May 8, 2007 -- One might be convinced it's a glorious week for our aging bones.
The Food and Drug Administration willing, we could soon be lining up for our annual quick infusion of zoledronic acid and, wonder of wonders, within three years, our risk of hip fractures would be reduced by some 40 percent — and our risk of spine fractures even more.
One might be convinced it's a glorious week for our aging bones, but I'm not. And I won't let my patients fall victim to this hype.
The devil is in the details of the Horizon Pivotal Fracture Trial, published in the May 3 issue of the influential New England Journal of Medicine, to much fanfare. This trial received much publicity, as it studied the effect of a bone-protecting treatment that those going through menopause would only have to take once every year.
But the same devil underlies all the hype about the competing pharmaceutical remedies.
Our nation has been taught to fear the consequences of our thinning bones. Women flock to get the mineral density of their bones measured -- older and younger women -- and likely consume pharmaceutical remedies whenever they are told their bones are too thin. They take pills, and often at considerable expense to ward off the horror of fragility fractures of the spine and hips.
The Devil and the Details
The Horizon trial studied nearly 8,000 women, the majority over 70 years old, and all with some evidence of collapsing of a spinal bone, a spinal fragility fracture.
Hence, these women have thin bones that can collapse without unusual trauma — osteoporosis.
They were randomized so that 4,000 were to receive the annual drug infusion for three years. The study was designed to see if the women who received the infusion had fewer hip fractures or less evidence of spinal fragility fracturing. Let's focus on the more severe and more unequivocal hip fractures:
Number of Women Who Suffered a Hip Fracture Despite Receiving the Drug: 52
Number of Women Who Suffered a Hip Fracture Without Receiving the Drug: 88
So, if you infuse the drug every year for three years into 4,000 women, 36 might be spared a fractured hip. That's an absolute difference in hip fracture frequency of less than 1 percent, which is not a number likely to engender so much excitement in the media.
However, the reduction in frequency from 2.5 percent to 1.4 percent on the drug is a reduction that approaches the "40 percent reduction" in the hype I am decrying.
No one, not you or I, not the media or the journals should ever be offered a relative difference without first emphasizing the absolute difference.
What does this mean? Well, let's say you can take a pill that reduces your chance of dying in a year from 40 percent to 20 percent. Let's say there's another pill you can take that reduces your chance of dying in a year from 2 percent to 1 percent.
Both pills reduce your relative risk of dying by 50 percent, but the absolute risk reduction is dramatically different.
Based on the absolute difference with this new drug, I'd have to treat about 100 women for three years to spare one a hip fracture. Before I ask you to ponder whether such a potential benefit is worth it to you, I need you to consider if such a benefit is believable. I do not find it believable for the following reasons:
Small Effects and the Limits of Science
Horizon is a randomized controlled trial. Half of the 8,000 women were randomly chosen to receive the infusions of the drug.
The assumption is that these women will be split so that all important causes of hip fractures would be equally represented in each half: their ages, the thinness of their bones, the degree to which they already had spinal fragility fractures, and even their body mass index.
This was all checked, and indeed, these features split 50-50 between the treated and untreated halves. But what if something important wasn't measured and did not split 50-50?
The most important cause of hip fractures in the elderly is not the thinness of bones. The most important cause is falling down.
Furthermore, the most important cause of falls in the elderly is instability. Attention should be focused on the living environment to remove obstacles that could trip the person up, and to provide railings and other assistive devices that promote stability of gait.
There are promising trials that explore the role of strength and balance training and of hip protectors to decrease the likelihood of hip fractures, but the results are inconsistent.
The reason so many elderly die within the year after a hip fracture is not a result of the fracture itself, which orthopedists can stabilize expeditiously. It's because the instability is but one feature of their decrepitude — it's a reflection of their ripe old age. Their time is near.
The Horizon trial design did not include a measurement of stability. What if instability did not randomize 50-50? What if 51 percent of the most unstable women were in the untreated group and 51 percent of the most stable women in the treated group? That's not too unlikely. Such skew could easily account for a 1 percent absolute difference in the result.
For that reason, I simply discount 1 percent absolute differences in outcomes.
If I have to treat 100 patients in order to get an important benefit in just one of those patients, I consider the treatment to be ineffective. Other clinical scholars start to gain confidence with a 2 percent absolute difference. I require 5 percent; I am comfortable advising my patient that a treatment is beneficial if I can expect benefit in one out of every 20 patients I treat.
In the Horizon trial, as many as a third of the subjects were ill for a few days following the infusion of the drug. There was about a 1 percent absolute difference in decrease in kidney function or a serious problem with heart rhythm; women who did not receive the drug were spared. These small effects are as impressive, or unimpressive, as the hip fracture difference.
However, I worry about the rare effect that would not happen at all without the drug.
The reason this drug can be infused only once a year is that this class of drug enters into the bone and stays there for a very long time, all the while influencing the fashion in which the cells in the bone try to keep the bone healthy.
There is also a rare, unique and horrifying complication that is well described. Drugs of this class can cause the bone to die, particularly the jaw bone. I am not reassured by a three-year experience in 4,000 women. I am particularly wary since I am not convinced of any benefit.
For Whose Benefit?
The debate on efficacy commences at a 2 percent absolute difference in outcome.
The misleading nature of relative results, such as relative risk reduction, has been widely decried.
The international authorship listed on the masthead of the HORIZON paper includes some of the leading clinical investigators in the osteoporosis field (along with employees of the sponsoring pharmaceutical firm, Novartis) who most probably are aware of these issues in data interpretation.
The editors of the august New England Journal of Medicine and the authors' "peers" responsible for reviewing the paper prior to acceptance for publication, are also probably aware of the data interpretation issues.
So, why is the paper published in a format that engenders the hype I am decrying? Could it be that there is more at stake than would be served by reporting a marginal effect on hip fractures?
Certainly, there is much at stake for all those involved with the trial itself. Novartis has invested a fortune in the development of this drug, and another fortune supporting the trial, participating in the data analysis and the preparation of the manuscript. All the masthead authors declare financial arrangements with pharmaceutical firms, most with multiple firms and nearly all with Novartis.
Then, again, there are some elderly folks for whom osteoporosis is the bane of their sunset years. I applaud the goal of trying to spare them such a fate.
However, pursuing that goal demands as much rigor in reporting the science as in performing the science. If the science demonstrates a tenuous, small effect, then no one should be led to think otherwise.
Dr. Nortin Hadler is professor of medicine and microbiology/immunology at theUniversity of North Carolina at Chapel Hill, and an attending rheumatologist for University of North Carolina Hospitals.