What Works for Knee Pain? Good Medicine, Bad Medicine, and Wasted Money

Knee pain is a very common problem, affecting young and old alike.  Among athletes, knees take a beating, particularly in sports that involve running and twisting.  Among older people, the cartilage that provides a cushion in our knees often just wears out, producing chronic stiffness and pain.

I've had knee problems myself, so I was interested to see an article posted on CNN, with content from Harvard Medical School called "Alternative Treatments for Knee Pain."  Would it describe "alternative" medicine, as in "complementary and alternative medicine," or would it present real medicine for knee pain?

A little of both, as it turns out.  But it does more: it inadvertently illustrates one of the major flaws with the U.S. health system.  We don't discriminate between effective and ineffective treatments, and some doctors seem content to let patients try anything, regardless of efficacy or cost.

The article describes several treatments for knee pain, and for each one it turns to Eric Berkson, M.D., for an opinion on how well the treatment works.  Berkson is an orthopaedic surgeon at Massachusetts General Hospital and an Instructor in Orthopaedic Surgery at Harvard Medical School.

Despite these excellent credentials, Dr. Berkson doesn't seem to have a firm command of science-based medicine. The article starts out strong, recommending the most effective therapies, but then wanders into unproven therapies, and concludes with Berkson making an unscientific recommendation for the most wildly ineffective treatment of all: acupuncture.  Let's look quickly at each "alternative."

The most effective treatments, according to Dr. Berkson, are physical therapy and weight loss.  Berkson is on solid scientific ground here: physical therapy strengthens the muscles around the knee, relieving some stress on the joint, and weight loss does the same thing by reducing the load directly.  If you stopped reading at this point, you'd be in great shape.

Next is a discussion of chondroitin and glucosamine, two very popular supplements that are often used to treat joint pain.  After many years of competing claims about these supplements, NIH conducted a large, $12.5 million study called GAIT to test whether these supplements worked for knee pain. The researchers looked at glucosamine and chondroitin separately and together, and compared them to a standard pain reliever (celecoxib, brand name Celebrex®, an NSAID) and to a placebo.

The conclusion: celecoxib worked, but the supplements did not.  In a small subset of patients with moderate to severe pain, there was a hint of a benefit for glucosamine-condroitin, but it wasn't significant.  For patients with mild pain, though, only celecoxib was better than a placebo.

Despite this large and compelling study, Berkson says
"there's a lot of evidence that they [glucosamine and chondroitin] work, but only in a certain percentage of patients." 
Perhaps he's referring to patients with moderate to severe pain from the GAIT study, but the article doesn't explain if that's what he means.  And then Berkson recommends them anyway, saying "there's little downside to trying the supplements."  Especially if it makes the patient think the doctor is helping.

The article then describes three different treatments that involve injections of various substances into the knee.  To keep this brief, I'll just consider the first: viscosupplementation, a fancy name which means that hyaluronic acid is injected into the knee. It's supposed to help lubricate the joint, which sounds plausible: after all, we lubricate machines to keep them running smoothly.  Shouldn't some "grease" help our knees?

For hyalonuric acid, the answer is simply no.  A large review just last year, involving over 12,000 patients (Rutjes et al. 2012) shows that hyaluronic acid has little or no benefit, and possibly causes harm.  Their conclusion:
"In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events."
Berkson's own colleagues, the American Academy of Orthopaedic Surgeons, just issued a 1200-page report on treatments for knee osteoarthritis, and they found strong evidence against the use of hyalonuric acid.  To be specific, the AAOS says "We cannot recommend using hyaluronic acid for patients with osteoarthritis of the knee."  They label this a "strong" recommendation.

Despite the the advice of his own professional organization, Dr. Berkson says
"I have some patients who think [hyalonuric acid is] a miracle drug that keeps their symptoms at bay.  Given that the risks of injection are very low, it makes sense to try it if insurance will pay."
Oh my.  Here we have a medical expert recommending an expensive treatment - he estimates the cost is about $1500 - despite the evidence, apparently because he has patients who think it works.  Paying for expensive, ineffective procedures is a poor way to treat patients and a great way to run up costs.

(Aside: I might seem to be picking on Dr. Berkson here, but I think his responses are probably typical of many practicing doctors.  Not to excuse him, but it's easy to follow your instincts and to rely on anecdotes from patients.)

After briefly discussing two other injection therapies, the CNN/Harvard article addresses one last alternative: acupuncture.  It quotes Berkson again, this time saying:
"Acupuncture works in some patients, although I don't think science knows exactly why it works. It's worth trying if other things aren't working for you."
Despite Dr. Berkson's comment, the science doesn't support him.  Acupuncture for knee pain, and for other pain, simply doesn't work.  (See this article for a lengthy discussion, with citations.)  Just to pretend for a second: in order for acupuncture to work, there would have to be lines of force (called "meridians") through which a mystical, apparently unmeasurable life force ("qi") flows, and furthermore you'd have to be able to manipulate this life force by plunging needles into the skin.  There is no support whatsoever for these ideas in human biology and physiology.

The American Academy of Orthopaedic Surgeon's report addresses acupuncture too, stating that "We cannot recommend using acupuncture in patients with symptomatic osteoarthritis of the knee."

Dr. Berkson's recommendation is akin to a shrug: while admitting that he doesn't know why it might work, he just says to give it a try.  His own professional organization, after an extensive review of the scientific evidence, disagrees.

The CNN Health article, with "content provided by the faculty of the Harvard Medical School," demonstrates in a microcosm how health care dollars are wasted in the U.S.  First it recommends the most effective and least expensive treatments: weight loss and exercise.  Both of these involve lifestyle changes that are difficult for many people.  The article then suggests alternative treatments for knee pain that include:

  1. Glucosamine and chondroitin supplements - ineffective but cheap. 
  2. Knee injections of hyalonuric acid - ineffective and very expensive.
  3. Acupuncture - ineffective, wildly implausible, and sort of cheap.

Despite the evidence against them, the doctor quoted throughout the article recommends trying all three, especially if (as is common) the patient doesn't have to pay the bills.

Science only supports three treatments for knee pain, as physician Harriet Hall summarized in her recent blog post: exercise, weight loss, and NSAIDs.  The "alternatives" described by CNN, no matter how appealing they sound, are a waste of time and money.

Supreme Court bungles the science in DNA patent decision

[This is slightly modified from my post 2 days ago at Forbes.]

The Supreme Court ruled this week that Myriad Genetics doesn't own your DNA after all.  Myriad holds patents on the BRCA1 and BRCA2 genes, which are linked to an increased risk of breast and ovarian cancer, and they charge exorbitant fees for their DNA diagnostic test of those genes.  As I've written before (such as this 2012 Clinical Pharmacology article), Myriad didn't invent the genes, and the patents should not have been granted.  So in large part the Supreme Court got it right.

But they got the science wrong, as any geneticist reading today's decision will realize immediately. In the very first paragraph, they make no less than three errors of fact.  First, they write:
"The nucleotides that code for amino acids are 'exons,' and those that do not are 'introns.' "
Not correct.  Here's the facts: when making DNA into a protein, the cell copies DNA into RNA.  Big chunks of the RNA are spliced out and discarded.  Those are "introns."  What remains is "exons."  That's it.  The nucleotides that code for amino acids are contained within the exons, but they are not the same thing. It's not unusual for 25% or even 50% of the nucleotides in the exons to be ignored when stringing together amino acids to make a protein.

Error number 2 comes next, when the Court writes:
"They [scientists] can also synthetically create exons-only strands of nucleotides known as composite DNA (cDNA)."
Wrong again.  cDNA stands for complementary DNA, because the DNA produced is the complement of the original strand. This means that each nucleotide is replaced with its complement: A and T are complementary, and C and G are complementary.  The court gets this right later on in the ruling.

Just after this, they write:
"cDNA contains only the exons that occur in DNA, omitting the intervening introns."
Ouch! Wrong again.  cDNA simply means a complementary copy of DNA, which doesn't have anything to do with exons.  If you make a cDNA from a mature messenger RNA transcript, then yes, it will contain only the exons.  But you can make cDNA from other parts of the genome, and from other types of RNA transcripts.

There are more errors further down in the decision. For example, they write that "Nucleotides that do not code for amino acids, in contrast, are known as 'introns.' "  This just compounds one of the errors above.  They also used the term "pre-RNA" instead of the correct term "pre-mRNA."  I could go on.

It's troubling that the highest court in the land can't get even the basic facts of molecular biology right when writing a decision that has such fundamental importance to genetic testing, the biotechnology industry, and health care.  I cannot pretend to know who they got to do their biology background research, but any genetics graduate student could have done far better.

PNAS and the eHarmony dating site: a perfect match

Well, here's a shocker.  eHarmony, the online dating service, commissioned a survey that found out that couples who get married after meeting online are more satisfied than other couples.

I'm sure there's no bias in that survey.

But here's another shocker: a leading scientific journal just published the eHarmony survey as a bona fide scientific study.  The lead author is a consultant to eHarmony (and a former advisory board member) and another author is eHarmony's former research director, Gian Gonzaga.  According to the published paper, Gonzaga designed the study.

The journal in question is the Proceedings of the National Academy of Sciences (PNAS), a high-profile journal that is published by the prestigious U.S. National Academies.

Why would PNAS publish an article that is basically an advertisement for eHarmony.com?  I'm sure the editors at PNAS would argue that it's a well-executed scientific study, but they sure got lots of publicity, with articles in the Los Angeles Times, USA Today, and Nature, not to mention a short piece in Forbes. (And yes, I'm doing it too.) A cynic might point out that both eHarmony and PNAS got what they wanted.

But what about the study itself?  Well, let's take a look.  The study, titled "Marital satisfaction and break-ups differ across on-line and off-line meeting venues," is based on a survey of 19,131 people who got married between 2005 and 2012.  6,654 of these people met online, 35% of the total, which is a surprisingly high percentage.

The headline result is the claim that couples who met online have "higher marital satisfaction." People who met this way reported a satisfaction of 5.64, on average, versus 5.48 for those who met offline.  That's a very small absolute difference, but with such large numbers in the survey, even this small difference is, in a narrow technical sense, statistically significant. The satisfaction scale ranged from 1 "Extremely Unhappy" to 7 "Perfect."  So all this fuss and publicity is over a difference between 5.5 and 5.6 in a survey.

But the higher average satisfaction might have nothing to do with how the couples met.  In my reading of the study, it seems much more likely that other factors explain the difference.

Several things are immediately obvious when one looks at the composition of the online versus offline couples.  The online couples are significantly older, wealthier, and more educated: for example, 40.5% of those who met their spouse online reported an income of $100,000 or more, compared to just 26.1% of the offline couples.  These factors alone could explain the difference in marital happiness.

The authors claim that they controlled for all of these confounding factors, and that the marital satisfication score was still significantly higher for online couples. Alas, they don't provide enough details, even in their supplementary data, to evaluate this claim. I guess we're just supposed to trust them. (Note: I believe them when they say they controlled for these variables.  I'm just not sure precisely how they did it, or if the control function really eliminated all bias.) They did recruit two independent statisticians as co-authors, which is supposed to assure us that they were unbiased. But these steps wouldn't eliminate bias that might have crept in earlier, when the eHarmony-sponsored survey was being conducted.

The article also reports the marital satisfication score of specific online dating sites. Guess which one scores the highest? That's right: eHarmony.  Why am I not surprised?

At the end of the article, the authors speculate about why couples who met online might have more satisfaction in their marriages.  (This assumes, of course, that the effect is real.)  They suggest that
"among on-line dating sites, it is also possible that the various matching algorithms may play a role in marital outcomes."  
There it is!  That's the conclusion that eHarmony wanted.  I think they got their money's worth.

In many ways, this study seems like the often-criticized studies funded by drug manufacturers that find small but significant benefit for the sponsors' drugs. Certainly there's a difference here, in that the only result is that someone might be convinced to try an on-line dating site, which might not be harmful at all.

It seems that eHarmony has found another perfect match: PNAS and eHarmony.com.

(Note: The authors did make all their raw data available, a feature that is still quite rare in scientific publishing.  They deserve kudos for doing so.  I've long advocated for more openness in data release and these authors have done the community a service by releasing theirs.)