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Source – Columbia University Press Release

Finding, in Animal Model, Offers Proof of Principle that Inhibiting Serotonin in the Gut Could Become a Novel Treatment for Tens of Millions of Osteoporosis Sufferers.

NEW YORK (February 7, 2010) – An investigational drug that inhibits serotonin synthesis in the gut, administered orally once daily, effectively cured osteoporosis in mice and rats reports an international team led by researchers from Columbia University Medical Center, in the Feb. 7 issue of Nature Medicine. Serotonin in the gut has been shown in recent research to stall bone formation. The finding could lead to new therapies that build new bone; most current drugs for osteoporosis can only prevent the breakdown of old bone.

Gerard Karsenty, M.D., Ph.D.

“New therapies that inhibit the production of serotonin in the gut have the potential to become a novel class of drugs to be added to the therapeutic arsenal against osteoporosis,” said Gerard Karsenty, M.D., Ph.D., chair of the Department of Genetics and Development at Columbia University College of Physicians and Surgeons, lead author of the paper. “With tens of millions of people worldwide affected by this devastating and debilitating bone loss, there is an urgent need for new treatments that not only stop bone loss, but also build new bone. Using these findings, we are working hard to develop this type of treatment for human patients.”

The Nature Medicine paper follows on a major discovery, also made by Dr. Gerard Karsenty’s group (published in the Nov. 26, 2008 issue of Cell), that serotonin released by the gut inhibits bone formation, and that regulating the production of serotonin within the gut affects the formation of bone. Prior to this discovery, serotonin was primarily known as a neurotransmitter acting in the brain. Yet, 95 percent of the body’s serotonin is found in the gut, where its major function is to inhibit bone formation (the remaining five percent is in the brain, where it regulates mood, among other critical functions). By turning off the intestine’s release of serotonin, the team was able, in this new study, to cure osteoporosis in mice that had undergone menopause.

Based on their findings reported in the Cell paper, Dr. Karsenty and his team postulated that an inhibitor of serotonin synthesis should be an effective treatment for osteoporosis. Shortly thereafter, they read about an investigational drug, known as LP533401, which is able to inhibit serotonin in the gut. “When we learned of this compound, we thought that it was important to test it as proof of principle that there could be novel ways to treat osteoporosis with therapies that can be taken orally and regulate the formation of serotonin,” said Dr. Karsenty.

Dr. Karsenty and his team developed a research protocol to test their theory, where they administered the compound orally, once daily, at a small dose, for up to six weeks to rodents experiencing post-menopausal osteoporosis. Results demonstrated that osteoporosis was prevented from developing, or when already present, could be fully cured. Of critical importance, levels of serotonin were normal in the brain, which indicated that the compound did not enter the general circulation and was unable to cross the blood-brain barrier, thereby avoiding many potential side effects.

Implications for the Treatment of Osteoporosis

Most osteoporosis drugs, including those currently under clinical investigation, do not generate new bone but rather, prevent the breakdown of old bone. Only one drug currently on the market can generate new bone – but it must be taken by injection once a day, and because it may increase the risk of bone cancer, at least in rats, its use is restricted for short-term use in women with severe osteoporosis.

“There is an urgent need to identify new, safe therapies that can increase bone formation on a long term basis and to such an extent that they compensate for the increase in bone resorption caused by menopause,” said Dr. Karsenty. “Furthermore, it is important to note that since this study was conducted in rodents, it will need further confirmation in human subjects.”

Osteoporosis: A Disease of Bone Mass Decline…

Osteoporosis is a growing public health concern, with the aging population and the incidence of post-menopausal osteoporosis on the rise. It is a disease of low bone mass, most often caused by an increase in bone resorption not compensated by a similar increase in bone formation.

Far from being inert, bone constantly undergoes renovation, with some cells responsible for removing old material and other cells responsible for creating new bone. In humans, after age 20, the balance between bone formation and breakdown tips toward breakdown, and bone mass starts to decline. In women, the rate of decline increases after menopause, when estrogen levels drop and cells that tear down old bone become overactive. Osteoporosis is a disease in which bones become fragile and porous, increasing the risk of breaks. It is diagnosed when bone mass drops below a certain level.

As reported in the U.S.News and published in the Archives of Internal Medicine, a study has been carried out using a group of 638 back pain sufferers and four different treatments;

• The first group received individualized acupuncture treatment from a practitioner,
• The second group received a ’standardized’ acupuncture regimen,
• The third group received a sham acupuncture treatment where toothpicks housed in needle guide tubes were used (so the participants could not visually recognize the difference),
• And the fourth group received only drugs typically taken for back pain.

The volunteers in the study received 10 treatments over a seven week period. None of the volunteers had previously received acupuncture for back pain and all were allowed to continue taking their regular medication which consisted mainly of anti-inflammatory drugs and pain relievers.

The Results.

Interestingly, a week after the last treatment about three-fifths of those receiving the acupuncture, both the ’sham’ treatment and ‘real’ treatment, reported significant improvement in disabilities brought on by their back pain, compared with only two-fifths of those not receiving any real or simulated acupuncture.

This tells us that acupuncture succeeds in reducing pain levels for a good percentage of people, but what about those receiving the ’sham’ treatment? Unlike the acupuncture needles, the toothpicks did not penetrate the skin which raises the question of  “the acupuncture’s purported mechanism of action”.

The study co-author Daniel Cherkin hypothesizes that if acupuncture has a physiological effect, the stimulation of certain points on the skin may result in the same nerve-related benefits or it could be the placebo effect in which a patient’s belief in the treatment induces improvements. Pain relief may even result from a combination of the two, he says.

My Thoughts.

If you have read any of my previous posts you would know that I am a great believer in acupuncture as a pain reliever, although I have not found it to have any great lasting effects beyond a day or two of pain-free bliss. When I had my first session of acupuncture I had no preconceived notions of what it could do for me, all I knew was it involved a lot of small needles and probably some pain! I have to say that after that first visit I was impressed, the pain relief was immediate and made life all that much more bearable.

So how do we explain a number of the volunteer’s receiving the ’sham’ treatment noticing ’significant improvement in disabilities brought on by back pain’? As stated above, I think there is only two possible causes – the subject’s knew enough about the desired outcome for the brain to take control of their pain levels or surface stimulation of the skin was enough in a number of people to provoke a nerve response resulting in a pain decrease (something similar to the feelings we can get from a light massage). Either way there is no ‘hard evidence’ here that says the traditional acupuncture methods don’t work.

To my way of thinking this study proves nothing other than if your acupuncturist is out of town you may be able to get some form of relief from the humble toothpick! I mean we could go on forever doubting the technique used by acupuncturist’s but could hundreds of years of Chinese generations have got it that wrong? I don’t think so and while it keeps on providing me with pain relief when things are really bad I’ll keep going back for more. Perhaps their time would have been better spent working on a cure for cancer or A.I.D.S., you know something actually useful.

Readers Thoughts.

I think this comment posted on U.S.News sums up the ‘misguided-ness’ ( a new word for the dictionary!) of the study;

The Facts

This study is not new. I have been reading these for years. As far as RCT’s are concerned this is actually a very good one given that it included a standard treatment branch as opposed to simply control and treatment. It is nice to see researchers getting out of their box. In the end however it is not possible to study such a dynamic animal as chronic pain and a holistic treatment approach that understands that the body and the mind are intimately connected.

Anyone who reads or posts to this article should have an understanding of how incredibly complex chronic pain is. We are not just speaking about pain. We are speaking about living with pain, losing work, changing the dynamics of the household when someone cannot fully contribute, possibly loss of income, loss of sleep and stress; which all have a psychological component that triggers very real chemical responses in the body that prevent healing. Being one of my specialties I could go on but the real controversy seems to center on the placebo effect and sham acupuncture.

The answer is quite simple. The sham acupuncture was not sham at all. The toothpicks touched the skin. The skin contains 3 afferent sensory nerves that signal the CNS as well as modulate the sympathetic and parasympathetic nervous system specifically the vagus nerve.

The toothpicks stimulated the cutaneous nerves to send a signal to the spinal cord activating the spinal neurons that secrete enkephalin and dynorphin that inhibit pain messages. Then the signal continues up to the midbrain and pituitary that activates the raphe descending pain-inhibitions system which secretes monoamines, serotonin and norepinephrine that further inhibits pain through a couple different mechanisms that gets quite complicated. If you are interested see Biomedical Acupuncture for Pain Management.

Additionally, once the sensations from the toothpicks reached the spinal cord several nerve pathways are excited that reaches the cerebral cortex which releases numerous neurochemicals that not only inhibit pain but also promotes homeostasis. Homeostasis is incredibly important because as I said before we are not just talking about pain. This is a human being whose thoughts and emotions influence their body and whose body in distress can influence their mind.

There are too many valid articles and scientific research to speak any further on this. Any one who does not believe in acupuncture can look up studies done with fMRI in which sham and placebos do not exist.

Lastly the term acupuncturist is a misnomer. Acupuncturists practice traditional Chinese medicine which incorporates other modalities such as herbal formulas, massage, tui-na, diet, exercise, lifestyle counseling, tai-chi, qi-gong etc. It is a complete system of medicine that with proper communication with other alternative practitioners and open minded Md’s strives to help people find health and balance in their lives.

Christopher Salah, DAOM., L.Ac.

In closing, have you tried acupuncture for pain relief? Did you find it gave you relief or where you disapointed in the results? Please share with us any thoughts you have on this subject (yes, toothpicks included!) .

Take Care,

Craig

First of all I would like to welcome all of our readers to 2009. I hope that everyone had a happy and above all relatively pain-free Christmas and New Year. I guess the most important thing we as humans have when facing adverse situations is hope, and with the new year kicking in we can renew our hope for a pain-free future and raise our spirits a little.

I had to laugh when I read the title of this article featured on the Functional Path Training website, MRI – Might Reveal Injury. Although in reality it is no joke and the article originally published in the New York Times explains why MRI and similar scans are not always effective for finding the actual cause of pain and are the reason that many unnecessary and unsuccessful surgeries are carried out every year in our hospitals. I think you will find this information very interesting, or disturbing depending on which way you look at it!

Cheryl Weinstein’s left knee bothered her for years, but when it started clicking and hurting when she straightened it, she told her internist that something was definitely wrong.

It was the start of her medical odyssey, a journey that led her to specialists, M.R.I. scan that showed a torn cartilage and convinced her that her only hope for relief was to have surgery to repair it. But in fact, fixing the torn cartilage that was picked up on the scan was not going to solve her problem, which, eventually, she found was caused by arthritis.

Scans — more sensitive and easily available than ever — are increasingly finding abnormalities that may not be the cause of the problem for which they are blamed. It’s an issue particularly for the millions of people who go to doctors’ offices in pain.

The scans are expensive — Medicare and its beneficiaries pay about $750 to $950 for an M.R.I. scan of a knee or back, for example. Many doctors own their own scanners, which can provide an incentive to offer scans to their patients.

And so, in what is often an irresistible feedback loop, patients who are in pain often demand scans hoping to find out what is wrong, doctors are tempted to offer scans to those patients, and then, once a scan is done, it is common for doctors and patients to assume that any abnormalities found are the reason for the pain.

But in many cases it is just not known whether what is seen on a scan is the cause of the pain. The problem is that all too often, no one knows what is normal.

“A patient comes in because he’s in pain,” said Dr. Nelda Wray, a senior research scientist at the Methodist Institute for Technology in Houston. “We see something in a scan, and we assume causation. But we have no idea of the prevalence of the abnormality in routine populations.”

Now, as more and more people have scans for everything from headaches to foot aches, more are left in a medical lurch, or with unnecessary or sometimes even harmful treatments, including surgery.

“Every time we get a new technology that provides insights into structures we didn’t encounter before, we end up saying, ‘Oh, my God, look at all those abnormalities.’ They might be dangerous,” said Dr. David Felson, a professor of medicine and epidemiology at Boston University Medical School. “Some are, some aren’t, but it ends up leading to a lot of care that’s unnecessary.”

That was what almost happened with Mrs. Weinstein, an active, athletic 64-year-old who lives in New London, N.H. And it was her great fortune to finally visit a surgeon who told her so. He told her bluntly that her pain was caused by arthritis, not the torn cartilage.

No one had told her that before, Mrs. Weinstein said, and looking back on her quest to get a scan and get the cartilage fixed, she shook her head in dismay. There’s no surgical procedure short of a knee replacement that will help, and she’s not ready for a knee replacement.

“I feel that I have come full circle,” she said. “I will cope on my own with this knee.”

In fact, Mrs. Weinstein was also lucky because her problem was with her knee. It’s one of only two body parts — the other is the back — where there are good data on abnormalities that turn up in people who feel just fine, indicating that the abnormalities may not be so abnormal after all.

But even the data on knees comes from just one study, and researchers say the problem is far from fixed. It is difficult to conduct scans on people who feel fine — most do not want to spend time in an M.R.I. machine, and CT scans require that people be exposed to radiation. But that leaves patients and doctors in an untenable situation.

“It’s a concern, isn’t it?” said Dr. Jeffrey Jarvik, a professor of radiology and neurosurgery at the University of Washington. “We are trying to fix things that shouldn’t be fixed.”

As a rheumatologist, Dr. Felson saw patient after patient with knee pain, many of whom had already had scans. And he was becoming concerned about their findings.

Often, a scan would show that a person with arthritis had a torn meniscus, cartilage that stabilizes the knee. And often the result was surgery — orthopedic surgeons do more meniscus surgery than any other operation. But, Dr. Felson wondered, was the torn cartilage an injury causing pain or was the arthritis causing pain and the tear a consequence of arthritis?

That led Dr. Felson and his colleagues to do the first and so far the only large study of knees, asking what is normal. It involved M.R.I. scans on 991 people ages 50 to 90. Some had knee pain, others did not.

On Sept. 11, Dr. Felson and his colleagues published their results in The New England Journal of Medicine: meniscal tears were just as common in people with knee arthritis who did not complain of pain as they were in people with knee arthritis who did have pain. They tended to occur along with arthritis and were a part of the disease process itself. And so repairing the tears would not eliminate the pain.

“The rule is, as you get older, you will get a meniscal tear,” Dr. Felson said. “It’s a function of aging and disease. If you are a 60-year-old guy, the chance that you have a meniscal tear is 40 percent.”

It is a result that paralleled what spine researchers found over the past decade in what is perhaps the best evidence on what shows up on scans of healthy people. “If you’re going to look at a spine, you need to know what that spine might look like in a normal patient,” said Dr. Michael Modic, chairman of the Neurological Institute at the Cleveland Clinic.

After Dr. Modic and others scanned hundreds of asymptomatic people, they learned abnormalities were common.

“Somewhere between 20 and 25 percent of people who climb into a scanner will have a herniated disk,” Dr. Modic said. As many as 60 percent of healthy adults with no back pain, he said, have degenerative changes in their spines.

Those findings made Dr. Modic ask: Why do a scan in the first place? There are some who may benefit from surgery, but does it make sense to routinely do scans for nearly everyone with back pain? After all, one-third of herniated disks disappear on their own in six weeks, and two-thirds in six months.

And surgeons use symptoms and a physical examination to identify patients who would be helped by operations. What extra medical help does a scan provide? So Dr. Modic did another study, this time with 250 patients. All had M.R.I. scans when they first arrived complaining of back pain or shooting pains down their leg, which can be caused by a herniated disc pressing on a nerve in the spine. And all had scans again six weeks later. Sixty percent had herniated disks, the scans showed.

Dr. Modic gave the results to only half of the patients and their doctors — the others had no idea what the M.R.I.’s revealed. Dr. Modic knew, though.

In 13 percent of the patients, the second scan showed that the herniated disk had become bigger or a new herniated disk had appeared. In 15 percent, the herniated disk had disappeared. But there was no relationship between the scan findings at six weeks and patients’ symptoms. Some continued to complain of pain even though their herniated disk had disappeared; others said they felt better even though their herniation had grown bigger.

The question, though, was whether it helped the patients and their doctors to know what the M.R.I.’s had found. And the answer, Dr. Modic reported, is that it did not. The patients who knew recovered no faster than those who did not know. However, Dr. Modic said, there was one effect of being told — patients felt worse about themselves when they knew they had a bulging disk.

“If I tell you that you have a degenerated disk, basically I’m telling you you’re ugly,” Dr. Modic said.

Scans, he said, are presurgical tools, not screening tools. A scan can help a surgeon before he or she operates, but it does not help with a diagnosis.

“If a patient has back or leg pain, they should be treated conservatively for at least eight weeks,” Dr. Modic said, meaning that they take pain relievers and go about their normal lives. “Then you should do imaging only if you are going to do surgery.”

That message can be a hard sell, he acknowledged. “A lot of people are driven by wanting to have imaging,” Dr. Modic said. “They are miserable as hell, they can’t work, they can’t sit. We look at you and say, ‘We think you have a herniated disk. We say the natural history is that you will get better. You should go through six to eight weeks of conservative management.’ ”

At the Partners Healthcare System in Boston, spine experts have the same struggle to convince patients that an M.R.I. scan is not necessarily desirable, said Dr. Scott Gazelle, director of radiology there.

“The consensus is that you are a surgical candidate or not based on your history and physical findings, not on imaging findings,” he said.

Dr. Gazelle had a chance last year to test his own convictions. He had the classic symptoms of a herniated disk — shooting pains down his left leg, a numb foot and difficulty walking.

Dr. Gazelle went to see his primary-care doctor but, he said, “I didn’t get an M.R.I.” That decision, he added, “was the right thing to do.”

About three months later, he had recovered on his own.

In 1998, two medical scientists, writing in The Lancet, proposed what sounded like a radical idea. Instead of simply providing patients and their doctors with the results of an X-ray or an M.R.I. scan, he said, radiologists should put the findings in context. For example, they wrote, if a scan showed advanced disk deterioration, the report should say, “Roughly 40 percent of patients with this finding do not have back pain so the finding may be unrelated.”

It is an idea that only would work for back pain, because that is the one area where radiologists have enough data. But it made eminent sense to Dr. Jarvik. “It gives referring physicians some sort of context,” he said.

So, a few years ago, with some trepidation, his radiology group starting including epidemiological data in their reports. “We thought, ‘What’s going to be the reaction among referring physicians?’ ” Dr. Jarvik said. Their fear was that doctors would start choosing other places for M.R.I.’s and that Dr. Jarvik’s group would lose business.

Because of the way the university’s records are kept, it’s hard to know whether the new reporting system had that effect, Dr. Jarvik said. But he was heartened by the responses of some doctors, like Dr. Sohail Mirza, who recently moved to Dartmouth Medical School.

“We often see patients who have already had M.R.I. scans,” Dr. Mirza said. “They are fixated on the abnormality and come to a surgeon to try to get the abnormality fixed. They’ll come in with the report in hand.”

The new sort of report, Dr. Mirza said, was “very helpful information to have when talking to patients and very helpful for patients to help them understand that the abnormalities were not catastrophic findings.”

Others, like Dr. Modic, are hesitant about reporting epidemiology along with a patient’s scan findings.

“It’s an interesting idea,” he said. But, he added: “The problem isn’t what happens after they get their imaging. It’s that they get the imaging in the first place.”

That was what happened with Mrs. Weinstein.

When she started looking up her symptoms on the Internet, she decided she probably had a meniscus tear. “I was very forceful in asking for an M.R.I.,” she said.

And when the scan showed that her meniscus was torn, she went to a surgeon expecting an operation.

He X-rayed her knee and told her she had arthritis. Then, Mrs. Weinstein said, the surgeon looked at her and said, “Let me get this straight. Are you here for a knee replacement?”

She said no, of course not. She skis, she does aerobics, she was nowhere near ready for something so drastic.

Then the surgeon told her that there was no point in repairing her meniscus because that was not her problem. And if he repaired the cartilage, her arthritic bones would just grind it down again.

For now, Mrs. Weinstein says she is finished with her medical odyssey.

“I continue to live with this, whatever they call it, this arthritic knee,” she said.