A recent story on NPR accused the drug manufacturer Merck of inventing a disease, osteopenia, in order to sell its drug Fosamax. It showed how the definition of what constitutes a disease evolves, and the role that drug companies can play in that evolution.

Osteoporosis is a reduction in bone mineral density that leads to fractures. The most serious are hip fractures, which require surgery, have complications like blood clots, and carry a high mortality. Many of those who survive never walk again. Vertebral fractures are common in the osteoporotic elderly and are responsible for dowager’s hump and loss of height. There is also an increased risk of wrist and rib fractures.

Bone density tends to decrease with age. Postmenopausal women are particularly susceptible to osteoporosis when their production of estrogen declines. The risk is increased in people taking corticosteroids and in people with certain diseases like rheumatoid arthritis. Other risk factors are European or Asian ancestry, smoking, excess alcohol, a family history of fractures, vitamin D deficiency, too much or too little exercise, malnutrition, and low body weight.

When a measurement like bone density varies widely in a population and decreases with age, how can we decide where to draw the line and call it abnormal? When does it become a disease requiring treatment?

For a long time, the diagnosis of osteoporosis depended on the occurrence of a fracture. In 1992 a group of experts convened by the World Health Organization agreed to define osteoporosis as a bone density 2.5 standard deviations below that of an average 30 year old white woman. They defined osteopenia as a bone density one standard deviation below that of an average 30-year-old white woman. The decision to use one standard deviation and 2.5 standard deviations was arbitrary, and it was meant as a tool to measure the emergence of a problem in a population rather than to have precise diagnostic or therapeutic significance for an individual. Nevertheless, these criteria were widely interpreted to mean that half the population has a disease they need to worry about.

Bisphosphonate drugs like Merck’s Fosamax and Sally Field’s beloved Boniva were intended to reduce the risk of fractures in patients with osteoporosis. They are effective in reducing spine fractures and in increasing bone density measurements, but some studies have shown no reduction in non-spine fractures, which are more common, and in the case of hip fractures, more significant. A British Medical Journal article pointed out,

Two thirds of vertebral fractures are subclinical or asymptomatic and may not affect quality of life. As a consequence showing that drugs reduce vertebral fractures may not be as important to patients as it seems.

According to a table published by the USPSTF (US Preventive Services Task Force), among women aged 50-54, 60 women need to be treated to prevent one vertebral fracture and 227 to prevent one hip fracture. Among women aged 65-69, 30 must be treated to prevent one vertebral fracture and 88 must be treated to prevent one hip fracture. Sally is 63: the numbers for her age group are 30 and 121. One wonders if she is aware of these numbers.

These drugs are not benign. To prevent ulceration of the esophagus, for 30 minutes after taking Fosamax patients must avoid eating or drinking anything but plain water; they must not lie down or recline, or take any other medications during that time. Bisphosphonates have been linked to osteonecrosis of the jaw. There are as yet no long-term studies. Case reports suggest the possibility that they might paradoxically increase fractures in the long run. By one estimate, the NNH (Number Needed to Harm) is 16 as measured by discontinuing treatment due to adverse effects.

When Merck started marketing Fosamax, not many women were being screened for osteoporosis because the standard DEXA (dual energy x-ray absorptiometry) test required expensive equipment and was not readily available. They thought if they could increase the rate of diagnosis they could sell more pills. Merck promoted the development of small, less expensive scanners that could be used on a heel or wrist in a doctor’s office. Merck even set up a nonprofit organization called the Bone Measurement Institute, which worked to spread the use of these machines and bring down the price of bone exams. Unfortunately, the results of those scans did not correlate well to the results of the gold standard DEXA scan.

A doctor quoted by NPR said,

The problem with the smaller peripheral machines is that taking a measurement of someone’s heel or forearm isn’t going to tell you what you need to know about the bones in the parts of the body that, if fractured, increase a woman’s risk of death — the hip and spine.

Who should be screened? The USPSTF found that, for women 55 to 59 years of age, the number needed to screen (NNS) over five years was more than 4,000 to prevent one hip fracture and 1,300 to prevent one vertebral fracture. The NNS to prevent one hip fracture over five years declines with age, to 1,856 for women 60 to 64 years of age, 731 for women 65 to 69 years of age, and 143 for women 75 to 79 years of age.

The USPSTF currently recommends that women aged 65 and older be screened routinely for osteoporosis. It recommends that routine screening begin at age 60 for women at increased risk for osteoporotic fractures (there is a handy online FRAX tool for estimating an individual’s risk of osteoporotic fractures). It found insufficient evidence to make any recommendations for younger women or for men. Meanwhile, direct-to-public ultrasound screening companies have jumped on the bandwagon and are offering poor quality osteoporosis screening to men and women of all ages, with innumerable false positives requiring further testing and unnecessary worry.

The results of the scans promoted by Merck were reported either as normal bone density, osteopenia, or osteoporosis. Osteopenia carries only a small increased risk of fractures, but the assumption was that left untreated it would progress to osteoporosis. It is really more of a risk factor for osteoporosis than a disease in its own right. Some women diagnosed with osteopenia may not even have bone loss; they may just be at the low end of normal on a wide spectrum. But osteopenia sounds abnormal, and it sounds like a diagnosis, and it sounds to a lot of people like it needs treating. A new disease was born with a ready-made treatment.

There are other pharmaceutical options for osteoporosis. Estrogens reduce osteoporosis risk but carry too many other risks to be used for that indication alone. Raloxifene is a selective estrogen receptor modifier that has estrogenic effects on bone but anti-estrogenic effects on the uterus and breast. It reduces the risk of vertebral fractures but not other fractures. It increases the risk of thromboembolism and fatal stroke although it does not reduce the overall death rate. Another option is calcitonin, but it is less effective.

Pharmaceutical treatments are not the only option. Weight-bearing exercise, prevention of falls, quitting cigarettes, curtailing alcohol, and ensuring adequate intake of calcium and vitamin D are all beneficial. A recent study showed that higher doses of vitamin D supplements (over 400 IU a day) reduced fractures by 20%.

Merck’s actions may have been misguided, but I don’t see this as a scam. Merck employees were trying to make money for the company, but that doesn’t mean they weren’t also genuinely trying to do the right thing to help patients. They had a product that they thought would prevent fractures and save lives, and they wanted to get it to everyone who could benefit. In their enthusiasm, they overshot and went beyond the science.

The NPR article admitted that there are two sides to this story.

…drug companies produce incredible drugs that can greatly relieve suffering. But one way they profit from those drugs is to extend their use to as many people as possible, which frequently means that medications are used in populations with milder and milder versions of a disease, so that the risks of medicating can come to outweigh the benefits.

Big Pharma advertises but it is doctors who write the prescriptions: when drugs are over-prescribed, only the prescribers are to blame. What should doctors do? In the first place, they should be recommending preventive lifestyle changes to all their patients. They should stick to the best science-based practices and evaluate the evidence for themselves rather than being influenced by Sally Field or by Big Pharma propaganda. They should prescribe drug treatments only when fracture risk is significant, when a fracture has already occurred, or when they think bone density is significantly low (still a judgment call). They should explain the gray areas to their patients and involve them in the decision to treat. They should think in terms of number needed to treat and number needed to harm. And they should be aware of the games Big Pharma plays.



Posted by Harriet Hall