on Fosamax.

You might ask: Why haven’t I heard this before? Why do researchers report such findings as “significant”? Answers: Many prescribing doctors themselves don’t understand biostatistics; the word significant—to researchers—means “not due to chance,” the statistics can be trusted. Also, researchers tend to look at things in public health terms: a fraction of a 1% benefit means a lot when an estimated four million women in the U.S. are taking a bisphosphonate.

Back to Dr. Ott, who acknowledges “some emerging evidence of harm after 5 years of bisphosphonate treatment; to date the incidence of serious side effects is less than 1 in 1,000, but the risks beyond 10 years are unknown.” The serious side effects include spontaneous thighbone (femur) fracture, osteonecrosis of the jawbone.

The most obvious candidates for bisphosphonate therapy, according to Dr. Ott, are women whose risk of hip fracture is higher than 3% in the next decade and elderly women who already had compression fractures of the spine or a hip fracture. As for the risks the latter group might suffer, “women with a vertebral fracture have a one-in-five chance of fracturing another vertebra, which is a far higher risk than any of the known [emphasis mine] long-term side effects from bisphosphonate.

She is against prescribing bisphosphonates to women with osteopenia who have not had a fragility fracture, saying this common use is “based on hope, not evidence.”

Maryann Napoli, Center for Medical Consumers©

Related articles
Effectiveness of the bisphosphonates’ fracture-prevention benefit in doubt    click here

Fosamax-induced osteonecrosis of the jaw—more common thant preveiously thought     click here

Spontaneous thighbone fracture—thought to be rare      click here

Susan Ott’s website

Posted in osteoporosis, unnecessary treatment, Women's Health | Tagged: , , , , , , , , , , , , | 2 Comments »

Drugs for bone loss

Posted by medconsumers on April 1, 2011

It’s never fails to amaze me how long a drug can be in use before its benefits and harms are fully understood. This is particularly troubling where it concerns drugs given to healthy people to prevent something that might happen to them sometime in the future. On my mind right now is the bone drug Fosamax prescribed since the mid-1990s to symptomless women with bone loss usually detected on a bone density measurement test.

Concern over the lack of good information about this widely prescribed drug and it multiple knockoffs (Actonel, Boniva, Didronel, Reclast, Aredia) has galvanized several research teams around the world. The impetus is the unusual thigh bone fractures initially reported over six years ago in women taking Fosamax click here. The international researchers analyzed all relevant studies to determine whether these bone drugs “prevent or cause bone fractures”. Their unenthusiastic conclusion: The drugs have “some effectiveness” in preventing vertebral fractures in the short-term (one to three years). Brace yourself for this clarification: Effectiveness is limited to “vertebral fractures demonstrated by x-ray” (translation: tiny symptomless spinal fractures that the women themselves are unaware of). The researchers go on to point out, “The efficacy with regard to preventing hip fractures is uncertain.”

Wait a minute…wasn’t hip fracture prevention the big selling point of Fosamax and its knockoffs? Remember those scary statistics indicating how many of us would die within the year of a hip fracture.

The harms of these bone drugs are usually determined to be rare, for example, the rotting jawbones (osteonecrosis of the jaw) of women given oral surgery while on Fosamax click here. So are the esophageal ulcers and those spontaneous thigh bone fractures we’ve been hearing about for at least five years. Has anyone tallied up all these “rare” harms so they can be weighed against the small, uncertain benefits of bone drugs? The researchers addressed this question, but said, in effect, “Hold off, we still don’t have a good count yet”. In other words, people on one of these bone drugs are participating in one long, ongoing experiment.

Most of the studies, by the way, were done on Fosamax because it has the longest track record. There is no evidence that the other drugs in this class known as bisphosphonates are any safer or more effective because no head-to-head comparison has been done.

In case you’re wondering how these drugs got FDA approval in the first place, the new analysis gives a brief history. Merck, maker of Fosamax, had only to prove its drug increased bone density… on the shaky assumption that this would translate to fracture prevention. (To gain FDA approval, drug makers test their products against a placebo which means they need only to prove their drug is better than nothing.) In time, the aforementioned x-ray evidence of fracture reduction became acceptable proof of a bone drug’s effectiveness. Only a third of the people with vertebral fractures that show up on x-ray have symptoms.

By 2006 long-term data came from a trial, known by its acronym FLEX, that followed women taking Fosamax for three to ten years. The aim of this trial was to determine whether Fosamax can achieve what matters most to women taking this drug: Does it reduce hip fractures? It found no significant difference between Fosamax and placebo in terms of preventing any type of fracture.

And so it goes. This new analysis is available online at Therapeutics Initiative, published by the University of British Columbia (UBC), Vancouver, click here. It is based on the combined findings of the Cochrane Collaboration and other independent groups in France and Spain. The conclusion: “Given that bisphosphonates can cause severe adverse effects including fractures, which they are meant to prevent, it is urgent that the overall benefits and harms of long-term treatment be clarified. The available evidence suggests that the benefit-harm balance may be unfavorable for their use in osteoporosis.”

The UBC research team plans to take it from there and conduct “a full systematic review and critical appraisal of this widely prescribed class of drugs.”

More to consider about these drugs
-If you have no bone symptoms and have decided that you’ll never take one of these drugs, think twice about having your bone density measured. This screening test is all about unproven predictions of who will suffer a fracture after age 70 and directing them to long-term drug therapy.

-If you think you’ve been injured by a bisphosphonate drug, contact the FDA’s Medwatch Program click here.

Maryann Napoli, Center for Medical Consumers©

Posted in osteoporosis, Pain | Tagged: , , , , , , , , , , | 3 Comments »

Bone drugs’ adverse effect found to be very rare

Posted by medconsumers on May 28, 2010

Remember those scary reports of spontaneous thighbone fractures that occurred in some women who were taking fracture-prevention drugs like Fosamax? The bone breaks for no apparent reason. (In one memorable case, a woman said her thighbone broke while standing in a stalled subway train that lurched suddenly.) Such fractures are described as very rare (0.03%), according to a new analysis of the data generated by three large trials. These are the same clinical trials that proved bone drugs like Fosamax and Zometa are more effective than no treatment (placebo) in reducing hip fracture—the most serious complication of osteoporosis. Now the results of these trials were searched solely for the rate of spontaneous thighbone fracture.

It’s a relief to know that this is “a very rare” side effect of osteoporosis drugs. But looking at these trial results again reminds me that their hip fracture prevention benefit is also pretty rare. The first to win FDA approval was Fosamax (generic name: alendronate), produced by Merck. After three years, only 1% fewer drug-treated women suffered a hip fracture, compared to untreated women. The drugs’ effectiveness looks much better when the company-sponsored researchers throw in fractures in other sites—spine, wrist, and forearm. In one osteoporosis research sleight of hand that’s always bothered me, it is common to count a reduction in spinal fractures that are symptomless and can be seen only on X-ray.

But I digress. Back to the spontaneous thighbone fractures and how we now know they are very rare. The three major trials that provided the data for this conclusion had a combined total of 14,195 women randomly assigned to take either a placebo or a bone drug (Fosamax in two trials, Zometa in one). Keep in mind that most of what are called hip fractures are actually breaks in the “neck” of the femur, or thighbone, where it meets the pelvis in the ball and socket joint.

So here’s final count: Of the 284 women who had hip or femur fractures, only 10 had what’s called atypical thighbone fractures. It’s interesting to note how few hip or femur fractures—atypical or not—occurred, considering that the 14,195 study participants were considered to be at high risk for fracture and between the ages of 65 and 80 years when they entered the study. Could it be that this isn’t the biggest health threat we face in old age? Or could it be that the study participants weren’t followed long enough?

This analysis appeared in The New England Journal of Medicine and was funded by Merk and Novartis (maker of Zometa). How long can people safely take this drug is not answered by this analysis. It’s a question that lingers over all bone drugs called bisphosphonates (other brand names: Boniva, Actonel, Reclast). The authors of this analysis conclude that the risk of spontanous thighbone fracture remains rare “even among women treated with bisphosphonates for as long as ten years.” Buried deep in this paper, however, is the fact that few women were followed this long. The majority were followed only three to four years. Women on long-term bisphosphonate therapy are advised to report thighbone pain immediately to their doctors as this was the telling symptom that preceded a spontaneous fracture.

For more information

To determine whether you can benefit from Fosamax or any other bisphophonate drug, see this chart from the Cochrane Collaboration, which is based on the results of the above-mentioned three clinical trials. You will see that women who have been diagnosed with low bone density or who have broken bones in their spines are more likely to benefit than those whose bone density is near normal (osteopenia) or who do not have spinal fractures. click here

Update added April 2011: Read the latest article called “Bisphosphonate drugs—more harm than good?” click here

Visit the Web site of Susan Ott, MD, an expert in bone physiology at the University of Washington, Seattle. Everything from osteoporosis prevention to summaries of the latest bisphosphonate studies.

For background on how osteoporosis became a much-feared disease, read this 2009 article for the American Journal of Nursing, The Marketing of Osteoporosis.

Osteonecrosis of the jaw, another rare side effect of bisphosphonate drugs, was not addressed in the new analysis. For more information, click here.

Maryann Napoli, Center for Medical Consumers(c)

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Posted in Drugs, osteoporosis, Pain, Scans and X-rays, Women's Health | Tagged: , , , , , , , , , | Leave a Comment »