Avoid Drug-Related Injury

One Way to Avoid a Drug-Related Injury

It can take years to learn the full range of serious adverse reactions to prescription drugs. That point was driven home last month when, in one issue of the journal Archives of Internal Medicine, several studies revealed new-found harms. The popular diabetes drugs, Actos and Avandia, increase the chance of having a fracture. Fosamax and other drugs in the class known as bisphosphonates, widely prescribed for osteoporosis since 1995 to prevent fractures, can cause an irregular heartbeat called atrial fibrillation. And postmenopausal hormone drugs, once aggressively urged for all women over 50 to prevent heart attacks and strokes actually cause strokes in some women, regardless of the type of hormone regimen or when it was started.

You get the picture: the drugs taken to prevent one major health problem can often cause another. The editorial that accompanied these new studies offered the excellent suggestion that doctors should quantify the benefits and risks so their patients can fully understand what they are getting into once they are told to go on long-term drug therapy. If, say, a bone drug helps only one in 100 women avoid a hip fracture and the same drug causes a potentially fatal atrial fibrillation in one in 100, then it’s a wash.

Jerry Avorn, MD, and William H. Shrank, MD, Harvard Medical School, offered a more immediate suggestion for avoiding drug-related injuries that targets people over the age of 65 years, the group with a high prevalence of adverse drug reactions. In a recent issue of the British Medical Journal, Avorn and Shrank wrote, “When an elderly person experiences an adverse drug reaction, it may be mistakenly attributed by the patient or doctor to a new disease or (even worse) the aging process itself. Examples include the parkinsonian side effects of many antipsychotic drugs and the fatigue, confusion, or depression-like symptoms that can result from excessive use of heavily marketed psychoactive drugs.”

Avorn and Shrank go on to describe what they called an opportunity for “total cure” by stopping the offending drug or lowering its dose. “In our own practices we have often seen patients on a seemingly inexorable trajectory towards institutional care whose functional capacity was restored by thoughtful reassessment of their drug regimens. This has led to the useful if overstated recommendation that any new symptoms in an older patient should be considered a possible drug side effect until proved otherwise.”

Maryann Napoli, Center for Medical Consumers ©
May 2008

Osteoporosis: Many Drugs Prescribed, Not So Many Hip Fractures Avoided

Fracture prevention is focused on bone density, but other factors like bone quality and muscle strength are also important, according to a recent commentary by two Toronto physicians for the Journal of the American Medical Association. They advocate a broader view of osteoporosis prevention but first, here is an historical context for this disease that has become a major health concern for women.

Osteoporosis was unknown to the public until the 1980s. The disease used to be diagnosed in the elderly only after a “fragility fracture” had occurred. But a new definition, based on bone mineral density, was established in 1993 at a World Health Organization meeting of osteoporosis researchers. Soon bone scans became a must for all women over age 50.

In 1995, the first non-hormonal drug to prevent osteoporotic fractures—Fosamax—came on the market. Its manufacturer, Merck, sponsored an aggressive ad campaign initially aimed at doctors, featuring a woman who looked no more than 45 and this message: “Don’t wait for a fracture.” Merck’s ads aimed at women simply told them to “ask your doctor whether a bone density test is right for you.” Chances are high that widespread use of bone scans would identify many women as having bone loss. The first step toward a drug prescription.

Many middle-aged women who had never had a fracture were put on Fosamax. It is unlikely that they were told that the drug had been tested only in elderly women who already had a fracture, and the results were unimpressive. After three years, hip fractures occurred in 1% of those on Fosamax, compared with 2% of those on a placebo. (A 50% reduction in hip fracture!” screamed some of the ads.) In time, another “condition” called osteopenia, or pre-osteoporosis, was created by drug makers. By then, other drug companies had introduced their own Fosamax knockoffs like Actonel, Boniva, Reclast, Zometa, etc. All are in the same drug class called bisphosphonates.

Drug prescribing is clearly tied in with bone mineral testing, but the now-popular scanning technique known by the acronym DEXA is not good at predicting which women in their early 50s will have a hip fracture at age 80 years, when it would most likely occur. This was the conclusion of a 1998 report from the British Columbia Office for Health Technology Assessment. The report was ignored in the U.S. where Merck was financing the installation of DEXA machines in doctors’ offices.

In 2005, The Seattle Times published an investigative series of medical articles. The in-depth report on the selling of osteoporosis revealed that two multi-national pharmaceutical giants had financed that 1993 World Health Organization meeting. (Ostensibly, the meeting was about a multi-country study of the prevalence of osteoporosis.) The pharmaceutical funding of this WHO meeting sheds new light on the revised definition of osteoporosis. What had been simply a risk factor (bone loss) became a disease (osteoporosis) at that meeting, where an arbitrary definition of bone loss was also created. Overnight, the number of potential customers for bone drugs had been expanded greatly.

The story of Fosamax and its knockoffs perfectly illustrates how the pharmaceutical industry starts creating a market for a new drug years before it is approved. First industry must sell you fear of a disease, then comes the drug to “prevent” its most serious consequences.

Today, the guidelines for bone density measurement recommend testing not begin before age 60, but now there’s a bigger problem Researchers have known, at least since 2000, that bone strength or bone quality are better predictors of hip fracture than bone density. In 2001, the National Institutes of Health redefined osteoporosis as a combination of bone mineral density and bone quality. But here’s the rub: There is no test for bone quality or bone strength.

In their recent commentary for the Journal of the American Medical Association, the Toronto physicians, Angela M. Cheung, MD, and Allan S. Detsky, MD, said that bone density and bone quality are just two of many factors to be taken into consideration for fracture prevention—in addition to the usual advice about calcium intake, vitamin D, exercise, smoking cessation and reducing alcohol intake. They call for more research into the reasons why elderly people fall, such as oversedation with prescription drugs, orthostatic hypotension (low blood pressure upon standing), impaired gait or balance, poor eyesight and hearing, arthritis, etc. They also want more attention given to tai chi exercises to improve balance and muscle strength. Research for fracture prevention should move beyond the realm of endocrinologists and rheumatologists to include neurologists, physiatrists, physiotherapists, engineers and muscle activation therapists.

Where can someone with osteoporosis find an engineer or a muscle activation therapist? “At an osteoporosis center based at an academic medical center,” answered Dr. Cheung in a telephone interview. “We have much to learn from these folks, and we need to engage in a dialogue with them to help people reduce their fracture risk.” Dr. Cheung, who is at the University Health Network and Mount Sinai Hospital in Toronto, was asked why she still sees a role for bisphosphonates when the trials cited in her commentary had such negative findings. [“…in two well-designed randomized controlled trials in which high-risk elderly people without fracture but low bone mineral density, treatment with bisphosphonates did not decrease the risk of hip fractures.”] “These drugs are not just for hip fractures, but for overall fractures,” she answered, citing the example of her patients who have difficulty eating because the rib cage has collapsed due to spinal fractures. She also praised a 2007 study by Black and colleagues, which showed that hip fracture can be reduced with a more potent bisphosphonate given intravenously to participants, aged 70 to 90 years. [Note: This study showed only a 1% difference between the drug-treated and the placebo groups in terms of hip fracture reduction.]

Unfortunately, the current TV ads for this intravenous once-a-year bisphosphonate drug are conveying the same misleading message shown in the early ads for Fosamax. They feature a thin, fit 60ish woman—far younger than those who participated in the clinical trial.

Maryann Napoli, Center for Medical Consumers ©
April 2008

FDA Alert about Osteoporosis Drugs

The FDA posted an alert on its Web site, “…highlighting the possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates. Although severe musculoskeletal pain is included in the prescribing information for all bisphosphonates, the association between bisphosphonates and severe musculoskeletal pain may be overlooked by healthcare professionals, delaying diagnosis, prolonging pain and/or impairment, and necessitating the use of analgesics.”

Bisphosphonates are a popular class of drugs prescribed to reduce the risk of fractures from osteoporosis. The alert applies to all drugs in this class, including Fosamax, Boniva, Actonel, Aredia and Didronel. The FDA reports, “The severe musculoskeletal pain may occur within days, months, or years after starting a bisphosphonate. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution.”

WWW.FDA.gov/medwatch/safety, 1/7/08

Heartburn Drugs & Hip Fractures

Heartburn Drugs Linked to Hip Fractures

An increased incidence of hip fracture is associated with long-term use of the top-selling heartburn drugs like Nexium, Prevacid, and Prilosec. People on high doses of these prescription drugs called proton pump inhibitors (PPI) were the most likely to experience a hip fracture if they stayed on them for more than a year. This finding was published at the end of 2006 in the Journal of the American Medical Association.

PPIs are potent drugs that suppress stomach acid. Their long-term use is often advised as a preventive against the gastrointestinal bleeding that can occur with chronic use of drugs like aspirin and other non-steroidal, anti-inflammatory drugs taken regularly by people with arthritis and other chronically painful conditions.

PPIs are also heavily marketed for gastroesophageal reflux disease, otherwise known as frequent or severe heartburn, which occurs when stomach acid flows up into the esophagus causing a burning sensation in the chest and throat. Other PPIs include omeprazole (brand names: Losec, Zegerid), lansoprazole (Zoton, Inhibitol), pantoprazole (Protonix, Pantoloc), and rabeprazole (Rabecid, Aciphex).

For the new study that found a link between hip fracture and long-term PPI therapy, Yu-Xiao Yang, MD, and colleagues at the University of Pennsylvania, drew on the computerized medical record system in the United Kingdom. Their search was confined to the records of people older than 50 years who had been treated by their general practitioners between 1987 and 2003.

Users of PPI drugs and non-users were separated into two groups. There were 13,556 hip fracture cases in the database, which were compared to the medical records of a similar number of older people who did not suffer a hip fracture. The average age of the people in this study was 77 years. The findings confirm those of a similar study conducted in Denmark.

Dr. Yang and colleagues found that the odds of having a hip fracture increased with the duration of PPI therapy. A regular dose of PPI therapy for over one year was associated with a 44% increase in hip fracture risk; the risk of hip fracture among those on high-dose PPI therapy for more than one year was 2.6 times higher compared with those who never took PPIs.

In a telephone interview, Dr. Yang was asked for a rough estimate of what that means to the individual on long-term PPI therapy. “For every 336 people who took high doses of the drugs for more than a year, there was one extra hip fracture a year attributable to the drug,” he responded, stressing that this is just an extrapolation and the frequency would differ according to each person’s baseline risk of having a hip fracture without taking a PPI. It is difficult to be precise, Dr. Yang explained, because people in our study were on widely differing doses.

“PPIs are the best, most potent drugs in controlling [stomach] acid,” said Dr. Yang who is a gastroenterologist and assistant professor of medicine and epidemiology at the University of Pennsylvania. “They have saved people’s lives. People with ulcer disease can die from bleeding ulcers,” he said. “Their risks—hip fracture, pneumonia—can only be teased out after people begin using them for many years, and it has been 15 years since PPI first came on the market.” [A link between PPI use and pneumonia was found in a similar study conducted in The Netherlands.]

Though long-term PPI therapy is often needed, the clinical trials required by the FDA before the drugs went on the market usually last only several months and 6-12 months at the longest. The written information, produced by the drug company with FDA oversight and aimed primarily at physicians, clearly advises short-term use. In the case of Nexium for the “healing of erosive esophagitis,” the drug should be limited to no more than four to eight weeks of treatment. As for the use of Nexium to reduce the risk of drug-induced gastrointestinal damage, “controlled studies do not extend beyond six months,” according to the FDA-required written information. In the case of Prevacid, the FDA-required trial for this usage lasted only 12 weeks.

How can people protect themselves from the adverse effects of long-term PPI therapy? “Determine whether you are benefiting from the drug,” suggested Dr. Yang. “If you can get by with a lower dose, then do it.” But if you need a high dose, say, to prevent gastrointestinal bleeding from regular use of a non-steroidal, anti-inflammatory drugs [e.g., aspirin, ibuprofen and Celebrex], then make sure you’re getting enough calcium in your diet, or with a supplement called calcium carbonate, and vitamin D3. Take the supplements with a meal because if you take them on an empty stomach, they won’t be absorbed. Calcium malabsorption is what we think is the mechanism [for the increase in hip fracture among the people on long-term PPI therapy].” The men in this study on long-term PPI therapy had about twice the risk of hip fracture as did the women. Dr. Yang and colleagues could only guess at the reason—women are more likely to take regularly calcium supplements once they pass menopause.

The study was funded by the National Institutes of Health and the American Gastroenterological Assn./GlaxoSmithKline Institute for Digestive Health. GSK makes several calcium carbonate products.

Maryann Napoli, Center for Medical Consumers ©
February 2007

Postmenopausal Hormones: An Update

Postmenopausal Hormones: An Update
by Maryann Napoli

Postmenopausal hormones have been promoted to women (and doctors) for nearly four decades with promises of everything from youthful skin to increased longevity. The currently popular indications-prevention of heart attack and hip fracture-are not supported by good research. Two large trials, which randomly assigned women to take hormones or not, have failed to confirm estrogen’s heart protective effects. And while many randomized controlled trials (RCTs) have proven estrogen’s ability to stop the loss of bone density, none lasted long enough to show that this hormone actually prevents fractures.

Estrogen is still prescribed to women as a treatment for osteoporosis (bone loss), though the Food and Drug Administration removed this indication in 1999 because of lack of evidence. Only one indication for taking hormones is backed up with good research support-the relief of menopausal symptoms, such as hot flashes.

The two large RCTs, which provided the heart-related results, are the Women’s Health Initiative (WHI) and the Heart and Estrogen/Progestin Study (HERS). Together they included about 30,000 participants. The HERS was designed to determine whether hormones can prevent heart attacks in women, aged 44 to 79 years, who have heart disease. And the WHI, which includes healthy women, aged 50-79 years, is exploring the effects of hormone therapy on the prevention of heart disease and osteoporosis-related fractures, and on the risk of breast and uterine cancers. All participants had been randomly assigned to take a placebo (inactive pill) or hormones (estrogen alone for women who had a hysterectomy or estrogen plus progestin for women with an intact uterus).

The data from these and other RCTs are being searched for information about a range of health effects associated with hormone therapy:

Cardiovascular Events: Both the HERS and the WHI found a small increase in the number of heart attacks, strokes, and blood clots in the lungs in the first one to two years of hormone use. Researchers initially thought that this small risk (fewer than 1% altogether) would disappear after two years, but longer follow-up showed otherwise. Last year, the WHI reported a continued increase in heart attacks, strokes, and blood clots in women taking hormones.

Prevention of Another Stroke: Among 652 women (mean age 71 years) who had suffered a non-disabling stroke or a transient ischemic attack, those who had been randomly assigned to take oral estradiol did not show a lower incidence of death or stroke. Worse, the rate of fatal stroke was significantly higher among those taking estradiol (a form of estrogen).

Fractures: The WHI is designed to answer the question of whether hormones prevent fractures, following its participants for eight to 12 years.

Urinary Incontinence: 1,525 women with urinary incontinence participated in the HERS. All were younger than 80 years and had experienced at least one episode of urinary incontinence per week. Incontinence improved in 26% who had been assigned to take a placebo for four years, as compared with 21% assigned to take hormones. Urinary incontinence worsened in 27% of the placebo group, as compared with 39% of the hormone group.

Dry Eye Syndrome: 665 participants of Women’s Health Study, a RCT that began in 1992, found a slight increased incidence of dry eye syndrome in hormone users (past and current), especially among the women on estrogen alone. According to questionnaires completed by the participants: 9% of those taking estrogen alone reported severe symptoms diagnosed by physician, as compared with 7% among the estrogen plus progesterone or progestin, and 6% among those who never used hormones. Dry eye syndrome, a condition with no effective treatment, can damage the surface of the eye.

Urinary Tract Infection: Women in the HERS who had been randomly assigned to take hormones for four years did not have a lower incidence of urinary tract infections.

Gallbladder Disease: The HERS showed gallbladder disease to be 38% higher among those who had been assigned to take estrogen/progestin therapy.

Annoying “Minor” Side Effects: Breast tenderness with uterine bleeding caused 30% to stop taking hormones by the end of one year.

What’s Wrong With Observational Studies?

Many benefits attributed to hormones, such as prevention of Alzheimer’s disease, have yet to be validated in an RCT. Such information comes from less reliable research, known as observational studies. Such research takes a backward look at women who chose to take hormones to determine whether their health status differs from that of women who did not take hormones.

The problem with observational studies is this: Women who take hormones tend to be upper income and well educated. Both characteristics are associated with better heart health and longevity. Susan Love, MD, author of Dr. Susan Love’s Hormone Book, identified the problem: “We don’t know whether hormones made the women healthy, or whether healthy women take hormones.” It is the observational studies that misled so many gynecologists to believe that estrogen prevents heart disease.

An RCT provides more trustworthy results because participants of similar age, health status, etc, are randomly assigned to take the drug or not. Then they are followed for years. Most RCTs are double-blind, which means that neither the participants nor the health professionals monitoring them know who is on the placebo and who is taking the active drug.

Benefits and Risks Yet to Be Confirmed:

Colorectal Cancer: Observational studies have produced inconsistent findings regarding the possibility that hormones lower the risk of colorectal cancer. The results range from no reduction to a 33% reduction in colorectal cancer.

Cognition: Observational studies suggest that hormone therapy may reduce the risk of cognitive decline. A systematic review of all studies, including some RCTs, that explored this topic was published last year in the Journal of the American Medical Association. The participants, who had been taking hormones for the symptoms of menopause, showed improvements in “verbal memory, vigilance, reasoning, and motor speed, but no enhancement in other cognitive functions.” The authors went on to explain that most of these studies had significant limitations.

Alzheimer’s Disease: No RCT has been conducted regarding the risk of dementia. Earlier observational studies suggest that women taking hormones were less likely to develop Alzheimer’s disease, but more recent observational studies did not find this benefit.

Breast Cancer: Does estrogen use increase the risk of developing breast cancer? More than 30 observational studies have been conducted to answer this question. But, here too, the results have been inconsistent. Some found estrogen use to be associated with a reduced risk of developing breast cancer; others found an increased risk of breast cancer beginning after five years of use. And some studies found no risk. The WHI has been designed to provide a reliable answer to the question of whether there is an association between estrogen and breast cancer.

Endometrial (uterine) Cancer: Ever since it became known that estrogen increases a woman’s odds of developing uterine cancer, the drug is now prescribed with another hormone, progestin, to women with an intact uterus. Not all doses of progestin protect the uterus, however. For the results of a review of all trials that determined appropriate doses, see “Protecting the endometrium” by Gibbons and Thorneycroft in the Journal of Reproductive Medicine (2/99).

For More Information About the WHI:

The Women’s Health Initiative is sponsored by the U.S. National Heart, Lung and Blood Institute. Visit its Web site at www.nhlbi.nih.gov/whi/hrt/htm for more information about the progress of this trial.

(March 2002)