The drug for memory loss

“Is it simple memory loss? … Or is it Alzheimer’s disease?” This was the headline—over the photo of a worried adult—for a pervasive drug ad of yore. It sent chills up the spines of many a middle-aged and older person.  Aricept, a drug for Alzheimer’s disease, quickly became a blockbuster in the U.S. to the tune of $2 billion in annual sales. All the more amazing, considering that Aricept is barely better than a placebo. Well before Aricept’s patent would expire, the company in charge of marketing had to come up with a plan for keeping profits high while fending off generic competition. Pfizer’s plan was simple—just increase the drug’s dosage.  Same useless drug, but a new improved dose!

The story of how Pfizer and Eisai, the company that developed Aricept, managed to pull this off was laid out in last month’s issue of the British Medical Journal.  I confess that when the co-author of this paper sent me a copy, I thought for a minute that I was reading satire (British publications have that effect on me). Somehow I had missed Aricept’s higher-dose ad campaign.

What makes this especially appalling and different from the usual ineffective-drug-makes-billions story, is this: Aricept is for people with a particularly devastating disease whose treatment decisions are usually made by the patient’s relatives who are often desperate for anything that might work.

Approved only months before Aricept was to lose its patent protection at the end of 2010, “The ‘new’ 23 mg product would become patent protected for three more years,” wrote Lisa M. Schwartz, MD, and Steven Woloshin, MD, both of the Center for Medicine and the Media at the Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire, with a long and impressive history of activism on the topic of misleading drug ads.  Why 23 mg?  Answer: Aricept is now available generically (donepezil), but only in 5 mg and 10 mg doses, and there’s no way these two doses can add up to 23.  Got it?

Initially, the U.S. Food and Drug Administration required the higher dose be proven superior to the 10 mg dose.  Eisai, Aricept’s manufacturer, agreed to the FDA’s demand that this be shown for both cognitive and overall functioning. The pre-approval trial of 1,400 patients barely showed improvement in the former and failed completely on the latter. Yet Aricept 23 mg received the FDA’s approval anyway.

Drawing from the FDA’s own publicly available documents, Drs. Schwartz and Woloshin found that Aricept 23 mg had been approved over the objections of the FDA’s medical and statistical reviewers. Russell Katz, director of the FDA’s Division of Neurology Products, who initially required the higher dose be proven superior on two measures, inexplicably, chose to reverse himself. “In my view, this strongly argues for a conclusion that the 23 mg does is very likely to also have an effect on overall functioning, despite this not having been demonstrated directly in this study…I believe that the sponsor has demonstrated that the 23 mg dose of Aricept is effective…I will approve this application.”

Russell Katz also went on record ignoring his own alarming assessment of the 1,400-person pre-approval trial: “There is a clear increase in the incidence of adverse events on the 23 mg dose compared to the 10 mg dose…These are not trivial events; in these patients, these could lead to significant morbidities and even increased mortality.”

All Pfizer and Eisai needed from then on was an immense marketing budget. Nurse educators were sent to the heavy-duty prescribers—neurologists at high-volume long-term care facilities. The sales pitch: “There are no ‘stable’ Alzheimer’s disease patients—therefore aggressive treatment is required.”

The Aricept 23 mg ads aimed at consumers relied primarily on visuals—shots of loving caregivers with a spouse or parent with Alzheimer’s disease and this implied message: Truly caring people would ask their doctors for Aricept 23 mg for their loved ones.  The ads say that the drug improves cognitive symptoms but not overall functioning, wrote Drs. Schwartz and Woloshin.  “But there is no explanation of why that matters.”  Side effects are mentioned without any information about how serious or frequent they can be.

The ad aimed at doctors is worse, according to Drs. Schwartz and Woloshin, because it contains “a stunningly erroneous statement in a large bold font: ‘Patients on Aricept 23 mg/day experienced important clinical benefit on both measures [cognitive and overall functioning]’.  “Worse, this statement is directly contradicted in smaller plain font that says ‘the results for global function did not show statistical significance’.”

Drs. Schwartz and Woloshin were shocked to find that this erroneous statement also appears on the Aricept’s label [the detailed information aimed at health professionals], “This study showed that patients on 23 mg per day experienced important clinical benefit on both cognitive and global measures (overall functioning).

Will the two companies get away with the deceptions? The stats are only just coming in. More than 68,000 prescriptions were written for Aricept 23 mg in the first six months after approval. The only bright spots in this saga are Drs. Schwartz and Woloshin, who have outdone themselves in exposing this particularly cruel drug industry deception. They have perfectly illustrated the M.O. for many big drug companies:  Why waste money developing a drug that actually works when profits can stay steadily high with one that doesn’t?

Maryann Napoli, Center for Medical Consumers©

A new take on bone density retesting

Screening creates drug customers. Keep this little-known consumer beware maxim in mind when you read the new finding about bone density retesting.  Frequent screening bone scans, starting in early middle-age, have been the norm ever since osteoporosis was discovered in the 1980s. (Believe me, no one ever heard of osteoporosis before then, other than the few health professionals who cared for people of advanced old age.)  The new study shows that women whose first test at age 67 indicates normal bone density can safely delay having a second test for as long as 15 years.  There was a time, not so long ago, when women were advised to start bone density testing right after menopause. But then again, there was also a time when the diagnosis of osteoporosis was not made until a person suffered a fragility fracture.

Before I describe the new study, an historical context is in order. Merck, maker of the first osteoporosis drug, may also have been the first company to establish a winning “formula” for blockbuster drugs: 1) lower the cutoff point for the diagnosis of osteoporosis, better yet, fund a meeting in a beautiful place (like Italy) of high-profile osteoporosis researchers (aka, hired “consultants”) who will do it for you; 2) mount an “osteoporosis awareness” campaign to scare women into thinking the risk of hip fracture starts soon after menopause; 3) expand your market share with frequent mention of a new “disease” called osteopenia, a diagnosis that can be given to anyone who almost has osteoporosis; 4) encourage use of a new screening technology for identifying “at risk” women, and do it with an ad campaign that doesn’t mention your drug so it looks educational; 5) provide financial incentives to doctors who want to purchase screening equipment for their offices; 6) introduce your new drug Fosamax, which received FDA approval in 1995 and soon became a top-selling drug worldwide, despite its minimal effectiveness in reducing the chance of having a hip fracture (1%).  For more, read “The Marketing of Osteoporosis.”

Now for the study that appeared today in The New England Journal of Medicine. It followed nearly 5,000 women, 67 or older, with normal bone density at the hip and no history of hip or spinal fractures, or osteoporosis treatment. The research team led by Margaret L. Gourlay, MD, University of North Carolina, took off from the current advice that women should start having bone-density tests at age 65. This study was designed to determine how long it took for osteoporosis (defined as bone mineral density T score, −2.50 or lower) to develop in women with normal bone density or osteopenia.

The women were followed for 10 to 15 years. The findings were unexpected, according to Dr. Gourlay, who told the New York Times that she and her colleagues were surprised by how slowly osteoporosis progressed. Osteoporosis developed in fewer than 10% of the women who started the study with normal bone density and in fewer than 10% who had either “mild or moderate osteopenia.”  (And I was surprised that the New England Journal of Medicine would allow researchers to use the industry-created term osteopenia.) In summary, women with normal bone density or “mild osteopenia” at age 67 can safely delay having a second bone density test for 15 years.

I hope that word gets out to women about this study because it should cut back on the overuse of bone-density tests, as well as the overuse of Fosamax and other drugs in the same class called bisphosphonates (e.g., Boniva, Actonel, etc.). The test was initially portrayed to women and doctors as predictive of who is likely to suffer a hip fracture.  But Canadian consumer advocate Barbara Mintzes, University of British Columbia, had a more realistic take on this claim over ten years ago: “Bone mineral density testing is a poor predictor of future fractures, but an excellent predictor of start of drug use.” The overwhelming majority of hip fractures, by the way, occur after the age of 70.

Something to think about: Most medical research is now funded by industry, particularly the companies that make drugs, devices, and testing equipment. This study was funded by the U. S. National Institutes of Health.

For information about these serious adverse events associated with these drugs, read “Drugs for bone loss.”   And read this to learn why women should stop taking them after five years.  And here is Dr. Susan Love’s description of how bisphosphonate drugs work and why no one should be surprised that they are causing problems.

This post has been revised to reflect the following correction, added January 21, 2012.

The first version of this article, posted January 19, misstated the conclusion of this study.  The authors did not specify when women should be retested.  The original title of this post and the post itself have been changed accordingly.

Maryann Napoli, Center for Medical Consumers(c)

Whistleblower’s story: New book reviewed

“Blood Feud: the man who blew the whistle on one of the deadliest prescription drugs ever” (NY: Dutton, 2011)  by Kathleen Sharp 

This is the true story of an expensive anti-anemia drug that came on the market for one purpose; was heavily promoted for several unproven uses; and how the drive for profits led two drug companies to commit fraud. Kathleen Sharp, a veteran investigative reporter, describes what happened from the perspective of a drug salesman whose company pressured him into achieving higher and higher sales targets. The drug maker provided a playbook of tactics known to manipulate physicians into writing more prescriptions and at higher, more dangerous, doses. Eventually, the drug salesman-turned-whistleblower comes to the horrifying conclusion that over a half a million people have died as a result of this drug. Its benefits, if any, remain unclear; its safety never established.  It is still on the market.

Central to the story is one of the first biotech drugs to go on the market. Erythropoietin is the man-made version of human erythropoietin, which is produced naturally in the body and stimulates the bone marrow to make red blood cells. Epo, as it is called, became known as a “blood booster,” sold by Amgen and Johnson & Johnson under the brand names: Procrit, Epogen, Aranesp, and Eprex (Europe).

Epo received FDA approval in 1989 to reduce cancer chemotherapy patients’ need for blood transfusions after it became known that the nation’s blood supply was infected with the HIV virus. In time, epo would be heavily promoted as an instant cure for chemotherapy-related fatigue and for anemia in kidney dialysis patients. (Disclosure: I am quoted in the book, speaking before the FDA Oncologic Drug Advisory Committee against J&J’s fraudulent direct-to-consumers advertising campaign for Procrit.)

The whistleblower ‘s story begins in 1992 when Mark Duxbury became a Procrit sales rep at J&J’s new biotech division, Ortho. Initially, Duxbury believed that he was selling an important quality-of-life enhancing drug for cancer patients suffering the debilitating effects of chemotherapy. Procrit, so he thought, would allow them to complete the treatment regimen.

The methods used by J&J to get its sales reps to turn Procrit into a blockbuster drug make for fascinating, though appalling, reading. Doctors were easily manipulated into prescribing more epo with rebates, secret discounts, honoraria, and other kickbacks.  In time, the entire Procrit sales force was encouraged by J&J to break the company’s own product license agreement with its partner Amgen. This agreement stipulated that J&J would stay away from the kidney dialysis market. (Amgen, maker of Aranesp, was the start-up company that did the original epo research.)

By 1993 Duxbury was a company award-winner for the greatest overall growth in sales in the western region of the U.S. He was rewarded with a higher income and an all expenses paid trip to a luxury resort. Still, J&J didn’t let up on the pressure to increase sales, making Duxbury conclude that the only way to meet his escalating quota was to “steal dialysis business”.

Doctors were encouraged to prescribe Procrit in high doses, particularly for cancer patients, because this would increase sales by hundreds of millions of dollars. That the deaths of about a dozen high-profile European cyclists were already linked to high dosing with epo (accessed via the black market) should have served as a warning.

This book is a goldmine of information about how the nation’s pharmaceutical companies inflate the cost of medicines while hiding the true cost from consumers as well as the government payers. What’s more, the drug makers in this story monitor doctors’ prescribing habits to determine the marketing strategies that work best; violate patient confidentiality laws by encouraging sales reps to troll medical records for the best drug-testing candidates; and use study participation to get doctors to prescribe epo for dangerous off-label purposes. Such tactics are not confined to the selling of epo.

Duxbury’s sterling career started to go downhill when he was deposed as a result of a lawsuit initiated by Amgen against J&J. (Depositions conducted over the course of several years serve as a major source for this book.) As a result, his own in-office memos revealed J&J’s orders to encroach on Amgen’s kidney dialysis territory.

Duxbury soon became a liability to his own company, which turned on him as if he were the one who thought up the illegal sales tactics.  He was fired in 1998. Many of the reps who had been instructed to sell Procrit for dialysis were also fired or resigned. Many would not learn—until years later—that their order to promote Procrit as an anti-anemia drug for kidney patients was an off-label use (unproven) use and thus a federal crime. (The FDA had approved Procrit to treat anemia only in cancer patients.)

The rest of the story involves Duxbury’s downward spiral— unemployment, lawsuits, depression, and self-destructive behavior—as he tried to alert the public about the dangers of epo.  The sinister way the Ortho division of J&J treated its own employee who, after all, was just following orders, should confirm your worst fears about corporate misbehavior. As Duxbury put it after his own lawsuit for wrongful termination turned up information new to him. “I was shocked to learn that everything I did at Ortho was illegal. They cheated not just the government but their own people too!”

Author Sharp says that the safety tests were never conducted for epo drugs, though such testing was required by the FDA contingent on approval. By the late 1980s, she states, “scientists knew that boosting red blood cells also thickened the blood, which increased the risk of clotting. Blood clots lead to strokes, heart attacks, and brain aneurisms.” What’s more, she writes, “No one could be sure that Procrit was safe at even recommended doses, according to several sources.”

In 2007 the FDA finally got around to protecting the public. The agency issued a warning about all epo drugs which by this time were also marketed for AIDS patients. New studies showed epo drugs associated with an increase in death, heart attack, stroke and tumor growth in subgroups of people with cancer and those with chronic kidney failure. Click here

Epo drugs continue to generate billions in annual revenues.  Duxbury’s whistleblower case is still making its way through the courts.

Maryann Napoli, Center for Medical Consumers©

The end of cholesterol…

It’s somewhat like observing the first signs of spring. Lipitor, the last of the block-buster cholesterol-lowering statin drugs, is about to go off patent, so you look around for signs that the affected drug companies have found a way to keep revenues up. Lovaza, a prescription-only capsule of omega-3 fatty acid may well fit the bill. It’s time to scare us about another blood lipid — triglycerides. After all, the statin drugmakers have gone about as far as they can go with the dangers of high cholesterol.

“Very high triglycerides [TG], or too much fat in the blood, are a “very serious medical condition,” say the Lovaza ads. Then comes the scary but vague, “having too many triglycerides in your blood may lead to future health problems.” And here’s the best part: “Lavaza has not been shown to prevent heart attack or stroke.” (Occasionally, the FDA requires drug ads to be honest.)

Are high TG really dangerous to health? “Not particularly is the short answer,” responded cardiologist Vikas Saini, MD, president of the Lown Cardiovascular Research Foundation,  which is affiliated with the unique second-opinion consultation center near Boston. In a telephone interview, Dr. Saini explained that when you pool the results of observational studies, there may be a little extra risk to having very high TG, but no one knows whether lowering TG will reduce the risk of cardiac events. Usually, elevated TG comes with high blood sugar and low HDL (good) cholesterol, so it’s hard to tease out the independent effect of TG alone. “I view high TG as a signal that that a patient’s energy balance is out of whack. In the vast majority, high TG is due to inactivity, weight gain, and a diet too high in carbs, specifically simple sugars and sweets.”

The statin drugmakers have always given lip service to lifestyle changes, knowing full well that many of us would prefer to pop a pill. The statin companies already made a bundle successfully marketing a drug that benefits only a tiny minority who take it (click here) and are unlikely to walk away from the goldmine without finding some way it can be reworked into another goldmine. One company has already tried—and failed—to get the FDA to allow the sale of its statin over-the-counter. (The FDA sees this as too risky without doctor supervision, but it could come around as pressure to reduce drug costs intensify.)

GlaxoSmithKline (GSK), maker of Lovaza, seems to have another plan. First, it can rightfully claim to be the only producer of fish oil capsules to have tested its product against a placebo to the FDA’s satisfaction. And as of four years ago GSK bought the right to make a generic version of the statin Mevacor after it lost patent protection.

GSK is positioning itself to produce a combination statin/fish oil drug and has already passed the FDA-required tests. (Agency standards aren’t all that rigorous; approval was based on two trials that went no longer than 16 weeks and showed TG went down and LDL cholesterol improved.) Once the combination drug becomes available, all GSK has to do now is make us think that purchasing its costly fish oil plus a statin in one pill is more convenient than taking them separately.  And perhaps an insurance company or two will pay a portion of the tab. This wouldn’t be the first time an off-patent statin was reworked into an expensive combination drug.  Remember Vytorin?   (See “Why is anyone taking Zetia or Vytorin?”)

“Fish oil is good,” says Dr. Saini, “but as a prescription drug [Lovaza] is likely to be more expensive than the over-the-counter fish oil capsules and/or eating fish high in omega-3 fatty acid [blue fish, mackerel, lake trout, anchovies, etc.], but then again I haven’t done any price comparison.”

Yes, but.   As with all dietary supplements, fish oil supplements do not have to meet any quality standards. The companies that make fish oil supplements are not required to conduct clinical trials to prove safety, effectiveness, or even that the product actually contains fish oil.  We can thank GSK for its tests which showed that the adverse effects like belching, indigestion and taste perversion, occurred in 3% more of the people on Lovaza, compared with those on the placebo. And the FDA-required label for Lovaza warns of fish oil’s potential effect on prolonged bleeding, advising physicians to monitor people taking anticoagulants or other drugs affecting coagulation (e.g., aspirin, NSAIDs, warfarin, Coumadin).

If you want to take a fish oil supplement, see which products were found to be the most trustworthy, according to the independent testing of ConsumerLab.Com (subscription fee is required).

Maryann Napoli, Center for Medical Consumers©

Most drugs don’t work…

“Most drugs don’t work on most patients.” When I first read this statement many years ago in the British Medical Journal, a light bulb went off. I’d been a medical writer for a long time and knew it to be true. Yet I had never seen prescription drug effectiveness summed up so accurately. In a medical journal, no less! Unfortunately, drug study results are routinely reported in statistical terms known to make the drug’s benefit appear larger than it really is. More on that later.

The trigger for my light bulb moment was a 2003 editorial entitled, “Drug Don’t Work” by Richard Smith, MD, who explained, “This is of course no news to doctors. Anybody familiar with the notion of ‘number needed to treat’ (NNT) knows that it’s usually necessary to treat many patients in order for one to benefit. NNTs under 5 are unusual, whereas NNTs over 20 are common.”

The latest research, however, indicates that Dr. Smith may have overestimated physician understanding of medical statistics. A new Cochrane review of all relevant studies found that the most common statistical terms for expressing drug study results—in medical journals and the media—are misunderstood by doctors and consumers alike. In fact there was no difference in understanding between physicans and the lay public.

For the Cochrane review entitled, “Using different statistical formats for presenting health information,” the authors identified the 35 best studies designed to evaluate how well people understood the different ways of expressing the same study results. This review came down in favor of absolute risk reduction rather than relative risk reductions (RRR), as described below:

“You read that a study found that an osteoporosis drug cuts the risk of having a hip fracture in the next three years by 50%. Specifically, 10% of the untreated people had a hip fracture at three years, compared with 5% of the people who took the osteoporosis drug every day for three years. Thus 5% (10% minus 5%) less people would suffer a hip fracture if they take the drug for 3 years. In other words, 20 patients need to take the osteoporosis drug over 3 years for an additional patient to avoid a hip fracture. ‘Cuts the risk of fracture by 50%’ represents a relative risk reduction. ‘Five per cent less would suffer a fracture’ represents an absolute risk reduction. ‘Twenty patients need to take the osteoporosis drug over 3 years for an additional patient to avoid a hip fracture’ represents a number needed to treat.”

To people without statistical training—and that includes most physicians—the “cuts your risk by 50%” RRR example appears more impressive. And too often this is the sole way drug study results are described in medical journals, as well as ads aimed at physicians and the general public. Rarely is it explained that the 50% simply represents the difference between the treated and the untreated.

Here’s a real world example: Your doctor says, “You have mild hypertension and should go on a blood pressure lowering drug for the rest of your life because it will cut your risk of stroke by 50%.” Sounds good, maybe even worth the risk of sexual dysfunction and depression—two common side effects of anti-hypertensives. But here’s the other side of the story: A person with mild hypertension has only an infinitessimal chance of having a stroke, so the drug will reduce that infinitessimal risk by 50%

The common usage of RRR comes from the biostatisticians and the methodologists whose job it is to determine whether studies are conducted rigorously and results reported accurately. The fact that the Cochrane Collaboration’s own biostatisticians and methodologists are concerned enough to have produced this new review signals some recognition that it’s time for a change. (Long overdue, given that the sole use of RRR serves the pharmaceutical industry’s interest.) The Cochrane Collaboration itself has produced too many drug reviews with results expressed solely as RRR. Here’s one improvement under consideration because it is better understood: 100 of 1,000 untreated people will have a hip fracture in the next three years; 50 of 1,000 people taking an osteoporosis drug will have a hip fracture in the next three years.

The most easily understood way of expressing “most drugs don’t work on most people” can be found at this website: www.TheNNT.com Say, you are suffering from acute sinusitis but wary of taking an antibiotic for this distressing condition. You want to know how well the drug is likely to work and the likelihood of harm. TheNNT.com shows that 93% will not benefit from antibiotics; nearly 7% saw a faster resolution of their symptoms; and just over 1% were harmed by the antibiotics (e.g., diarrhea, vomiting). Even more interesting, four out of five people (in the placebo group) got better without antibiotics.

Maryann Napoli, Center for Medical Consumers(c)

Cancer screening tests right to the grave

When my husband and I picked up his mother after yet-another hospitalization for complications of congestive heart failure, I read her discharge orders. “Be sure to schedule a Pap test and a mammogram after you get home.” Naturally, we ignored the directive as absurd for a woman in her mid-nineties who clearly had a condition that would soon cause her death.

Apparently, this is more common than I’d ever imagined. A new study, published today in the Journal of the American Medical Association, found “a sizeable proportion” of people with terminal cancer are given screening tests for common cancers. And the testing is beyond the two recommended to my mother-in-law. Nearly 9% of the advanced cancer patients in this study were tested for new cancers.

Here’s how the study, funded by the U.S. National Cancer Institute, was done. Researchers at Memorial Sloan-Kettering Cancer Center, New York, searched the data from Medicare claims to determine the number of cancer screening tests given for new cancers to people already diagnosed with an advanced cancer. The reseachers assessed data on 87,736 people ages 65 and older who had been diagnosed with advanced lung, colorectal, pancreatic, gastroesophageal, or breast cancer between 1998 and 2005. All were followed up until death or December 2005, whichever came first. Each was matched by age, sex, and race to Medicare enrollees without cancer.

Keep in mind that screening is the testing of people without symptoms, and the tests may have been ordered without much thought as to what would be done once a new cancer is detected. Would a surgeon do a prostatectomy on a man with an incurable cancer some place else and a life expectancy of less than two years? I suspect the answer is yes. Why else would the test be ordered?

The tests most commonly given to advanced cancer patients were predicable. Mammography was number one, received by nearly 9% of the women with advanced cancer, with the Pap test running a close second at nearly 6%. As for the men, 15% got a PSA test and nearly 2% of all got a colonoscopy. As for the age-matched people without cancer in the control group, 2-3 times more of them had at least one of the cancer screening tests.

Who are the most likely to be screened right to the grave? Married people with higher socioeconomic status. And people who were screened regularly before they were diagnosed with the cancer that would eventually cause their death.

On this last point the research team led by Camelia S. Sima, M.D., hypothesized that “efforts to foster adherence to screening have led to deeply ingrained habits. Patients and their health care practitioners accustomed to obtaining screening tests at regular intervals continue to do so even when the benefits have been rendered futile in the face of competing risk from advanced cancer.”

Maybe so, but I suspect that something more than mindless aggressive testing is at play here. America has a death-denying culture. Continued testing keeps hope alive and avoids that unpleasant conversation about the end-of-life. It’s not over until your doctor stops ordering cancer tests.

Maryann Napoli, Center for Medical Consumers©

Rethinking calcium

For over 25 years women have been told to take daily calcium supplements to prevent fractures. Now we learn that this may “modestly” increase the risk of having a heart attack. The finding came not just from one study but a meta-analysis of 11 clinical trials with a combined total of 12,000 participants; about half of whom were randomly assigned to take a placebo or more than 500 mg calcium a day. The study participants—all over the age of 60 years and mostly women—either had osteoporosis or were trying to prevent it.

The new finding is contested for several reasons that I’ll get to later. But even if the calcium-heart attack connection is never confirmed, the unsung contribution of this meta-analysis may be the spotlight it shines on the uncertain value of calcium supplements.

The new-found harm may be modest in size but so is the benefit of taking calcium supplements. Here’s how the British Medical Journal editors summarized the meta-analysis: “Given the modest benefits of calcium supplements on bone density and fracture prevention, a reassessment of the role of calcium supplements in the management of osteoporosis is warranted.” The accompanying editorial went a step further suggesting that, however modest, the heart attack increase shouldn’t be dismissed: “Given the uncertain benefits of calcium supplements, any level of risk is unwarranted.”

Let us pause for a moment here to think about those annoying Sally Field commercials for the osteoporosis drug Boniva. Next time you see one notice that she makes no claim that the drug will prevent fractures. Instead, she tells us that she has osteoporosis and the drug has stopped and reversed her bone loss. The same careful choice of words should be directed at calcium supplements. While they may improve bone density, the jury is still out when it comes to fracture prevention.

Some critics of the meta-analysis say it should be ignored entirely because the study participants were not taking vitamin D, just calcium. Today, most women following the standard osteoporosis prevention advice take both. The British Medical Journal editorialists, who clearly saw this one coming, wrote, “No conclusive data are available to show that current doses of vitamin D supplements with or without calcium supplements reduce the rates of fracture…”

The state of calcium and vitamin D effectiveness research was summed up this way in an earlier issue of the BMJ: “Conflicting evidence exists on the role of vitamin D, either alone or in combination with calcium, in reducing fractures. Some studies have shown a reduction in the risk of fractures, others have shown no effect, and one recent study found an increased risk of hip fracture.”

Sally Field aside, fracture prevention is what it’s all about, or rather what it’s supposed to be all about.

For another reaction to the heart-attack problem, I turned to the Web site of Susan Ott, MD, who specializes in osteoporosis and bone physiology. A News Flash on her Web site (see the calcium section) announces the meta-analysis and its heart-attack finding, which Dr. Ott dismisses as due to chance. The reason: Too few participants. She supplies a link to a 2006 study, which she prefers because it has three times the number of participants. Although they were taking calcium and vitamin D, they had no increased risk of heart attack.

Unfortunately, this 2006 study isn’t the best choice for defending the use of calcium and vitamin D, given the fact that the combo did not reduce the participants’ rate of hip fracture but instead increased the risk of kidney stones. (See for yourself, click here.) Elsewhere on her Web site, Dr. Ott speculates that the same 2006 study included some participants taking too much calcium (over 2,000 mg/daily). The high doses didn’t reduce fractures but just stressed the kidneys.

What to do? One possibility to consider: focus on diet and ditch the supplements until fracture-prevention is proven. But even here, the longstanding advice to increase intake of dietary calcium in adulthood appears to have no fracture-prevention advantage. (The operative word there is “increase”.) This was shown in a 12-year study of women, age 34 to 59, who did not take calcium supplements. (See “Calcium in Adulthood” click here). This 1997 study was co-authored by Dr. Diane Feskanich, Harvard Medical School, who published one more recently that clarified things further with an 18-year follow-up study of postmenopausal women.

Neither milk nor a high-calcium diet reduced their chance of having a hip fracture. But the Harvard researchers did make a case for the use of vitamin D supplements and consumption of dark fish for hip fracture prevention because American women commonly consume less than the recommended intake of vitamin D.

Addendum: Several months after this article was posted, the New York Times announced a new report from the Institute of Medicine that questioned the need for high doses of calcium and vitamin D (click here).

Maryann Napoli, Center for Medical Consumers©

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MDs OK with industry gifts

One thing that adds to the inefficiency of our medical care system is the distorting influence of the pharmaceutical industry’s marketing techniques. A new survey of 600 doctors, surgeons, and medical students found that most have positive attitudes towards the marketing activities of the drug companies. Unfortunately, most seem to miss the fact that marketing is all about getting them to prescribe the most expensive drugs.

The most disturbing finding in this survey, published in Archives of Surgery, is the 58% of respondents who said they believe that drug samples improve patient care. Free drug samples to doctors—one of the pharmaceutical industry’s most effective marketing strategies—are all about increasing the sales of brand-name drugs. They tend to be the newest, most expensive drugs, offered to patients in this way, “Try this free drug sample and see how you do.” The patients who do just fine continue with the expensive drug, which may very well have a less expensive alternative that is just as good…or safer. So far, no one has come up with any good evidence that free samples improve patient care.

The pharmaceutical indstry would have us believe that the free drugs go to low-income patients, but that didn’t hold up once researchers took a hard look. They found that the people most likely to receive free drug samples from their physicians are the financially well off and the insured. (Click here) Another study showed that the people who get free samples wind up with significantly more out-of-pocket expenditures than those who don’t.

Three-fourths of the doctors in the new survey believe that accepting free gifts and free lunches did not influence their own prescribing practices, but 52% said other doctors are likely to be swayed by such marketing tactics.

I think we can safely assume that the pharmaceutical marketing pros know exactly what works in terms of gifts to doctors, be it a free mug with drug company logo or a lavish dinner at the local French restaurant. One anti-drug industry documentary featured a former drug saleswoman turned whistle-blower. She said that her company could clock an uptick in drug prescriptions after something as seemingly minor as bringing a $10 take-out Chinese lunch for each person on the doctors’ staff.

You have no way of knowing how much marketing influences your own doctor’s prescribing behavior. A doctor too ready to prescribe the newest drug is a bad sign. So is the doctor whose waiting room often includes a well-dressed drug sales representative (usually female) and/or an office that is heavy on the industry-generated posters, pens, mugs, and brochures. One friend noticed the place she was expected to place her feet on the scale in her doctor’s office had a paste-on ad for Meridia, the weight-loss drug.

Revealing as this survey is, it centers on marketing tactics that are small potatoes compared to what’s happening at academic medical centers and is largely hidden from public view. It’s the fact that half of all continuing medical education is funded by industry. It’s the large consulting fees paid to key opinion leaders to “educate” their peers about the latest drugs. (For the definitive article describing how this works, click here.) Things have gotten so bad that medical students at Harvard are reportedly asking hard questions about which of their professors are paid consultants for the pharmaceutical industry (click here).

Reforms are on the way but still relatively new. Under a new federal law, drug and device companies will soon have to disclose, on a publicly accessible website, the names of doctors who accept speaking fees, as well as the value of all gifts. We already know that this will have an immediate effect. Vermont is one of three states that lead the way and put this law into practice in 2002. Early this year, the attorney general of Vermont released data showing that total payments to doctors in Vermont dropped 13% in 2009 to $2.6 million. Vermont now plans to improve its law with an outright ban on most gifts, including food, which amounts to $800,000 of the 2009 total.

Several years from now we can look forward to another survey to see how doctors react to the new federal law.

Maryann Napoli, Center for Medical Consumers©

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Anemia drugs hasten death in some cancer patients

For seven years Johnson & Johnson ran deceptive ads on prime time TV and in magazines with this recurring theme: A cancer patient cannot continue working because of debilitating fatigue due to chemotherapy. The ads told people in similar circumstances to ask their doctors about Procrit, which always quickly put an end to the fatigue. There is no published evidence to support the cure-for-fatigue claim, according to a 2007 press briefing at the FDA. Eventually, the agency required warning labels for Procrit, Aranesp, and Epogen —- all drugs widely prescribed to treat anemia in cancer patients. Warning label refers to the black box warning that appears in the 20 or so pages of information that comes with the drug (sometimes). The warnings for Procrit, Aranesp, and Epogen now list a higher incidence of potentially fatal blood clots, heart damage and increased tumor growth.

Now they can add “decreased survival” to the list. This week, the Cochrane Collaboration, the independent, international organization that evaluates research, published a meta-analysis of the information generated by the care of nearly 14,000 cancer patients entitled, “Anti-anemia drugs shorten survival for some cancer patients.” This meta-analysis is co-authored by Maryann Napoli, Center for Medical Consumers. For background on how their drugs came on the market and how financial incentives encouraged oncologists to overprescribe them, see her testimony on this topic before the FDA’s Oncologic Drug Advisory Committee in 2007 and one year later in 2008.

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The Marketing of Osteoporosis

How a risk factor (bone loss) became a disease (osteoporosis) by Maryann Napoli. Originally published in American Journal of Nursing, May 2009

Nurses probably get the same question I often get as a consumer advocate.  Should I be on this drug? You’re asked because you’re seen as the expert or simply a knowledgeable friend.  In fact, it’s a valid question not only to ask but also to look beyond the prescribing health care provider for answers.

In the name of prevention, millions of Americans have accepted the idea that it is reasonable to treat a risk factor (e.g., high cholesterol, bone loss) as if it were a disease. Think back to the 1990s when virtually all menopausal women were advised—pressured, according to accounts that came my way—by their gynecologists to go on hormone therapy to prevent heart disease and hip fractures.

More people should question the wisdom of going on long-term drug therapy. Often the magnitude of the risk factor has been overestimated; or the danger of the disease itself may be exaggerated by people trying to sell us something—like a drug you must take for the rest of your life.

Osteoporosis provides an excellent example of how the pharmaceutical industry begins creating a market for a new prevention drug years before it is approved.  The disease has become a major health concern for older women, though it was unknown to the general public until the early 1980s when the drug industry-led awareness campaign began.  It used to be that osteoporosis was not diagnosed until a fragility fracture had occurred.[1]

But a new definition, one based on bone mineral density, was established in 1993 at a World Health Organization meeting of osteoporosis researchers.  Its ostensible purpose was to determine the global prevalence of osteoporosis, but this meeting is where the definition of osteoporosis was radically changed.  What had been simply a risk factor (bone loss) became a disease (osteoporosis), complete with an arbitrary cutoff (bone density more than 2.5 standard deviations below the normal bone mass in young women).[2]

Overnight, the market for bone drugs had been expanded. Years after that WHO meeting, I would learn that it was sponsored by several pharmaceutical companies.² Hormone drugs were the standard preventive treatment at the time of the meeting, but three years later the first non-hormonal drug for bone loss—alendronate (Fosamax)—was launched.

Getting symptom-free women to accept drug therapy requires scarey statistics that imply the danger period starts right after menopause, leaving the impression that hip fractures, the most disabling consequence of osteoporosis, often occur soon after the hot flashes are over.  Here’s one stat you would see often: 24% women, aged 50 and over, die within a year of a hip fracture.[3]  And here’s one you don’t see often: over 90% of the hip fractures occur in people over 70 and the average age is 80.[4]  Elderly men have hip fractures, too, but the early marketing of alendronate was all about the ladies.

How Predictive are Bone Scans?

In the initial phase of the industry-funded osteoporosis awareness campaign, the scan known by the acronym DEXA was advised for women at the time of menopause. Scanning caught on in a big way, especially after Merck, the maker of alendronate, began financing the installation of DEXA machines in doctors’ offices.[5]  Nothing creates drug customers faster than getting people to be routinely scanned.

Unfortunately, scanning is not good at predicting which women in their early 50s will have a hip fracture at age 80. This was known in 1997 thanks to a report from the British Columbia Office for Health Technology Assessment, which—to my knowledge—is the first to reveal industry sponsorship of that 1993 WHO meeting where osteoporosis was redefined.[6]

Unfortunately, the report had no effect on U.S.testing guidelines, but consumer advocate Barbara Mintzes, Universityof British Columbia, summed up the situation nicely, “Bone mineral density testing is a poor predictor of future fractures, but an excellent predictor of start of drug use.”[7] Merck’s ads aimed at women did not even mention alendronate, they simply said, “Ask your doctor whether a bone density test is right for you.”  Sure, low calcium/vitamin D intake, scatter rugs, poor muscle strength, certain medications, impaired vision were given lip service as contributing factors to osteoporotic fractures, but loss of bone density always seemed front and center.

How Good is the Drug?

In the initial phase of DEXA promotion, many women in early middle-age, with low bone density but no history of fracture, were put on alendronate, despite the fact that the drug was tested only in elderly women with vertebral fractures. The results, even for this supposedly high-risk elderly group, were not impressive. In the Merck-sponsored three-year trial that received Food and Drug Administration approval, hip fractures occurred in 1% of those on alendronate, compared with 2% of those on a placebo. [8] (A “50% reduction in hip fracture” is the accurate, though misleading, way these results were often portrayed.)

Here is where the nurse/advocate can serve as a sounding board for patients deciding whether to go on drug therapy, helping them consider questions like:  Are you similar in age and fracture history to the women in this trial? What does that 1% fewer hip fractures mean to you? Let’s compare that 1% benefit with the 1.5% risk for a alendronate-induced esophageal ulcer found in this trial? Consider what happened to the study participants who did not take alendronate (98% of the untreated women—i.e., the placebo group—did not have a hip fracture).  The “script” for this discussion is the drug’s official FDA-approved label and the Physicians’ Desk Reference where the trials that won FDA approval are described.

When alendronate was put to the test for elderly women with bone loss but no vertebral fractures, the four-year trial showed that the hip fracture rate was no different for the drug-treated participants than it was for the women taking a placebo.In short, the drug is good at improving bone density but not so good at reducing hip fractures. This did not stop other drug companies from introducing their own alendronate knockoffs—risedronate, ibandronate, pamidronate, etidronate and zoledronic acid.  All are in the same drug class called bisphosphonates.  In an example of how long a drug has to be on the market before the full picture of harm is known, the FDA reported early this year that all bisphosphonates carry the risk of severe and sometimes incapacitating musculoskeletal pain.[9]

Drug Ad Campaign Misled Doctors

Why younger rather than elderly women became the likely recipients of a bisphosphonate prescription is no mystery.  Merck’s initial ads aimed at physicians encouraged it.  A multi-page glossy ad campaign that ran frequently in Annals of Internal Medicine featured a thin fortysomething white woman with a crumbling ancient stone column in the background.  “Don’t wait for a fracture… No matter what her degree of osteoporotic bone loss…” [10]  I wrote to the editor-in-chief of Annals, pointing out that alendronate had no proven benefit for women in early middle age.  Never got a reply, but Annals stopped running the ad about six months later.  Still, the message had already gone out, there and elsewhere—early middle age is the appropriate time to start fracture prevention with alendronate.  From the drug industry’s point of view, the younger customer is far more desirable than, say, the  elderly nursing home resident with a limited remaining lifespan in which to take drugs.

Today, women in the osteoporosis drug ads are usually in their early sixties.  The guidelines for bone density measurement currently recommend bone mineral testing not begin before age 65 (or 60 in some high-risk cases)[11], 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 there is no test for bone  quality or bone strength. ¹

It’s going to take time for the word to get out.

How relevant is this story to other drugs people take to treat a risk factor?  In a word: very.  Three-fourths of all Americans on cholesterol-lowering statins, the country’s top-selling drugs, do not have heart disease and are thus far less likely to benefit than people who do. [12]  (Statins are terrific at lowering cholesterol, but much less impressive at reducing the risk for heart attack[13]—sound familiar?)  The thresholds for high cholesterol[14] and high blood pressure were lowered several times over the years, each time making millions more people eligible for drug therapy. ⁵ 

Drug ads and industry-sponsored “education” programs are no longer the only major sources of biased information. Industry funding compromises the directives of non-profits like the American Heart Association and the American Cancer Society, as well as the experts who write treatment guidelines. [15]  One example of the latter: eight of the nine doctors who served on the 2004 government committee that expanded the guidelines for cholesterol-lowering drug therapy had financial ties to statin companies.[16]

More than ever, nurses must be knowledgeable advocates for their patients. You may be the last of the independent health professionals.

For More Information:

Added May 19, 2012: New take on bone density retesting.  and  Warning on bone drugs:  Stop after 5 years.

http://courses.washington.edu.bonephys    Web site of bone physiologist and osteoporosis researcher Susan Ott, MD, Associate Professor, Department of
Medicine, University of Washington.  Mostinteresting section: “When [drug] studies don’t give clear answers.”  Definitely take the quiz. (Accessed June 12, 2008.)

 

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[1] Cheung, AM and Detsky, AS. “Osteoporosis and Fractures: Missing the
Bridge?” JAMA. 2008;299(12):1468-1470.

2 Kazanjian A, et al. Normal bone mass, aging
bodies, marketing of fear: bone mineral density screening of well women. University of British Columbia Centre for Health
Services and Policy Research. British Columbia Office of Health Technology Assessment BCOHTA  98:10C Sept 1998. http://www.chspr.ubc.ca/files/publications/1998/bco98-10C.pdf  (AccessedJune 13, 2008.)

[3]
National Osteoporosis Foundation. www.nof.org
(Accessed June 5,
2008)

[4]
Love S.M. with Lindsey, K.  Dr. Susan
Love’s Menopause & Hormone Book.  New York: Three Rivers
Press, 2003.  P.109

[5]
Moynihan R and Cassels A. Selling
Sickness: How the world’s biggest pharmaceutical companies are turning us all
into patients. New York: Nation Books, 2005 page 142.

[6]  Kazanjian A, et al.  Bone Mineral Density Testing: Does the
Evidence Support Its Selective Use in Well Women? 1997 British Columbia Office for Health Technology
Assessment, University of British Columbia.  http://www.chspr.ubc.ca/files/publications/1998/bco98-07C.pdf   (AccessedJune 5, 2008)

[7] Mintzes, B. Direct to consumer advertising is medicalising normal human experience. BMJ 2002;324:908-911.

[8]Physicians’ Desk Reference, 59^th edition 2005, page 2051.

[9] FDA Alert: Bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Alendronate, Alendronate+D, Reclast,
Skelid, and Zometa). Posted Jan 7, 2008. http://www.fda.gov/medwAtch/safety/2008/safety08.htm#  (AccessedJune 12, 2008.)

[10] Napoli M. Alendronate: A new drug with an ad campaign that encourages misuse.   HealthFacts. July 1996.

[11] Agency for Healthcare Research and Quality. U.S. Preventive Services Task Force. Sept 2002. http://www.ahrq.gov/clinic/uspstf/uspsoste.htm
(Accessed June 13, 2008.)

[12]
Abramson J, et al. Are Lipid-Lowering Guidelines Evidence-Based? Lancet. 2007
Jan 20;369 (9557):168-9.

[13]
Carey J. Do cholesterol drugs do any good? Business Week, Jan 17,2008.
(Accessed onlineJune 16, 2008.)

[14]
Center for Science in the Public Interest. http://www.cspinet.org/integrity/press/200409231.html
(Accessed June 6, 2008).

[15]
Lenzer
J. Education and debate:  Alteplase for
stroke: money and optimistic claims buttress the “brain attack”
campaign.  BMJ 2002;324:723-729.  http://bmj.bmjjournals.com/cgi/content/full/324/7339/723#B14
(Accessed June
13, 2008.)

[16] National Cholesterol Education Program. Third Report of the Panel on Detection, Evaluation, and Treatment of high blood cholesterol in adults (Adult treatment panel III) 2004. http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3upd04_disclose.htm                    (Accessed June 6, 2008).