Articles

Vertebroplasty for compression fractures due to osteoporosis: Placebo medicine

If there’s one thing we emphasize here on the Science-Based Medicine blog, it’s that the best medical care is based on science. In other words, we are far more for science-based medicine, than we are against against so-called “complementary and alternative medicine” (CAM). My perspective on the issue is that treatments not based on science need to be either subjected to scientific scrutiny if they have sufficient prior plausibility or strong clinical data suggesting efficacy or abandoned if they do not.

Unfortunately, even though the proportion of medical therapies not based on science is far lower than CAM advocates would like you to believe, there are still more treatments in “conventional” medicine that are insufficiently based on science or that have never been validated by proper randomized clinical trials than we as practitioners of science-based medicine would like. This is true for some because there are simply too few patients with a given disease; i.e., the disease is rare. Indeed, for some diseases, there will never be a definitive trial because they are just too uncommon. For others, it’s because of what I like to call medical fads, whereby a treatment appears effective anecdotally or in small uncontrolled trials and, due to the bandwagon effect, becomes widely adopted. Sometimes there is a financial incentive for such treatments to persist; sometimes it’s habit. Indeed, there’s an old saying that, for a treatment truly to disappear, the older generation of physicians has to retire or die off.

That is why I consider it worthwhile to write about a treatment that appears to be on the way to disappearing. At least, I hope that’s what’s going on. It’s also a cautionary tale about how the very same sorts of factors, such as placebo effects, reliance on anecdotal evidence, and regression to the mean, can bedevil those of us dedicated to SBM just as much as it does the investigation of CAM. It should serve as a warning to those of us who might feel a bit too smug about just how dedicated to SBM modern medicine is. Given that the technique in question is an invasive (although not a surgical technique), I also feel that it is my duty as the resident surgeon on SBM to tackle this topic. On the other hand, this case also demonstrates how SBM is, like the science upon which it is based, self-correcting. The question is: What will physicians do with the most recent information from very recently reported clinical trials that clearly show a very favored and lucrative treatment does not work better than a placebo?

Here’s the story that illustrates these issues, fresh from the New York Times this week:

Two new studies cast serious doubt on a widely used and expensive treatment for painful fractures in the spine.

The treatment, vertebroplasty, injects an acrylic cement into bones in the spinal column to ease the pain from cracks caused by osteoporosis, the bone-thinning disorder common in older people. Doctors began performing it in this country in the 1990s, patients swore by it — some reporting immediate relief from terrible pain — and it soon caught on, without any rigorous trials to determine whether it really worked.

The new studies are exactly the kind of research that health policy experts and President Obama have been calling for, to find out if the nation is spending its health care dollars wisely, on treatments that work. A bill passed by Congress this year provides $1.1 billion for such so-called comparative effectiveness research.

The studies of vertebroplasty, being published Thursday in The New England Journal of Medicine, found it no better than a placebo. But it remains to be seen whether the findings will change medical practice, because they defy the common wisdom and challenge a popular treatment that many patients and doctors consider the only hope for a very painful condition.

These are the two studies in question, and they were published in last week’s New England Journal of Medicine. Whenever a journal as prestigious and widely read as the NEJM publishes two studies of the same clinical question in the same issue, as companion studies, it’s trying to send a message. This time, the message is loud and clear:

  1. Kallmes DF, Comstock BA, Heagerty PJ, Turner JA, Wilson DJ, Diamond TH, Edwards R, Gray LA, Stout L, Owen S, Hollingworth W, Ghdoke B, Annesley-Williams DJ, Ralston SH, Jarvik JG (2009). A randomized trial of vertebroplasty for osteoporotic spinal fractures. New Engl. J. Med. 361:569-579.
  2. Buchbinder R, Osborne RH, Ebeling PR, Wark JD, Mitchell P, Wriedt C, Graves S, Staples MP, Murphy B (2009). A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. New Engl. J. Med. 361:557-568.

Before I get into the meat of the studies, let’s take a look at what vertebroplasty is. Vertebral fractures in patients with osteoporosis represent a very difficult problem to deal with. The reason is that they can be extremely painful and, worse, very difficult to get to heal using conventional methods. Indeed, the pain can be so severe that powerful narcotics are the only thing that can control it. Given that it can sometimes take months for such fractures to heal (if they heal at all), “conservative” treatment is not very satisfactory. Not surprisingly, a search for treatments that could decrease the disability, pain, and even death from these fractures was imperative. Years ago, a procedure known as percutaneous vertebroplasty, which involved the injection of polymethylmethacrylate directly into the vertebral compression fracture under the guidance of fluoroscopy, was first reported. Initial anecdotal reports suggested a very rapid and effective relief of pain after the procedure. The other aspect of vertebroplasty that led physicians to believe that it could work to relieve pain from compression fractures is that the technique had some degree of prior plausibility. The concept was that the injection of cement into the fracture would provide rapid stabilization of the fracture and therefore rapid relief of pain. It’s never been proven that that is the mechanism, but, according to the principles of prior plausibility, there was at least a reasonable hypothesis as to how vertebroplasty might stabilize fractures and relieve pain.

Now let’s take a look at the introduction of Buchbinder et al:

Observational studies suggest that there is an immediate and sustained reduction in pain after this procedure is performed,5 but data from high-quality randomized, controlled trials are lacking. The best currently available evidence for the efficacy of vertebroplasty comes from one randomized, open trial involving 34 patients and two quasi-experimental, open, controlled, before–after studies that compared vertebroplasty with conservative treatment. Although each study showed an early benefit of vertebroplasty, methodologic weaknesses cast doubt on the findings. In particular, the lack of blinding and the lack of a true sham control raise concern that the observed benefits reflected a placebo response, an effect that may be magnified with an invasive procedure.

Does this sound familiar? For long-time readers of SBM, it should. I’ve written about it before, as have others, in two contexts. First, consider acupuncture. Time and time again, we have pointed out how acupuncture studies tend to be positive for early, smaller, less rigorously controlled studies but in larger and better-controlled studies the observed treatment effect disappears. This sort of progression is very typical for interventions that don’t produce an effect that is measurably greater than that of a placebo. And it is this sort of progression that appears to have occurred for vertebroplasty. Indeed, look at this New York Times article from four years ago:

No one is sure why it helps, or even if it does. The hot cement may be shoring up the spine or merely destroying the nerve endings that transmit pain. Or the procedure may simply have a placebo effect.

And some research hints that the procedure may be harmful in the long run, because when one vertebra is shored up, adjacent ones may be more likely to break.

But vertebroplasty and a similar procedure, kyphoplasty, are fast becoming the treatments of choice for patients with bones so weak their vertebrae break.

The two procedures are so common, said Dr. Ethel Siris, an osteoporosis researcher at Columbia University, that “if you have osteoporosis and come into an emergency room with back pain from a fractured vertebra, you are unlikely to leave without it.” She said she was concerned about the procedures’ widespread and largely uncritical acceptance.

Sound familiar? If not, consider this quote:

“I struggle with this,” said Dr. Joshua A. Hirsch, director of interventional neuroradiology at Massachusetts General Hospital in Boston. He believes in clinical trials, he said, but when it comes to vertebroplasty and kyphoplasty, “I truly believe these procedures work.”

“I adore my patients,” Dr. Hirsch added, “and it hurts me that they suffer, to the point that I come in on my days off to do these procedures.”

Again does this sound familiar? How many times have we heard the same sorts of quotes from CAM practitioners? Dr. Hirsch apparently started with the noblest of motives, wanting to relieve his patients’ unremitting pain from spinal metastases due to cancer or fractures due to osteoporosis. He still believed in 2005 that he was helping; otherwise he would probably have abandoned vertebroplasty. Many CAM practitioners start out similarly, no doubt. They come up with a method or a treatment, see what appears to be a good result, become convinced that it works, and thus become true believers. The difference is that, as an academician Dr. Hirsch at least felt uneasy about advocating this therapy without adequate research or strong objective evidence to show that it really works better than a sham procedure, because doing so goes against his academic training. Nonetheless, Dr. Hirsch convinced himself by personal observation and small pilot studies that the procedure works, even though before the studies I’m about to discuss the evidence supporting vertebroplasty was actually very similar to the state of evidence for acupuncture in that the best evidence for the efficacy of vertebroplasty were two unblinded trials comparing vertebroplasty with medical management. Not surprisingly, they were positive trials showing a benefit for vertebroplasty over medical management. That the the Director of Interventional Neuroradiology at Massachusetts General Hospital could convince himself that an unproven treatment works on the basis of personal observation and small pilot studies simply shows how easy it is to persuade oneself to believe what one wants to believe, no matter how scientific one views oneself.

Then comes hard, cold science.

First up is a multi-institutional study (Kallmer et al) involving five centers in the United States, five centers in the United Kingdom, and one center in Australia, led by David F. Kallmes, M.D. at the Mayo Clinic and Jeffrey G. Jarvik, M.D., M.P.H. at the University of Washington. According to the methods, “sites were selected on the basis of having an established vertebroplasty practice for osteoporotic fractures, an enthusiastic local principal investigator, and an available research coordinator.” The study was designed as a randomized, controlled, study, in which the experimental group underwent standard vertebroplasty, while the control group underwent a sham procedure in which local anaesthesia was infused, and verbal and physical cues, such as pressure on the patient’s back, were given. To complete the sham, the methacrylate monomer normally used to make up the glue was opened to simulate the odor associated with mixing of the cement. However, the vertebroplasty needle, the needle was not placed and the cement was not infused into the frature. Patients with fractures due to bone metastases, bleeding disorders, and a few other criteria were excluded. Overall it was a sound design, but the investigators had trouble recruiting patients to the trial. Indeed, the NYT article from 2005 describes just this for Dr. Jarvik’s trial:

In 2002, a group of researchers received a federal grant for a clinical trial that would be the first to rigorously assess vertebroplasty. But their study is faltering.

Patients in severe pain have proved unwilling to enter such a trial, in which they might be randomly assigned to get a placebo, and their doctors have been reluctant to suggest it. In 18 months, the investigators have been able to persuade just three medical centers to recruit patients, and only three patients have enrolled.

Now the investigators are looking for centers overseas, but they agree that the study’s prospects are dim and that its failure would leave critical questions unanswered.

“Whose responsibility is it to decide that something should be part of medical practice without adequate evidence that it works?” asked Dr. Jeffrey G. Jarvik, an investigator with the study and a neuroradiologist at the University of Washington.

Whose indeed? Once a belief has taken hold that a procedure works, it’s sometimes hard to persuade patients and physicians that a randomized study is ethical. Imagine how hard a sell this study would be to a patient at the apogee of pain from a compression fracture. That’s why there was a crossover design, in which patients, after one month, were allowed to crossover to the other group if they did not have adequate pain relief at one month.

In any case, this study was a resoundingly negative study. There were 131 patients enrolled (68 vertebroplasties and 63 simulated procedures), and the two groups were well matched. Both groups noted immediate and comparable improvement in disability and pain scores immediately after the intervention. At one month, there was no statistically significant difference between the control and vertebroplasty groups. The only hint of a possible effect is that there was a trend towards a higher rate of clinically meaningful reduction in pain in the vertebroplasty group, although, quite frankly, this result strikes me as a bit of the old trick of looking at multiple outcomes, trying to find one that comes out statistically significant. Let’s put it this way. This study is about as “positive” as any of the acupuncture studies we’ve dissected.

The second study (Buchbinder et al) was performed in Australia by a group led by Rachelle Buchbinder, Ph.D. It, too, was a multi-institutional study, with a control group that underwent vertebroplasty. The sham procedure was slightly different for this group, and, in my opinion, more rigorous. They underwent the same procedures as those in the vertebroplasty group up to the insertion of the 13-gauge needle, and to simulate vertebroplasty the vertebral body was gently tapped. As was done for Kallmes et al, the cement was prepared so that its smell permeated the room. Unlike Kallmes et al, there was no crossover was permitted in the design of this study. A total of 78 patients were enrolled and 71 completed the 6-month follow-up.

Buchbinder et al reported results that were just as unimpressive as those reported by Kallmes et al. In fact, they were more so, so much so that I will quote the abstract:

Vertebroplasty did not result in a significant advantage in any measured outcome at any time point. There were significant reductions in overall pain in both study groups at each follow-up assessment.

Can you say “placebo”? Sure, I knew you could.

Like Dr. Jarvik, Dr. Buchbinder crunched the data, looking for any outcome that could be considered even trending towards positive. She found none. This was about as negative a study as you can imagine, even more negative than most studies of homeopathy and acupuncture. This study found zero evidence that vertebroplasty is anything more than an elaborate placebo. Like acupuncture and homeopathy, come to think of it, the only difference being that there was some degree of prior scientific plausibility. Prior plausibility made vertebroplasty worth studying; however, these two trials provide emphatic evidence that it does not work, so much so that it surprised the authors, even though the very reason that the study had been done was because of nagging doubts that reported results seemed too good to be true:

Kallmes did the study because he always though the results reported for vertebroplasty seemed too good to be true–everyone got good results no matter how much cement was injected or what technique was used. And the mechanism through which vertebroplasty provided pain relief was a bit of a mystery. He figured if vertebroplasty was as good as promised, it would be easy to prove. He never expected results as stone cold negative as they were.

This is, of course, quite true. If vertebroplasty worked so well, it shouldn’t have taken much of a randomized trial to show it. If there’s one principle in medicine and clinical trials, it’s that dramatic treatment effects are much easier to demonstrate than weak ones. If vertebroplasty was as potent a treatment as advertised, these two trials should have easily shown its benefits. They did not. Indeed, in last week’s NYT article, there were a couple of more revealing quotes from the lead authors of these two studies:

“I’m going to be the most reviled radiologist on the planet,” said Dr. David F. Kallmes, the first author of one of the studies and a professor of radiology at the Mayo Clinic.

And:

“It does not work,” said Dr. Rachelle Buchbinder, a rheumatologist and epidemiologist at Monash University in Melbourne, Australia, and the leader of the Australian team. Dr. Buchbinder does not perform vertebroplasty and would “absolutely not” recommend it to patients, she said.

Dr. Kallmes, who helped develop vertebroplasty and has been performing it for 15 years, said his team was “shocked at the results.”

Shock is understandable. As had been pointed out in both papers, vertebroplasty had become the standard of care for the treatment of vertebral compression fractures. Medicare and insurance companies had, on the basis of unblinded studies, begun to reimburse for the procedure. Dr. Burbacher put it well:

Despite evidence that is acknowledged to be inadequate as a basis for justifying reimbursement, public institutions have recommended reimbursement for vertebroplasty. A recent position statement from various American radiologic and neurologic surgical societies also recommended funding the procedure.6 These endorsements have resulted in a dramatic increase in the number of vertebroplasties performed. For example, an examination of aggregate fee-for-service data from U.S. Medicare enrollees for the period from 2001 through 2005 showed that the rate of vertebroplasties performed during that time almost doubled, from 45.0 to 86.8 per 100,000 enrollees.14 There are also reports of repeat procedures for unrelieved pain at previously treated vertebral levels16 and of the prophylactic use of vertebroplasty in normal vertebrae that were deemed to be at high risk for fracture.

Not only is the short-term efficacy of vertebroplasty unproven, but there are also several uncontrolled studies suggesting that vertebroplasty may increase the risk of subsequent vertebral fractures, particularly in vertebrae that are adjacent to treated levels, sometimes after cement has leaked into the adjacent disk; controlled studies have shown conflicting results.

In other words, there’s money to be made. A lot of money. Combine that with “personal anecdotal experience” that suggests to both patients and the physicians who do the procedure that vertebroplasty “works,” giving interventional radiologists the feeling that they’re “doing good while doing well,” and you can see why the procedure’s use has taken off.

But what about all the reports of dramatic pain relief from vertebroplasty? They’re testimonials, of course. I’m going to go back to the 2005 NYT article:

Dr. Jensen knows firsthand how powerful such stories can be. In the late 1990′s, when vertebroplasty was new and many doctors were looking askance at it, she gave a talk to a group of doctors in Chicago.

“I could tell by looking at the audience that no one believed me,” she said. When she finished, no one even asked questions.

Finally, a woman in back raised her hand. Her father, she told the group, had severe osteoporosis and had fractured a vertebra. The pain was so severe he needed morphine; that made him demented, landing him in a nursing home.

Then he had vertebroplasty. It had a real Lazarus effect, the woman said: the pain disappeared, the narcotics stopped, and her father could go home.

“That was all it took,” Dr. Jensen said. “Suddenly, people were asking questions. ‘How do we get started?’”

Even after these two studies, there are patients who will not be convinced, as demonstrated in last week’s NYT article:

One patient in the study, Jeanette Offenhauser, 88, said she was convinced that the cement had helped her severe back pain, even after hearing the results.

One thing that people often don’t realize and even physicians sometimes forget is that surgery and invasive procedures provide one of the most powerful placebo effects there is; so it is not surprising that a procedural intervention like vertebroplasty could appear effective at the anecdotal experience level. A lesson in history might be in order here. There was an operation that was popular in the late 1930s through the 1950s for treating angina due to coronary artery disease. It was called pericardial poudrage, and it involved opening the chest and sprinkling sterile talcum powder on the heart. The idea was that the inflammation would cause angiogenesis (the influx of blood vessels into the heart to revascularize it). We know today that the inflammatory reaction thus caused is far too minor to make up for the loss of blood flow from a major coronary artery. Still, patients reported marked improvement of their symptoms. It wasn’t until the 1950s that an actual randomized blinded trial (the patients could be blinded but the surgeons couldn’t) was performed. It found no difference between patients who had poudrage and those who just had their chests opened and closed. (Imagine trying to get that one through the IRB today.) In other words, poudrage was no different than sham surgery.

So it appears to be with vertebroplasty.

Even doctors are having a hard time accepting these results. Even Dr. Kallmes himself argues that patients who want the procedure should still be able to get it, but only under the auspices of a clinical trial. That’s not entirely unreasonable, but Dr. Burbacher disagrees and says that these studies should be enough to abandon vertebroplasty. In an accompanying editorial, Dr. James Weinstein of the Department of Orthopaedics, Dartmouth Medical School, argued:

President Barack Obama has called for more comparative-effectiveness research as part of the American Recovery and Reinvestment Act. Although clinical trials are an integral part of such research, from a safety and effectiveness standpoint, data from clinical trials combined with those from registries or other large longitudinal databases are necessary to provide the best evidence. Americans prize advances in technology. However, if in major medical challenges, such as osteoporotic vertebral compression fractures, the alternative is to pay the cost of perpetual uncertainty, we need to support the research necessary to provide sufficient efficacy and safety information for patients to make a truly informed choice. Although the trials by Kallmes et al. and Buchbinder et al. provide the best available scientific evidence for an informed choice, it remains to be seen whether there will be a paradigm shift in the treatment of vertebral compression fractures with vertebroplasty or similar procedures.

That is indeed the question, isn’t it? Here’s the challenge. Given these two rather definitive randomized studies showing in essence no benefit for vertebroplasty over a placebo intervention, what will we as science-based physicians do? Will we abandon a procedure against which the evidence has been accumulating, culminating in two large randomized studies that found no real benefit in terms of pain relief? Unlike homeopathy, for instance, vertebroplasty has a complication rate. It’s low, but it’s there. Harm can be done, and these studies suggest there is no benefit to make the risks worthwhile. Or will we behave as CAM advocates behave and refuse to believe because we know from our own experience that it “works”?

What will we do?

Dr. Weinstein, ironically enough, suggests what may well happen:

In an interview, Dr. Weinstein, who does not perform vertebroplasty, suggested that rather than abandoning the procedure, doctors could let patients decide for themselves, by telling them, “This is a treatment option no better than a placebo, but if you want to consider a placebo because you might benefit from it, you might want to know that.”

A $3,000 placebo? If given the choice between a pricey $3,000 placebo and a CAM placebo like acupuncture, which is likely to cost less than that and not have the potential for complications, I would pick the acupuncture, quite frankly, because the potential for harm is less than sticking needles into vertebrae and injecting cement. Really, if allegedly science-based practitioners make this sort of argument, then why not just offer CAM to patients as a placebo?

Here’s my prediction. These studies will not be enough to change practice, at least not in the short term. Vertebral compression fractures are a serious problem for which other treatment options (bed rest, pain killers, and back braces while the fractures heal) are both slow and not palatable to patients or physicians, who want immediate results. However, unlike CAM practitioners, eventually physicians will yield to the weight of the negative evidence. There may be a few more studies, and it’s even possible that there may be found a subgroup of patients who actually do benefit from vertebroplasty, but eventually the procedure will either be abandoned or scaled back to patients who might actually benefit from it. The process may be far messier than we would like. It may take far longer than we would like. It may even take a turnover to a new generation of physicians for the process to be complete. But, make no mistake, science will win out.

Science-based medicine, in contrast to CAM, is inherently self-correcting. The problem is that we as science-based practitioners are just as prone to the same sort of thinking that causes CAM remedies that are no more effective than placebo persist against all negative scientific evidence. It’s a fact that we can easily forget if we are not careful. If we forget that we are just as prone to being fooled by personal anecdotal experience as any CAM practitioner, then we will be no different than they, the only difference being our choice of placebo-based therapies.

Posted in: Clinical Trials, Science and Medicine, Surgical Procedures

Leave a Comment (33) ↓

33 thoughts on “Vertebroplasty for compression fractures due to osteoporosis: Placebo medicine

  1. stephend50 says:

    Nice summary and editorial, I read the abstracts but muss confess that I did not read either of the articles. The point of your that struck home for me was how treatments with really significant results being easier to demonstrate in controlled trials. It would have been nice to hear that point of view back in medical school when we had lectures by CAM providers. They had elaborate reasons why CAM was sooo hard to study.

  2. Tim Kreider says:

    Thanks for this terrific post. It’s interesting how a pair of reports that fly in the face of prevalent beliefs and financial incentives got published in one of the most prestigious medical journals. Guess the system works, at least eventually!

  3. Ed Whitney says:

    OK, now the tricky part.

    Assume that vertebroplasty is not effective and ought to be abandoned. Is there any need to have a separate trial for kyphoplasty, or should it be abandoned as well because it is so similar to vertebroplasty that the effect is likely to be the same?

    The link to the earlier post on EBM (http://www.theness.com/neurologicablog/?p=51) notes that duloxetine is effective for diabetic neuropathy, and that it is likely to be effective for other kinds of neuropathic pain, and that off-label use of medication can be scientifically justifiable when the pharmacology is reasonable. Doing separate RCTs for every application of a drug would be impractical.

    So, now that vertebroplasty appears to be ineffective, there are two possible attitudes to take in the absence of a published trial. (There are 14 trials listed at clinicaltrials.gov, but nothing is yet published). One attitude is that kyphoplasty is so similar to vertebroplasty that it should be discontinued until the RCTs for compression fracture are published. The other is that kyphoplasty is so different from vertebroplasty that it should be continued until the RCT results are published.

    One other thing to think about. Vertebroplasty has been shown to be equivalent to a sham procedure in which the affected vertebra is injected with an anesthetic, and the vertebra is tapped gently to simulate the actual injection of cement. Does this mean that vertebroplasty is no different from patting the patient on the back (without needles) and told that there is no point in doing any additional procedures? The actual comparison in the NEJM is not with “doing nothing,” but with a minimally invasive procedure in which a pharmacologically active anesthetic is injected.

    I do not think that there are any right or wrong answers to these questions, but I do think that their discussion would shed more light on just what it means to do science-based medicine.

  4. Patricia says:

    I have a different take on the data.

    There wasn’t a third arm, conservative care. We don’t have data comparing either arm against conservative care

    So we have clinician and patient experience which says something happens during the procedure and many people get better, fast. We have data that shows injecting the cement doesn’t improve results compared to a sham procedure.

    Maybe local anesthesia around the fracture is actually beneficial, not the cement. Maybe the sham procedure really isn’t a sham, it has benefits of which we are unaware. We don’t know because that study hasn’t been done. Of course, who would do it? It would be an incredibly tough sell. I would be interested in seeing conservative care versus local lidocaine. The data suggest that may be an interesting study.

    I am a clinician who has seen that “Lazarus effect”. I’ve also seen plenty of people who get multiple vertebroplasties and don’t really get any better in the big picture, because they get accelerating fractures in their other vertebral bodies.

    I know people are VERY attached to this procedure and will never give it up voluntarily. This study has resulted in a lot of conversation where I work. I haven’t spoken to our interventional radiologists regarding this study. I am eager to see what their take is.

  5. I thought about kyphoplasty as well. There is at least one trial comparing vertebroplasty to kyphoplasty and showing no difference: http://www.ncbi.nlm.nih.gov/pubmed/19513578?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

    Perhaps that should be enough to ding kyphoplasty. Not in the real world, of course.

    Great post.

  6. David Gorski says:

    There wasn’t a third arm, conservative care. We don’t have data comparing either arm against conservative care

    Actually, we do. There are two studies that were unblinded and compared vertebroplasty to conservative care, both of which were referenced in each paper. All such a comparison would do in this study is to show the magnitude of the placebo effect due to vertebroplasty. Indeed, you’re making a very similar argument to the one made by acupuncture mavens when they see acupuncture trials that include only sham versus “real” acupuncture.

    As for whether the sham procedure was active, that possibility was addressed in both papers. Basically, the duration of the local anaesthetic is too short, and virtually the entire benefit in terms of pain relief from vertebroplasty occurs rapidly, within the first month.

  7. Ed Whitney says:

    The effectiveness of a sham procedure came up several years ago when Spine published a study of prolotherapy vs. saline injection and found them to produce equal and clinically significant improvements (Yelland et al, Spine 2004;29:9-16). The study had entry criteria which included having at least 6 months of pain not relieved by conservative treatment. The observation period was 2 years. Each group had 6 injections spaced 2 weeks apart.

    The comment on this article by John Loeser said, “Perhaps just putting a needle into someone’s back is beneficial, independent of what, if anything, is injected. We should remember, of course, that every needle has a sharp end that goes into the patient and a blunt end that is attached to a health care provider. Anyone who thinks that all of the action occurs at the sharp end does not understand human behavior. ”

    There are unmeasured variables that operate on the “blunt end” of the needle. As Spine noted in the prolo study, these variables would be intriguing to explore.

  8. David Gorski says:

    I note that in the Kallmer et al paper, no needle was actually inserted into the vertebrae, other than local anesthesia injected subcutaneously, which only lasted a few hours. I doubt “active placebo” was a factor in that study.

  9. Ed Whitney says:

    Buchbinder and Kallmer did things a bit differently indeed. I have not read the kyphoplasty protocols at clinicaltrials.gov to see the extent to which they are using needles in the control groups.

    I am still interested in what David thinks about how kyphoplasty should be approched pending the publication of the trials. I honestly do not know what I would tell a family member who had a painful compression fracture and was scheduled for kypho the day after tomorrow. Maybe the balloon makes a difference and maybe it does not. I would hate to dissuade them if kypho turns out to be effective, but also would hate to tell them to go through with it if the trials are going to come up with the same answer as vertebroplasty.

    Boils down to decision making under conditions of uncertainty I suppose.

  10. wertys says:

    This study very nicely illustrates science based medicine. At my public hospital unit we have been looking at the data over the last three years trying to decide whether we should get into vertebroplasty or not. The immediate appeal is that it seemed capable of reducing the lengthy admission period and immobility associated with these fractures. Our concerns were with safety and lack of convincing RCT efficacy data. This study is in fact so resoundingly and convincingly negative that further study looks unjustifiable. The treatment was given every fair chance to work in a well-powered and well-designed study, and it looks like a dud no matter how you slice the data. As always Dr Gorski, well summarized and presented.

  11. pmoran says:

    Wertys: “The immediate appeal is that it seemed capable of reducing the lengthy admission period and immobility associated with these fractures. ”

    As Patricia points out, the studies don’t really answer that question. They only show that if there is any such effect, it is due to an elaborate placebo being administered by ultra-confident medical personnel.

    The full procedure looks too invasive to be tolerated as placebo, even in the hands of any practitioners who continue to believe in it.

    But it would have been an interesting contribution to our understanding of medicine to know whether those patients who seem to be responding spectacularly to the treatment do become mobile and get home quicker.

  12. David Gorski says:

    Actually, it’s not true that the investigators didn’t look at disability. For instance, Kallmer et al looked at the Roland–Morris Disability Questionnaire (RDQ), Study of Osteoporotic Fractures–Activities of Daily Living (SOF–ADL) scale, the European Quality of Life–5 Dimensions (EQ–5D) scale (a generic health-status measure, reflecting mobility, self-care, activity limitations, pain, and psychological distress), and the Physical Component Summary (PCS) and Mental Component Summary (MCS) subscales of the self-administered Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36), version 2, as well as opioid use.

    Buchbinder et al looked at quality of life, as measured with the use of the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO), a 41-item vertebral-fracture–specific and osteoporosis-specific questionnaire (in which scores range from 0 to 100, with lower scores indicating a better quality of life); the Assessment of Quality of Life (AQoL) questionnaire, a well-validated instrument that is sensitive to changes in the frail elderly (scores range from 0 to 1, with 1 indicating perfect health and 0.06 representing the minimal clinically important difference); and the European Quality of Life–5 Dimensions (EQ–5D) scale (scores range from 0 to 1, with 1 indicating perfect health and 0.074 representing the minimal clinically important difference). Other secondary outcomes included the scores for pain at rest and pain in bed at night (on a scale of 0 to 10, with higher scores indicating more pain); and the score on a modified 23-item version of the Roland–Morris Disability Questionnaire (RDQ, in which scores range from 0 to 23, with higher numbers indicating worse physical functioning, and 2 to 3 points representing the minimal clinically important difference).

  13. The Blind Watchmaker says:

    This reminds me of the recent article in Archieves (I think) about accupuncture. Both real and placebo accupunture produced the same results, and both were perceived as better than NSAIDS alone (all 3 groups got NSAIDS).

    The authors concluded that…Sham accupuncture works too!

    Dohhh.

    I guess sham vertebroplasty works too!

  14. pmoran says:

    “Actually, it’s not true that the investigators didn’t look at disability.”

    While answering a critical question, these studies could have provided more understanding of what was going on if they had included a “normal care” group.

    Yes, we would expect both “treated” groups to do better subjectively than the “normal care” groups, as is usual in studies with inadequate controls, but if the emphasis was upon more objective and independently confirmable end-points such as length of hospitalization and use of opiate analgesics, this would help separate “true” placebo influences from the reporting biases that plague such studies, as well as supplying some information as to the real worth of placebo responses in this clinical context.

    It is all very well to be now able to say that the previously fairly dramatic anecdotal responses to this treatment were “just placebo effects”. But might there also be a twinge of regret that patients with an otherwise difficult condition may now be denied something that significantly helped some? We still don’t know for sure.

  15. David Gorski says:

    While answering a critical question, these studies could have provided more understanding of what was going on if they had included a “normal care” group.

    Possibly, but these data are already known from open studies of vertebroplasty versus “normal care” (just as they are already known for acupuncture versus “normal care”). In terms of resource utilization, it may not have been feasible to do. After all, in Kallmer et al, for instance, any patient entering the study was virtually guaranteed to get vertebroplasty just by crossing over after one month. Also, consider that having three experimental groups decreases the chances that a patient enrolling in the study would receive vertebroplasty from one in two to one in three. These studies were hard enough sells to do to begin with. Finally, including a “regular care” group produces a mixed blinded/unblinded study, which is harder to do and interpret than a pure blinded study

    That being said, having a few more objective measures wouldn’t have been a bad thing.

    As for whether there were subgroups for which vertebroplasty might do good, well, given these studies it’s fairly unlikely but not impossible. The problem is that it would take a much larger study than either of these (or both combined) to find such subgroups.

    No one likes telling a patient that there is little that can be done for them other than pain relief and the tincture of time, but sometimes that’s the best we have. Certainly, I’m not a fan of suggesting an expensive and invasive placebo procedure.

  16. EddieVos says:

    You’ve got to love NEJM that about monthly, uniquely and proudly starts with studies that were entirely negative. Kudos! Always worth the price of admission!

    I don’t see much difference in believing in its own therapy between ‘CAM’ and mainstream medicine except for the potential of harm without benefit, and often cost. A generic multivitamin costs $0.10, generic lovastatin $1.50, Crestor $5.10 and a hospital Lipitor pill $22 as per yesterday’s CNN. http://transcripts.cnn.com/TRANSCRIPTS/0908/11/cnr.02.html

    Regarding spinal [compression fractures] without evident ‘cure’ and massive pain and expense, my question about this whole thing is prevention: does that surgeon going in on his spare time also get a blood vitamin D and homocysteine done that may tell WHY we have fracture, with the option to treat cause rather than symptom?

    While 80% of spinal compression fractures are asymptomatic, 100% of hip fractures are not. Is there any surgeon aware that a good multivitamin pill reduced hip fractures by 80% [CI 50-95%] in an undisputed 2 year clinical trial? Not NEJM, just 2005 JAMA:
    http://jama.ama-assn.org/cgi/content/full/293/9/1082

    Cost: about zero, benefit shown and with family doctors and surgeons on board also the placebo effect. Side benefits galore [stroke prevention, for example, also RCT], sustainable and ‘evidence based’. JAMA: “ No significant adverse effects were reported. as per the first-do-no-harm principle. Treating ’cause’ added to ‘the tincture of time’.

  17. daedalus2u says:

    A major cause of osteoporosis is low nitric oxide. The fundamental regulation of bone stiffness is via deformation in the bone causing movement of fluid in the pores in the bone, the shear from that moving fluid triggers nitric oxide synthase and NO is generated in the region of the bone that experiences the most deformation. That NO activates the cells that cause the deposition of bone mineral and inhibits the cells that cause resorption of bone mineral.

    Organic nitrates (such as nitroglycerine) have been reported to be as effective as estrogen in reducing osteoporosis in postmenopausal women. Nitroglycerine is a poor NO source with lots of side effects and should not be used to try and raise NO levels. Estrogen reduces osteoporosis via a NO pathway, estrogen activates the estrogen receptor which activates nitric oxide synthase and produces NO. There is considerable thought that it is the NO from estrogen that prevents heart disease in premenopausal women. Those NO effects are separate and distinct from any hormonal effects of estrogen.

    If someone I knew had osteoporosis, I would raise their NO level before doing something invasive. Done soon enough I think that would prevent the vertebral fracture in the first place. As I have said before, the physiological placebo effect occurs by increased neurogenic NO. Conditions caused by low NO (such as osteoporosis) are going to be particularly susceptible to placebos. If low NO is causing osteoporosis, raising NO levels by any mechanism is going to make it better.

  18. Ed Whitney says:

    The saga of back pain remedies goes on.

    Check out http://www.trufuse.com/index.aspx for the promotion of a product with potentially lucrative applications and next to no data. Click on the “Physicians” link and the FAQ link and you will see no published studies, only some fluff about FDA licencing of tissue banks as “evidence” of the procedure’s effectiveness. This is a fusion procedure that lets you have it both ways: “TruFUSE fixation allows micro motion while still firmly limiting range of motion, which theoretically stimulates the body’s natural healing response.” You, too, can be a spine surgeon!

    Small wonder that low back pain is in the top quartile of the Institute of Medicine’s 100 conditions that require comparative effectiveness research.

  19. skepticg says:

    As to EddieVos and daedulus2u suggesting preventive medicine via supplement of some nature…

    How about preventive medicine by NOT doing something that has almost reached a “Mass Hysteria” now…. the taking of a possible poison that is used on a very widespread basis?

    I am talking about “vitamin” D, or chemically named, “cholecalciferol”.

    EddieVos mentions two years for studying the question. However, is that really a sufficient time? Might not some much longer period, say twenty years, or even more, as being more necessary?

    Consider that the patent for “vitamin” D / cholecalciferol was developed in the 1920′s, and is owned by WARF. WARF stands for (University of) Wisconsin Alumni Research Foundation. Like all foundations, WARF is probably most interested in raising money for their projects, such as erecting buildings or laboratories for their beloved University, and so has done all in its power to market as much of the product as possible. Was not the beginning user of cholecalciferol the diary industry, of which Wisconsin has been a big producing state?

    Consider that when cholecalciferol was first synthesized in the 1920′s, lab equipment was not as sensitive as it is today. What looked good then, might not have been good in the long run. And our knowledge has also increased. The USDA research site has a small study that shows that a lack of cholecalciferol does not cause rickets.

    From WARF, comes warfarin, a rodent poison, and the Rx drug, coumadin, which is a very controlled product, as it should be.

    From WARF, comes QUINTOX, a rodent poison, whose active ingredient is cholecalciferol. QUINTOX is tauted to kill a Norway rat in two to four days time. The mode of action is to pull calcium from the bones, and deposit it in the arterial/cardiac system. How many diagnoses of human ailments are based upon those two actions, that we readily know about, and how many more are to be discovered, yet? Does osteoporosis, as a starter, sound familiar?

    Hmmmm! unknowledgeable about QUINTOX? Do a Google search on Pleasant Valley Farm Supply, then using their search engine, enter QUINTOX. Look at the links for its mode of action.

    From untold numbers of unknowledgeable promoters, jumping on the “Mass Hysteria” of today, come all sorts of products, doing the same thing as WARF… raising money, making a profit? and poisoning people?

    Hmmmm! could cholecalciferol act like arsenic, lead and mercury? In large enough quantities, they can kill a human rather fast. In even very small quantities, though it will take longer, the results can be the same, death… with lots of pain enroute.

    The EPA protects us from even being able to buy a mercury based thermometer today at the corner pharmacy store, for fear the thermometer will break and poison us. We can no longer buy “leaded” gasoline because the fumes were found to be detrimental to children living near highways.

    At the very least, might not cholecalciferol be a highly controlled substance, until such time as truly LONG-term true studies, not just “studies” based upon correlations, tell us what the full, meaningful effects of this product are to the human body?

    Also remember that cholecalciferol is NOT the end product that is needed by the body. It is turned into 25D by the kidneys. It is 125D that is needed/used by the body, and that is almost never assayed. Most think that knowing the status of the 25D will tell the status of the 125D. Biochemist have found that end products, such as 125D, have a way of regulating precursor products. High 125D can drive 25D down. Unless, of course, there is supplementing, in this case, with cholecalciferol.

  20. EddieVos says:

    Dear daedalus2, what is your reference for NO being a cause for osteoporosis?**) One can increase it with arginine and by using statin [that promotes NO/eNOS] but both don’t prevent bone fractures or osteoporosis for all I know when compared with placebo.

    About short term studies: well, if we DO find a benefit in those, we’re on to something! I.e. in lowering homocysteine for 2 years [less hip fractures] or adding some vitamin D [less any fractures], as per
    http://www.ncbi.nlm.nih.gov/pubmed/10227320?dopt=Abstract [observational JAMA] and http://www.ncbi.nlm.nih.gov/pubmed/1331788?dopt=Abstract or
    http://bmj.com/cgi/content/full/326/7387/0?etoc both interventional.

    Yes, one can harm a mammal with doses of “D3″ [cholecalciferol] that are many orders of magnitude greater than those needed to obtain 100 nanoMoles and where health benefits are likely and largely undisputed. I believe that last happened last in the 1940′s via injection by a doctor not understanding decimal points or orders of magnitude.

    The problem with long-term studies in humans is that the average life of a research career is shorter than the lifespan of a human subject and thus we have to deal with other than RCT trials [sometimes] if the alternative science [if ethical] would come out after the average doctor in long dead. In the mean time, I take a high dose multivitamin + a single 1.25 mg D3 pill every month in summer and double that in winter [cost: about zero].

    **) The TOUGHNESS of bone is collagen [vitamin C, copper, B-vitamins] and the DENSITY is basically determined by cholecalciferol, generated in skin or taken as a pill ["Boniva" may raise the latter but decrease the former with a nearly significant increase in hip fractures that depend on 'toughness', and bisphosphonates are always to be taken with D3 and sufficient calcium anyhow].

  21. skepticg says:

    Please excuse me for being respectfully contrary.

    Calcitriol is what is produced in the skin (and possibly in the eyes in a separate system).

    Cholecalciferol is what is taken as a pill.

    They are not one and the same product.

    I suspect that when the full knowledge is shaken out, and made available by the Lord, most of the current thinking about cholecalciferol will be found to be old thinking or false.

    But that is said by one that supplemented according to the old knowlege for nineteen years, and wound up with a diagnosis of osteopenia by ultra-sound device and DEXA, and, diagnosis by chest x-ray of “granulotmatous disease as evidenced by the depositing of calcium ( in what amounts to be the soft tissue of the chest)”

    After changing my intake to carefully eliminate as much of D3 as possible for three years, I no longer was diagnosed with osteopenia or the granulomatous disease, and my left femur had increased by 31%.

  22. EddieVos says:

    Skeptig, let’s be precise: cholecalciferol = D3 in pills and also skin derived when a B sterol ring opens by UV-B radiation. That D3 is then converted in the LIVER to the storage form calciDIOL 25-OH-D3 [half life ~1 month]. ONLY when needed is that stuff converted to calciTRIOL. Paraphrasing a handbook: low blood calcium causes parathyroid hormone PTH to be released which stimulates the kidney enzyme 1-hydroxylase**) that adds an OH to the DIOL storage form 25-OH-D3 making calciTRIOL. It is when messing with the extremely powerful TRIOL and PTH hormones that things may get whacky, not from sun or pill cholecalciferol.

    If you clicked on http://www.bmj.com/cgi/content/full/326/7387/469 you may read as per BMJ editors:
    What this paper adds:
    Four monthly oral supplementation with 100 000 IU vitamin D reduces fractures in men and women aged over 65 living in the general community.
    Total fracture incidence was reduced by 22% and fractures in major osteoporotic sites by 33%.

    They question if that was enough [optimal] and as I said, I take double that. Dirt cheap [1/3rd the cost of a monthly Boniva pill get you 8 years D3 at 1700 IU/day] and OTC [no relation, no conflict by yours truly]:
    https://secure.bio-tech-pharm.com/detail.aspx?product_id=20&cat_id=2&subcat_id=0

    What is keeping doctors suggesting monthly D3 based on such placebo controlled trial evidence while they know that little else [but B vitamins, C and sufficient calcium] deals with healthy bone maintenance.
    An excellent overview: http://en.wikipedia.org/wiki/Vitamin_D

    **) It appears that when that enzyme is expressed OUTSIDE the kidney there are issues with granulomatous diseases, such as affected you, and here the situation seems rare, genetic, immune related and calling for specific action –and is complicated since it’s not clear what is ‘rate limiting’. You might email the author of Medline 17368179 for the full review. I don’t argue with what works for you, but eliminating D3 from the sun [most people's major source] would force you to live a “Michael Jackson” type sun avoidance lifestyle.

  23. skepticg says:

    http://www.massgeneral.org/children/pdfs/cascades_fall_06.pdf from the study at this link, from MassGeneral Hospital by Dr. Lynne L. Levitsky, M.D., it seems that phosphorous [phosphate] is very importanat to bone mass [density].

    “The identification of these genes provided novel insights into regulation of the mineral phosphate, which is a critical factor in the development and functioning of healthy bone and organs.”

    “Much is known about parathyroid hormone (PTH), which is the most important peptide hormone for the regulation of calcium (and phosphate) homeostasis as well as bone strength and metabolism.”

    “In contrast, the regulation of phosphate homeostasis has remained incompletely understood.”

    I have to wonder just how much additional phosphorous the people might have gotten during the trails mention in the Uk to increase their bmd.

    I did forget to mention that in my case, I did increase my phosphorous uptake with my foods, intentionly, after reading of this study, and before my last DEXA. I realize that one case does not make a study.

    Again, I mention that the USDA has one small study that shows that a lack of cholecalciferol does not cause rickets. But a rodent control product [poison], Quintox, with cholecalciferol as the main ingredient, can kill by pulling calcium out of bone and depositing it in the arterial/cardiac area.

  24. daedalus2u says:

    EddieVos, Arginine only has a transient effect on NO levels. There is compensation by production of arginase and asymmetric dimethyl arginine (and likely other mechanisms too). NO levels are too important for physiology to allow arginine concentrations to determine how much is produced.

    http://www.ebmonline.org/cgi/content/full/227/2/88

    Many treatments that do increase bone mineralization do so via a common final pathway involving NO. The reason for this is because the fundamental regulator of bone stiffness is the strain in bone due to loading, which causes the bone to flex, and results in fluid flow in the porous channels in bone that connect the various bone cells. This shear causes activation of nitric oxide synthase, in ways analogous to how shear in the vasculature activates eNOS and generates the NO that causes vasodilation.

    The “NO sensors” only sense the sum of NO from all sources including the background level of NO. If the background is lower, then the stiffness of the bone goes down, until the shear mediated NO production is high enough for the sum of NO from shear and the NO from the background to equal the level that activated bone mineralization.

    Anything which lowers background NO levels, such as stress or inflammation, or estrogen decline following menopause, increases the need for shear generated NO to reach the action level and so shifts bone stiffness lower resulting in osteoporosis.

  25. EddieVos says:

    Skepticg, you seem to have an extremely unique genetic problem and this blog is probably not the place to elucidate this. You repeat the fact there is product to kill rodents with D3. True but that takes 100 million units [calculated human/mouse weight]. This has nothing to do with bone health or calcium homeostasis and where D3 is essential for mammalian health and YES, lack of D3 IS the cause of rickets. The famous picture: http://www.health-heart.org/rickets.gif

    Interestingly, in bone health and that IS the blog topic, -and may be in granulomatous diseases- vitamin K also plays a key role .. An antagonist for that vitamin can also kill a mouse [from lack of functioning vitamin K] in the form of warfarin, or a human in the case of Coumadin ..

    What Coumadin does to bone health has never been properly investigated however a caveat from Medline 9412619 CONCLUSIONS: Bone mineral density was significantly lower in stroke patients with long-term warfarin treatment than in untreated patients. Both warfarin-induced reduction in vitamin K function and lowered vitamin K1 concentrations are probable causes of this osteopenia. How ostopenia affects the spine, subject of this blog, is not evident, or is it?

    Toxicity or benefit is all in the dose, and rarely in one’s genetics..
    That BMJ study sent people 3 envelopes/year with 2.5 mg D3 or placebo: nothing else was altered.

  26. EddieVos says:

    Dear daedalus2u, thanks for that fascinating link to the mini review by Undurti Das. I’ve long been a fan of his writing [and even more so of nitric oxide] but here he stretches the science .. and ends with suggesting trying oral NO precursor, ie arginine. Yet, if he represents the best available science out there, I have a hard time buying into NO being crucial and primary actor in bone health. I think he generates a hypothesis to tickle people’s thinking about a possible player rather than anything else.

    I think it is much more likely that osteoblasts of any type are called to action by [normal**)] micro-fissures in the calcium mineral which tickles the protrusions [processes] of osteocytes, and that then trigger all kinds of cytokines and thus clasts and blasts. REGARDLESS, without healthy [high quality] collagen being redeposited in osteoclast built pits, bone strength will suffer, and that takes at least 6 micronutrients in which MOST modern H sapiens members are low in. Acrylate is not such nutrient, and no cure to symptoms.

    **) Bone absorbs forces 2 ways: by the bending of collagen [type I] rope and the micro fissuring of the apatite built around it. In compressive tissues like spine, ‘density’ and collagen are important. In bending [like hip], the collagen is all important [kids have poor bone density but don't break hips!]

  27. daedalus2u says:

    The suggestion to use oral arginine is pervasive in the NO research community, but it only works short term. This is pretty clearly shown here

    http://circ.ahajournals.org/cgi/content/full/116/2/188

    All the different NO pathways have to be regulated up and down “in sync”, or they won’t all work properly. That is what most NO researchers fail to appreciate, that there are so many pathways involving NO, that they can’t be regulated independently.

    There is a lot of stuff on bone and NO.

    Some of those NO producing pathways are regulated by feedback control, and if inhibited increase their output until the feedback control loop is satisfied. A NOS inhibitor can increase NO levels in some places while it is decreasing it in others.

    There are many NO pathways that don’t involve sGC and cGMP. When cGMP levels are increased with PDE5 inhibitors (such as Viagra), there is feedback diminution of NO production which adversely affects pathways not mediated through cGMP. A single dose of Viagra exacerbates obstructive sleep apnea. I think by lowering NO levels via feedback inhibition through cGMP pathways, which lowers the S-nitrosothiol level which is another breath control pathway (but one which is not well understood).

    The importance of NO/NOx physiology outside the NOS enzymes is not appreciated by most NO researchers. Many that are studying NOS don’t even want to consider stuff that is not NOS mediated.

  28. skepticg says:

    EddieVos, you suggested that I look at the famous picture of the three children with rickets: http://www.health-heart.org/rickets.gif However, that picture certainly is not a scientificly based proof that vitamin D causes rickets, even though that is stated in the picture caption.

    I do feel for the chidren, however! The picture appears to have been taken in the age of poor quality milk, milk that was known to be highly adulterated, ie, watered down, or worse. Therefore, maybe lacking in calcium and phosphorous. Then, too, people did not eat nearly as much meat in days gone by, as we do today. It was very common that poor people had meat on only one day per week, if that.

    Perhaps, you have not read the report at the USDA Research site (2004), http://tinyurl.com/l63hk which states that “Rickets in toddlers is a large problem in parts of Africa, especially Nigeria. It is not due to vitamin D deficiency but is caused by not having enough calcium in the diet.”

    Perhaps you will also consider a study from the MassGeneral Hospital in the U.S.(2006): http://tinyurl.com/objchg
    which seems to imply, if not actually state, that it is calcium and phosphate (phosphorous) that is important in bone density.

    From these two reports, I would conclude that maybe it is a lack of calcium and phosphorous that is the real cause of rickets, and if a cause of rickets, it might also be involved in osteoporosis, as well.

    While at first glance the report at http://tinyurl.com/oer2yv SEEMS to imply that the taking of vitamin D increases bone mineral density. It does report good results from less bone fractures. “Four monthly oral supplementation with 100 000 IU vitamin D reduces fractures in men and women aged over 65 living in the general community. Total fracture incidence was reduced by 22% and fractures in major osteoporotic sites by 33%.”

    However, that study does not state that the bone mineral density was tested by DEXA. Only that there were less fractures! Without using the scientific method of measuring the bone mineral density, we really do not know if the less fractures observed were due to taking vitamin D or some un-thought of consequence of some other process. It may turn out that the other process may be the palliation of some symptom that causes dizziness in the observed patients, that if the dizziness no longer was experienced, would allow the patients to not fall down as often. If the sum total of those patients experienced less dizziness for even just one year out of five years because of the palliation of the unknown symptom, that would cause an approximately 20% reduction in fractures, close to what is reported.

    This is what I have referred to elsewhere in this SBM blog as “studies of correlations”, not truly scientific studies based on measured cause and effect.

    Maybe, we need to take a look at old, dearly-held medical tales, such as cholecalciferol prevents rickets, even may cause osteoporosis, and indeed, the cholecalciferol may have other effects than what has been thought for so many years. It may be harmful at some level of intake, and even at a low level of intake over many, many years. Not just two, or even five!

  29. EddieVos says:

    Skepticg: Evidently, when no calcium is ingested, vitamin D derived hormones cannot absorb it, i.e. rickets type X -and your article in African kids also found that those with rickets had lower D. There are 8 major types of rickets / osteomalacia with each about 5 causes, many related to D, calcium, magnesium, phosphate, and others.

    The number of falls in the BMJ article was not reported but there is a small randomized study that found a non significant reduction in falls of 18%, not accounting for -33% fewer serious fractures. Rather than debating this here, why not go to a published debate here:
    http://www.bmj.com/cgi/eletters/326/7387/469

    There is a reason some apes like us are naked [we don't lick our UV-B blocking fur to get vitamin D] and the further from the equator we ventured, the more lethal [to women in child birth] the lack of vitamin D, if no other source [fish liver] was consumed. Every cell type reported has vitamin D receptors, i.e. every cell depends on it, and there are only 3 sources in real life: fish liver, over 45º sun angle skin exposure, or say 6-12 pills/year.

    I agreed before that some like yourself may have a rare genetic situation where things are more complicated than the average MD could possibly deal with.

    P.S. in the Mary Chapuy [800 IU D + 1.2 g calcium/day] trial, mean 84 year old women built bone density at half the rate placebo women lost it, and 30% fewer hip fractures. Cheers!

  30. skepticg says:

    EddieVos,

    I see that you are well grounded and regimented in your thinking as a classical medical student…you mention genetics as being the cause of many problems. Genetics is what gives you your eye and hair color. It is microbe infection that probably gives you most of your medical problems, IMHO.

    I would suggest that you read and think about the work of Dr. Elizabeth Kleinberger-Nobel, Phd, and Dr. Lida Mattman, Phd, both microbiologist of note.

    A conversation with them (if you were able to do such — both are dead now ) might convince you that many of the problems that are ascribed to genetics are really microbe induced, perhaps by what might be described by those ladies as bacterial, either L-forms or cell wall deficient.

    But, I suspect, since you were not really taught about that avenue of thought in medical school, you would only want to debate the subject as non-existing because they were not proven by the Koch Postulates, an antiquated aneurysm in the history of medical learning, and already proven false in some situations.

    There are numerous animals that never see the light of day so cannot produce the 25D necessary by the classical definition of production. They still produce the necessary 125D hormone for their lives.

    Many women suffer a placenta that produces an extremely high 125D that downregulates the more often assayed and thought about 25D. It is the 125D hormone that upsets her body and finally kills her, not a lack of 25D or cholecalciferol.

    I would like to point out that your famous picture of the children with rickets is captioned, “10 mg/yr of vitamin D prevents this”, TEN MILLIGRAMS PER YEAR, not the hundreds, possibly thousands, of milligrams of cholecalciferol that are put into the processed foods that are being consumed DAILY by children in the U.S. today.

    Again, citing less fractures as meaning greater bone mineral density does not take into account numerous other factors that could enter into the equation. Only a measure of the actual bone mineral density would be science-based-medicine, and proving anything beyond a question.

    Tis a shame for mankind that so many physicians still would say that disease is spread by the bad ethers coming out of swamps, or its equivalent.

    I will retire from further discussion, and just hope that the Mass Hysteria about “vitamin” [not] D will get corrected.

    Thank you for listening to an Old Codger who has observed much in his long life.

    The Skeptic

  31. EddieVos says:

    I’ll retire also from the discussion. That 10 mg is 400,000IU. The world is NOT consuming hundreds of thousands of mg’s day. Kids are NOT overdosing on D, that’s a fact –food processors don’t put much D, and mostly D2 [not as good but cheaper and/or easier]. A glass of milk may contain 2.5 millionth of a gram of D, that’s all.
    Note, I’m not a doctor, I’m a material sciences failure specialist, and the failure of bone, artery and heart is just a hobby -with about 15 ref’s to my name in Medline.
    If doctors say: “it’s genetic”, that 99% of the time means that they don’t know. IF IT IS genetic, like in your case, you’d better get a specialist -and knowledge yourself- to do the fine tuning!
    Best of luck, Eddie V.

  32. skepticg says:

    After I said that I would retire from this discussion, EddieVos left a message that I would like anyone who reads this blog, to think about. Additionally, I stand corrected about my comment about the caption under the famous picture that he linked for me. I had been working with the idea of milligrams for some time prior to writing my comment, and that unit must have locked into my mind. However, I still question the Mass Hysteria of adding even more cholecalciferol to our diet. There is exceedingly little, modern basic research into “vitamin” D. Most studies are really a re-hash of old, and most of those seem to be conclusions based on correlations, if one reads them carefully.

    EddieVos said, ‘If doctors say: “It’s genetic”, that 99% of the time means that they don’t know.’ I agree with this statement. Genetics is the new “bad vapors out of the swamps causing illnesses” that I mentioned earlier. The “science” of a certain time was genetics, just as the “science” of another time said the earth was flat and at the center of the universe.

    EddieVos also said, ‘IF IT IS GENETIC, like in your case, you’d better get a specialist – and knowledge yourself – to do the fine tuning.’ I believe that he is referring to my having been diagnosed with granulomatous disease by chest x-ray, as mentioned in my earlier comment. I think that this may have come about because of my supplementing with cholecalciferol for so long…at least nineteen years, as indicated in an earlier comment of mine. IMHO, this “process” is the other side of the coin to the way the rodent control product, QUINTOX, works. Pulling calcium from the bone is the other side….osteopenia/osteoporosis.

    IMHO, the “science” that needs to become learned today is that many, but not necessary all, of our illnesses are microbe originated, such as Drs. Elizabeth Kleinberger-Nobel, Phd, and Lida Mattman, Phd, and a few others, have spoken to as “L-forms” and “cell wall deficient” living within our bodies.

    I failed to mention in my earlier comment that I have been tested for “L-forms / cell wall deficient” bacteria, and found to be POSITIVE, for one known variety, by two different tests, twice each test. One test looked for the antigen itself and the other for the antibody to the antigen. This bacterial “L-form / cell wall deficient” form MAY be the basic cause of what EddieVos thinks is a “genetic” problem. Again, I say that I know that one case does not make a study, but it gives a clue that this might be an interesting avenue of research.

    For one to be “science-based-medicine” compliant, one should be willing to think outside-of-the-box for some “new” thinking [science], when the old ways [science ] have not given any good answers, IMHO. It may take some time for our “tools” to measure/observe to catch up with the actual doings of nature, not what our [mis-]conceptions of them are.

    I now have some inkling of how Galileo, Pasteur, Semmelweiss, and Listor must have felt without any journals around to back their positions. :)

  33. williamclark says:

    I was the Australian operator in Kallmes et al and regard the study as meaningless. I have conveyed this to Dr Kallmes. In Sydney the most appropriate patients by-passed the study and had a vertebroplasty. I have also spoken to every IR operator (all 4) in Buchbinder et al.
    This article is a rush to judgement on “science based medicine” without applying scientific technique in appraising the studies. Verebroplasty is usually applied (in Australia) to the exquisitely painful subgroup of acute osteoporotic fractures when the pain cannot be adequately controlled by oral medication. These elderly folks find themselves incapacitated and often hospitalized unable to cope. They cannot sleep, find the pain unbearable and can talk of suicide. They may have bowel or cerebral complications from the narcotic medications. Traditionally they had up to 6 weeks in hospital. Now they have 2 days and a vertebroplasty and go home. The technique can only be truly effective on un-united fractures. In this setting it provides internal fixation of the fracture fragments and ameliorates pain. Acute fracture fixation is well recognized to reduce acute fracture pain elsewhere in the skeleton.
    Both of these studies have incorrect patient selection with back pain for up to one year. These fractures unite in 6 weeks – to inject them at 6 months defies logic and, of course, can only have placebo effect. Kallmes et al excluded all inpatients from the study due to local logistics. This is the group most likely to benefit. It is unfortunate that the authors did not mention this in the manuscript. Furthermore, 4 weeks medical therapy was mandated prior to the “outpatient” vertebroplasty. Thus. the subacute fracture group has been completely removed from Kallmes et al.
    Buchbinder et al could not recruit (aimed to recruit 200) and required 4.4 years in Melbourne, a city of 4 million people to recruit 78 patients. Two of the four hospitals (The Alfred and Monash) dropped out having done 5 vertebroplasty trial patients between them. They were concerned by the ethics of the study. Only 23 patients in Buchbinder et al had pain less than 6 weeks – too few for statistical analysis. 68% of patients were performed in one centre (Cabrini Hospital) by one radiologist who had no input into patient selection. These patients were selected by the principle author who therefore had control over the outcome of the study.
    In both studies 70% of patients refused enrolment and were not followed. This alone makes the studies meaningless and makes a mockery of the hallowed concept of sham surgical studies.
    What amazes me, a physician who has performed 2,000 vertebroplasties almost exclusively on subacute osteoporotic fractures is the ease with which these second rate studies have been accepted. They have inappropriate patient selection, terrible recruitment and selection bias with the majority not followed.
    This is not surprising with Buchbinder et al where the first four authors are physicians who have never performed a single vertebroplasty. The craft group (IR) who practice the procedure were effectively locked out of patient selection.
    If they apply the same technique to appendicectomy (right iliac fossa pain for up to one year) then they can collectively prove that appendicectomy also does not work better than a sham.

    I would ask Dr Gorski to have a closer look. In both of these studies the important things are those not clearly annunciated in the manuscripts.

Comments are closed.