Osteoarthritis, Pain and Brain Rot
By Brian Sanderson
I read with interest a headline article "Study sheds more light on dementia" (Chronicle Herald, July 14). Dr Kenneth Rockwood has found that the risk of dementia is greatly increased for people over 50 who suffer other chronic health problems, although his study could not explain why this should be so. Osteoarthritis is by far the most common chronic and debillitating health problem. (It is also a major downer for economic productivity.) Short of joint replacement, our Canadian Health Care System is limited to recommending lifestyle advice and palliative treatment, mostly using nonsteroidal anti-inflamitory drugs (NSAID's like Celebrex) or steroid injections when NSAID's fail to provide relief. Of course television advertisements might lead one to believe that NSAID's are the solution for every ache and pain... don't believe the hype!
In 2009, Dr J.C. Breitner and colleagues published results from a study showing that the risk of developing dementia and Alzheimer's disease is greatly increased when older people take large doses of NSAID's. (But let's not blame everything on NSAIDs, there has even been a suggestion that "Lipitor makes women stupid".) This association of medication and pain with rusty bodies is entirely in accord with the more recent study by Dr Rockwood. An association is not necessarily a cause. People suffering painful inflamation may also be less able to exercise and more likely to gain weight --- both of which are also identified as being risk factors for Alzheimer's, osteoarthritis, and many other diseases. Interestingly, experiments indicate that pain can cause osteoarthritis PubMed abstract. Perhaps it is not a stretch that pain might also cause dementia? There are other medically-induced risk factors for osteoarthritis, like surgery to remove part or all of the meniscus, something I can attest to from personal experience. (Indeed, such surgery is commonly used to induce osteoarthritis in animals, for experimental purposes!) Numerous studies indicate that while high-dose steroid injections provide short term relief they cause long term damage to joints as do some anesthetics.
The published evidence presents a paradox for our "evidence-based" Canadian Health Care System which places a high reliance upon NSAID's and high-dose steroids for palliative care of patients suffering osteoarthritis, treatment compounds the problem. There must be a better way? Well, yes, and no.
Low impact exercise comes first on the positive side of the ledger. My doctors advised me "to keep riding that stationary bicycle". It was great advice, reducing inflamation, reducing pain and reducing my waistline. I've become convinced that the health of our nation would be greatly improved if every TV required the viewer to ride a stationary bicycle in order to power it. I have also found that the physical activity actually enhances the viewing experience, by keeping ones mind more alert. (Have you ever noticed how many people fall asleep while watching TV? I wonder how hours spent passively viewing TV correlates with the risk of developing dementia?)
So, exercise is good, sloth is bad. But let's not get too carried away, sport may not be the best way to get your exercise. I lost count of how many times I heard or read some reporter remark about multiple knee or shoulder reconstructions of this or that athlete had had prior to competing at the recent Vancouver Winter Olympics. In a few brief days, 11% of competitors sustained injuries and there was one fatallity. And let's not forget all those concussions in the hockey arena, they might also have something to do with dementia...
Second on the positive side of the ledger would be treatments that repair damaged cartilage, reversing osteoarthritis of older patients or preventing its onset by healing younger patients who have injured their joints. Human bodies are evolved (or designed, if God is your preferred theory) to wear and repair. Your adult Mesenchymal Stem Cells (MSC) and growth factors play key roles repairing your body. Unsurprisingly, from an evolutionary perspective, many medications have been shown to be harmful to MSC; NSAID's, steroids 1, and some local anesthetics. The inconvenient response of the human repair cells to commonly used medications is sadly consistent with Dr Rockwood's observation that risk of dementia increases as the occurrence of other health problems overwhelms brain repair.
Unfortunately, sometimes wear and tear get ahead of repair. The simple solution would be to boost the number of repair cells at the damaged site. The basic idea is to draw Mesenchymal Stem Cells from a patients bone marrow, culture the MSC to expand the number, then accurately place the cultured MSC and appropriate growth factors where the patients cartilage (or muscle/tendon/ligament) has been damaged. Clinical studies have published results 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 showing such treatments work --- not perfectly, better for some than others, but these are early times. Patients report less pain and demonstrate greater functionallity. Before and after MRI's show repaired cartilage/muscle/ligament. There is histological evidence of repaired articular cartilage. This is not just some placebo effect. Publications also show that it is safe to treat patients with their own MSC. It's hardly surprising, if our own repair cells were unsafe then we would be an evolutionary impossibility.
Adult stem cell therapy is the realization of Hippocrates philosophy "vis medicatrix naturae;" the body has the ability to heal itself.
Given a relatively safe tool, one might expect physicians to rush to develope its application. Alas, the quacks have been very quick into the fray but innovation by serious medical practioners has been pretty much crushed by overbearing bureaucracy. A recent review article discusses the response of FDA to physician-driven innovations in MSC therapies.
One can understand the bureaucratic dilemma. Stem cell clinics have sprung up all over the globe, with glossy websites that promise a quick fix for every problem. We should be skeptical. In truth, only a small number of clinics have demonstrated effective outcomes, for a small but growing number of health problems. As a patient, my personal criterion for sorting the wheat from the chaff is to make sure that the stem cell clinic is publishing outcomes in a respectable scientific/medical journal. But don't stop at that, read their publications and compare them to other published work. Different patients will, quite rightly, make different judgements of cost, risk and likelihood of benefit. Bloody bureaucrats, on the other hand, don't like people to be able to make their own informed decisions:
Horses get the treatment but the bloody bureaucrats at FDA have prevented me from getting my own cultured MSC back! My dog is vacinated for Lyme disease, I'm not. Better to be a horse or dog than a person, sometimes.
There is also a structural reason why cultured autologous MSC therapies are under-developed relative to the potential that the research indicates. First, we need to understand the nature of autologous therapies relative to competing therapies. Cultured autlogous MSC are subject to the Hayflick limit. Their number can only be expanded through a limited number of passages before they become senescent. Cells become less inclined to differentiate into fat and more inclined to differentiate into cartilage and bone as the number of passages increases. Genes involved in cell cycle, DNA replication and DNA repair are significantly down-regulated in late passages. What all this means is that autlogous MSC therapies do not fit into the mass-production business model of the pharmaceautical companies and their symbionts, the great regulatory bureaucracies. Mass-production of allogeneic cells is their preference. Obviously, Big Pharma would prefer not to have to compete with physicians weilding effective autologous therapies. Regulators know that if the host dies then so does the symbiont.
Personally, I'm quite happy that the allogeneic model is also developed. Everyone should be free to explore possibilities. On the one hand I see allogenic cells as potentially dangerous because it's growing someone elses DNA in your body --- beware The Borge. On the other hand, if your own DNA is the problem (as opposed to some injury) then the allogeneic cells might be the best part of you... So that is my philosophy, each to their own, according to their needs and judgment.
Some thoughts regarding: Timothy Caulfield
I think that Timothy has over-generalized. Yes, there are plenty of bogus clinical therapies, as Timothy Caulfield and his co-workers published in 2008: pdf
However, at about the same time we saw publications of clinical studies that showed that cultured autologous Mesenchymal Stem Cells can be used to repair articular cartilage in a few lucky human beings: PubMed PubMed. Of course, the above followed much work (and continuing work) with animal models.
I can point to at least 10 subsequent publications of clinical studies demonstrating efficacy and safety of this therapy for some orthopedic applications in humans. (But this work isn't done in Canada...) A problem with this therapy is that it does not fit a mass-production model. So there is no money in it for Big Pharma and the researchers who get much of their funding from Big Pharma. They are pursuing allogeneic and other approaches where the cells are more highly manipulated so as to fit their mass-production model. Another problem is that regulatory agencies (eg FDA, Health Canada etc) are forcing this practice-of-medicine-therapy to fit into the drug-mass-production model. In the meantime, some patients continue to be treated with drugs and surgeries that come with a much bigger sting-in-the-tail than your own Mesenchymal Stem Cells: see main article above.
It is long past time for patients to take a more active interest in the research, clinical applications and regulations. Ultimately, the patient is paying for all of this stuff!
Some thoughts regarding: Doug Sipp
Hi Doug,
I just finished reading your publication. You rightly point out some shoddy medical practices. However, in my view you have made a few errors.
You have treated evidence for safety and efficacy as a simple yes/no switch. This sort of thinking is convenient for regulators but it is not consistent with scientific thinking, as I know it. True, in mathematics one finds proofs of mathematical identities, and these seem to me to fit your yes/no philosophy. But in the real world that scientists measure, nothing is ever proven. There are just different degrees of knowing.
Dividing the practice of medicine into "conventional/evidence-based" and "alternative/unproven" is similarly wrong-headed. In the real world (where patients live) there are a continuum of therapies, ranging from the apparently absurd (injecting sheep cells and so forth) to the apparently reasonable (prescribing NSAIDs and cortisone injections to patients suffering osteoarthritis). OK, I know, there is evidence that NSAIDs and cortisone injections can actually damage articular cartilage... which sort of illustrates my point about regulators (and others) drawing lines between this and that type of medicine.
Many of the therapies which you criticize are clearly implausible and thoroughly deserve to be shut down by regulators. But when you generalize, you make errors.
Your statement "The owner of a second US clinic shut down by federal authorities, Stem Cell Pharma" incorrectly implies that the previously discussed US company was shut down. Regenerative Sciences merely suspended the provision of cultured autologous MSC to patients.
Contrary to your view (page 411), there is a huge difference between the orthopedic and cosmetic use of cultured autologous MSC. Different types of cells used in different ways. A plumber does not become a banker just because they both walk to work! This is bureaucratic thinking masquerading as science.
You make a mistake by presenting all of these stem-cell therapies as being unacceptable because they are not evidence-based... when there is, in fact, a good deal of supporting evidence. I can point to 8 publications (2008-2011) which provide clinical evidence supporting the efficacy of cultured autologous bone-marrow-derived MSC for some orthopedic uses. And the the evidence for safety is also published. To be scientifically honest, with respect to orthopedic therapies (like Regenexx), you should have cited the publications that provide scientific evidence for/against the therapy and then analyzed these in the context of your argument. At the very least, you must surely admit that the line between acceptable and unacceptable medical practice is blurred?
It is the black-and-white mentality of regulators (and others) that leads otherwise rational people to frame the "conspiracy theory" that you document on page 412. Personally, I suspect that there is an element of truth in this conspiracy theory... in as much as commercial interests definitely do play a major role determining the treatments that patients ultimately receive. You see, it's all about how you draw a sharp line through a gray zone.
Science and evidence are NOT absolute. The big mistake that you make is to promote drawing of sharp lines. I suggest that it would be better for regulators, and yourself, to be a little less yes/no.
There is another problem with the "evidence-based medicine" as it is practiced. The problem is that medical researchers seem to have a very narrow idea of exactly what type of measurements are required in order to make a medical procedure available to the public. Scientifically, different phenomenon are most efficiently addressed in different ways. If you treat 9 articular cartilage defects with cultured aMSC and get objective measurements (MRI/histology) showing half of them to be healed, then that is pretty strong evidence. Providing it's safe, why should patients be denied access to such treatment?
By Brian Sanderson
I read with interest a headline article "Study sheds more light on dementia" (Chronicle Herald, July 14). Dr Kenneth Rockwood has found that the risk of dementia is greatly increased for people over 50 who suffer other chronic health problems, although his study could not explain why this should be so. Osteoarthritis is by far the most common chronic and debillitating health problem. (It is also a major downer for economic productivity.) Short of joint replacement, our Canadian Health Care System is limited to recommending lifestyle advice and palliative treatment, mostly using nonsteroidal anti-inflamitory drugs (NSAID's like Celebrex) or steroid injections when NSAID's fail to provide relief. Of course television advertisements might lead one to believe that NSAID's are the solution for every ache and pain... don't believe the hype!
In 2009, Dr J.C. Breitner and colleagues published results from a study showing that the risk of developing dementia and Alzheimer's disease is greatly increased when older people take large doses of NSAID's. (But let's not blame everything on NSAIDs, there has even been a suggestion that "Lipitor makes women stupid".) This association of medication and pain with rusty bodies is entirely in accord with the more recent study by Dr Rockwood. An association is not necessarily a cause. People suffering painful inflamation may also be less able to exercise and more likely to gain weight --- both of which are also identified as being risk factors for Alzheimer's, osteoarthritis, and many other diseases. Interestingly, experiments indicate that pain can cause osteoarthritis PubMed abstract. Perhaps it is not a stretch that pain might also cause dementia? There are other medically-induced risk factors for osteoarthritis, like surgery to remove part or all of the meniscus, something I can attest to from personal experience. (Indeed, such surgery is commonly used to induce osteoarthritis in animals, for experimental purposes!) Numerous studies indicate that while high-dose steroid injections provide short term relief they cause long term damage to joints as do some anesthetics.
The published evidence presents a paradox for our "evidence-based" Canadian Health Care System which places a high reliance upon NSAID's and high-dose steroids for palliative care of patients suffering osteoarthritis, treatment compounds the problem. There must be a better way? Well, yes, and no.
Low impact exercise comes first on the positive side of the ledger. My doctors advised me "to keep riding that stationary bicycle". It was great advice, reducing inflamation, reducing pain and reducing my waistline. I've become convinced that the health of our nation would be greatly improved if every TV required the viewer to ride a stationary bicycle in order to power it. I have also found that the physical activity actually enhances the viewing experience, by keeping ones mind more alert. (Have you ever noticed how many people fall asleep while watching TV? I wonder how hours spent passively viewing TV correlates with the risk of developing dementia?)
So, exercise is good, sloth is bad. But let's not get too carried away, sport may not be the best way to get your exercise. I lost count of how many times I heard or read some reporter remark about multiple knee or shoulder reconstructions of this or that athlete had had prior to competing at the recent Vancouver Winter Olympics. In a few brief days, 11% of competitors sustained injuries and there was one fatallity. And let's not forget all those concussions in the hockey arena, they might also have something to do with dementia...
Second on the positive side of the ledger would be treatments that repair damaged cartilage, reversing osteoarthritis of older patients or preventing its onset by healing younger patients who have injured their joints. Human bodies are evolved (or designed, if God is your preferred theory) to wear and repair. Your adult Mesenchymal Stem Cells (MSC) and growth factors play key roles repairing your body. Unsurprisingly, from an evolutionary perspective, many medications have been shown to be harmful to MSC; NSAID's, steroids 1, and some local anesthetics. The inconvenient response of the human repair cells to commonly used medications is sadly consistent with Dr Rockwood's observation that risk of dementia increases as the occurrence of other health problems overwhelms brain repair.
Unfortunately, sometimes wear and tear get ahead of repair. The simple solution would be to boost the number of repair cells at the damaged site. The basic idea is to draw Mesenchymal Stem Cells from a patients bone marrow, culture the MSC to expand the number, then accurately place the cultured MSC and appropriate growth factors where the patients cartilage (or muscle/tendon/ligament) has been damaged. Clinical studies have published results 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 showing such treatments work --- not perfectly, better for some than others, but these are early times. Patients report less pain and demonstrate greater functionallity. Before and after MRI's show repaired cartilage/muscle/ligament. There is histological evidence of repaired articular cartilage. This is not just some placebo effect. Publications also show that it is safe to treat patients with their own MSC. It's hardly surprising, if our own repair cells were unsafe then we would be an evolutionary impossibility.
Adult stem cell therapy is the realization of Hippocrates philosophy "vis medicatrix naturae;" the body has the ability to heal itself.
Given a relatively safe tool, one might expect physicians to rush to develope its application. Alas, the quacks have been very quick into the fray but innovation by serious medical practioners has been pretty much crushed by overbearing bureaucracy. A recent review article discusses the response of FDA to physician-driven innovations in MSC therapies.
One can understand the bureaucratic dilemma. Stem cell clinics have sprung up all over the globe, with glossy websites that promise a quick fix for every problem. We should be skeptical. In truth, only a small number of clinics have demonstrated effective outcomes, for a small but growing number of health problems. As a patient, my personal criterion for sorting the wheat from the chaff is to make sure that the stem cell clinic is publishing outcomes in a respectable scientific/medical journal. But don't stop at that, read their publications and compare them to other published work. Different patients will, quite rightly, make different judgements of cost, risk and likelihood of benefit. Bloody bureaucrats, on the other hand, don't like people to be able to make their own informed decisions:
Horses get the treatment but the bloody bureaucrats at FDA have prevented me from getting my own cultured MSC back! My dog is vacinated for Lyme disease, I'm not. Better to be a horse or dog than a person, sometimes.
There is also a structural reason why cultured autologous MSC therapies are under-developed relative to the potential that the research indicates. First, we need to understand the nature of autologous therapies relative to competing therapies. Cultured autlogous MSC are subject to the Hayflick limit. Their number can only be expanded through a limited number of passages before they become senescent. Cells become less inclined to differentiate into fat and more inclined to differentiate into cartilage and bone as the number of passages increases. Genes involved in cell cycle, DNA replication and DNA repair are significantly down-regulated in late passages. What all this means is that autlogous MSC therapies do not fit into the mass-production business model of the pharmaceautical companies and their symbionts, the great regulatory bureaucracies. Mass-production of allogeneic cells is their preference. Obviously, Big Pharma would prefer not to have to compete with physicians weilding effective autologous therapies. Regulators know that if the host dies then so does the symbiont.
Personally, I'm quite happy that the allogeneic model is also developed. Everyone should be free to explore possibilities. On the one hand I see allogenic cells as potentially dangerous because it's growing someone elses DNA in your body --- beware The Borge. On the other hand, if your own DNA is the problem (as opposed to some injury) then the allogeneic cells might be the best part of you... So that is my philosophy, each to their own, according to their needs and judgment.
Some thoughts regarding: Timothy Caulfield
I think that Timothy has over-generalized. Yes, there are plenty of bogus clinical therapies, as Timothy Caulfield and his co-workers published in 2008: pdf
However, at about the same time we saw publications of clinical studies that showed that cultured autologous Mesenchymal Stem Cells can be used to repair articular cartilage in a few lucky human beings: PubMed PubMed. Of course, the above followed much work (and continuing work) with animal models.
I can point to at least 10 subsequent publications of clinical studies demonstrating efficacy and safety of this therapy for some orthopedic applications in humans. (But this work isn't done in Canada...) A problem with this therapy is that it does not fit a mass-production model. So there is no money in it for Big Pharma and the researchers who get much of their funding from Big Pharma. They are pursuing allogeneic and other approaches where the cells are more highly manipulated so as to fit their mass-production model. Another problem is that regulatory agencies (eg FDA, Health Canada etc) are forcing this practice-of-medicine-therapy to fit into the drug-mass-production model. In the meantime, some patients continue to be treated with drugs and surgeries that come with a much bigger sting-in-the-tail than your own Mesenchymal Stem Cells: see main article above.
It is long past time for patients to take a more active interest in the research, clinical applications and regulations. Ultimately, the patient is paying for all of this stuff!
Some thoughts regarding: Doug Sipp
Hi Doug,
I just finished reading your publication. You rightly point out some shoddy medical practices. However, in my view you have made a few errors.
You have treated evidence for safety and efficacy as a simple yes/no switch. This sort of thinking is convenient for regulators but it is not consistent with scientific thinking, as I know it. True, in mathematics one finds proofs of mathematical identities, and these seem to me to fit your yes/no philosophy. But in the real world that scientists measure, nothing is ever proven. There are just different degrees of knowing.
Dividing the practice of medicine into "conventional/evidence-based" and "alternative/unproven" is similarly wrong-headed. In the real world (where patients live) there are a continuum of therapies, ranging from the apparently absurd (injecting sheep cells and so forth) to the apparently reasonable (prescribing NSAIDs and cortisone injections to patients suffering osteoarthritis). OK, I know, there is evidence that NSAIDs and cortisone injections can actually damage articular cartilage... which sort of illustrates my point about regulators (and others) drawing lines between this and that type of medicine.
Many of the therapies which you criticize are clearly implausible and thoroughly deserve to be shut down by regulators. But when you generalize, you make errors.
Your statement "The owner of a second US clinic shut down by federal authorities, Stem Cell Pharma" incorrectly implies that the previously discussed US company was shut down. Regenerative Sciences merely suspended the provision of cultured autologous MSC to patients.
Contrary to your view (page 411), there is a huge difference between the orthopedic and cosmetic use of cultured autologous MSC. Different types of cells used in different ways. A plumber does not become a banker just because they both walk to work! This is bureaucratic thinking masquerading as science.
You make a mistake by presenting all of these stem-cell therapies as being unacceptable because they are not evidence-based... when there is, in fact, a good deal of supporting evidence. I can point to 8 publications (2008-2011) which provide clinical evidence supporting the efficacy of cultured autologous bone-marrow-derived MSC for some orthopedic uses. And the the evidence for safety is also published. To be scientifically honest, with respect to orthopedic therapies (like Regenexx), you should have cited the publications that provide scientific evidence for/against the therapy and then analyzed these in the context of your argument. At the very least, you must surely admit that the line between acceptable and unacceptable medical practice is blurred?
It is the black-and-white mentality of regulators (and others) that leads otherwise rational people to frame the "conspiracy theory" that you document on page 412. Personally, I suspect that there is an element of truth in this conspiracy theory... in as much as commercial interests definitely do play a major role determining the treatments that patients ultimately receive. You see, it's all about how you draw a sharp line through a gray zone.
Science and evidence are NOT absolute. The big mistake that you make is to promote drawing of sharp lines. I suggest that it would be better for regulators, and yourself, to be a little less yes/no.
There is another problem with the "evidence-based medicine" as it is practiced. The problem is that medical researchers seem to have a very narrow idea of exactly what type of measurements are required in order to make a medical procedure available to the public. Scientifically, different phenomenon are most efficiently addressed in different ways. If you treat 9 articular cartilage defects with cultured aMSC and get objective measurements (MRI/histology) showing half of them to be healed, then that is pretty strong evidence. Providing it's safe, why should patients be denied access to such treatment?