On the Myth About Steroid Joint Injections

Where does the evidence come from?

When I was fellow, I learned from my mentor Dr. Roy Altman, that joint injections of glucocorticoids (anti-inflammatory steroids) could be administered into a joint about once a month. Now, that's odd, I thought. When I was a resident in internal medicine I was informed by the Orthopedic Attending that one could only inject a given joint about 3 times, ever. Dr. Altman, being one of the world's leading authorities on bone and cartilage, now gave me a different answer and I was not about to argue. So, I decided to research the issue myself.

Every Thursday during lunch hour, the fellows in training met with Dr. Altman in a conference room. We were instructed to discuss various topics of our choosing during this lunch hour. It was the duty of one of the fellows to select a topic and present it to Dr. Altman. Now, Dr. Altman was not exactly the most lenient person in the world. He was known to nit-pick presentations to death. I heard that he made a fellow cry one time. She did graduate eventually and is doing well now in private practice. In any case, I decided to present the topic of steroid injections to the joints- a topic on which Dr. Altman is the foremost authority. What was I thinking?

I started the presentation by stating that (at the time) "there was no long-term evidence that repeated injections to the joints were harmful. Yet, many experts recommended only a few joint injections be administered to a particular joint in a lifetime given the potential damage to the joint. Back in the 1960's, there were a handful of case reports (individual patient reports by doctors) stating that injecting a shoulder joint multiple times, weekly for 10-20 injections for example, would result in damage to the joint*. A severe, destructive arthropathy (joint pathology) and that this treatment should be administered with great caution. Since then, most people only give a few injections to the joints. Animal studies have shown mixed effects on cartilage and are irrelevant in humans. They serve primarily for our understanding of the disease process and, of course, veterinarians." Dr. Altman was nodding. Phew! "The little evidence available at the time," I went on, "suggested that we should not inject the same joint less than 4 weeks apart and probably no more than 4 times a year**." He again was nodding. Interestingly, that was the recommendation that he authored for the American College of Rheumatology guidelines for management of arthritis of the hip and knee.*** I was off the hook!

Several years later, now 2003, a new study was published**** which validated these recommendations. A study comparing steroid injections into the knee with placebo over a two year period found no deleterious effect on the knee joint. Furthermore, the benefit of the injections was found to last anywhere between 4 weeks and 6 months. So now, not only is there no evidence to support the notion that only a limited lifetime number of injections can be given into a joint, but also there is evidence to support the opposing view. Moving forward, the latest edition of Hochberg Textbook of Rheumatology states that "(t)he risk of joint disorganization after steroid injection to the hip and knee may be exaggerated. Experimental joint damage described in rabbits is probably irrelevant and, in a large survey of patients receiving multiple intra-articular steroid injections for osteoarthritis (OA) and rheumatoid arthritis (RA), only two out of 65 patients demonstrated radiologic deterioration, and even this might have been consistent with the natural progression of the disease. It has been argued that, providing the interval between injections is not less than 4 weeks for a weight-bearing joint in man, the benefit is likely to outweigh the damage that might accrue by leaving the inflammatory arthritis untreated. " (p 395)

So, are we going to practice evidenced based medicine? Are we going to apply the best and latest availabe data to our clinical practice? To the naysayers I say, view the evidence. Do not withhold this beneficial treatment from patients simply because you think it may be harmful. The evidence is: benefits far outweight the potential risks. To the fearful patient I say the evidence supports this treatment and is recommended by the American College of Rheumatology. If used judiciously, this is a very helpful adjunct to standard therapy and more than once has helped patients delay or forego surgery. Not to mention relief for those patient who can neither have nor will have surgery.

*Chirurg. 1966 Apr;37(4):178-80.
[Serious complications in intraarticular injections][Article in German]Dederich R.

**Rheumatol Rehabil. 1977 Aug;16(3):137-40.
Repeated corticosteroid injections into knee joints.Balch HW, Gibson JM, El-Ghobarey AF, Bain LS, Lynch MP.The effect of intra-articular injections of corticosteroids repeated over a period extending from four to 15 years on the radiological appearances of knee joints affected by rheumatoid arthritis and osteoarthritis has been studied. In 65 cases, the X-ray films of 15 showed no deterioration, 38 showed minimal or moderate deterioration, 10 showed marked deterioration and only 2 showed gross deterioration. The results do not support the contention that repeated intra-articular injections of corticosteroids will inevitably lead to rapid joint destruction. The authors are of the opinion that intraarticular injections of corticosteroids, if used judiciously, have an important part to play in the management of chronic arthritis.

***Arthritis & Rheumatism
Volume 43, No. 9, September 2000, pp 1905-1915
Special Article
Recommendations for the Medical Management of Osteoarthrits of the Hip and Knee
American College of Rheumatology Subcommittee on Osteoarthritis Guidelines
Members of the Subcommittee on Osteoarthritis Guidelines arc as follows. Roy D. Altman, MD: Department of Veterans Affairs Medical Center, and University of Miami School of Medicine, Miami, Florida; Marc C. Hochberg, MD, MPH: University of Maryland School of Medicine, Baltimore; Roland W. Moskowitz, MD: Case Western Reserve University School of Medicine, Cleveland, Ohio; Thomas J. Schnitzer, MD, PhD: Northwestern University Medical School, Chicago, Illinois.

****Arthritis Rheum. 2003 Nov;48(11):3300. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial.Raynauld JP, Buckland-Wright C, Ward R, Choquette D, Haraoui B, Martel-Pelletier J, Uthman I, Khy V, Tremblay JL, Bertrand C, Pelletier JP.Hopital Notre-Dame, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada. jp.raynauld@videotron.caOBJECTIVE: To evaluate the safety and efficacy of long-term intraarticular (IA) steroid injections for knee pain related to osteoarthritis (OA). METHODS: In a randomized, double-blind trial, 68 patients with OA of the knee received IA injections of triamcinolone acetonide 40 mg (34 patients) or saline (34 patients) into the study knee every 3 months for up to 2 years. The primary outcome variable was radiologic progression of joint space narrowing of the injected knee after 2 years. Measurements of minimum joint space width were performed by an automated computerized method on standardized fluoroscopically guided radiographs taken with the patient standing and with the knee in a semiflexed position. The clinical efficacy measure of primary interest was the pain subscale from the Western Ontario and McMaster Universities OA Index (WOMAC). Efficacy measures of secondary interest were the total score on the WOMAC, physician's global assessment, patient's global assessment, patient's assessment of pain, range of motion (ROM) of the affected knee, and 50-foot walking time. Clinical symptoms were assessed just before each injection. RESULTS: At the 1-year and 2-year followup evaluations, no difference was noted between the two treatment groups with respect to loss of joint space over time. The steroid-injected knees showed a trend toward greater symptom improvement, especially at 1 year, for the WOMAC pain subscale, night pain, and ROM values (P = 0.05) compared with the saline-injected knees. Using area under the curve analyses, knee pain and stiffness were significantly improved throughout the 2-year study by repeated injections of triamcinolone acetonide, but not saline (P <>

On Exercise and Chronic Back Pain

Systematic review: strategies for using exercise therapy to improve outcomes in chronic low back pain.JA Hayden, MW van Tulder, G TomlinsonAnn Intern Med 2005 5;142(9):776-85


In this paper, the authors review in a systematic manner the literature on exercise intervention characteristics to identify those exercises (and associated features) that are more likely to improve function, decrease pain and diminish work absenteeism in adults with chronic low back pain. Forty three trials (72 exercise treatments and 31 comparison groups, 3226 participants) were included. Significant improvements on pain and function scores were observed for individually designed programs, supervised home exercise programs and group and individually supervised programs as compared to home exercises only. Stretching and strengthening exercises were the best. In addition, more intensive programs (more than 20 hours total time) and those that included additional conservative measures were also more beneficial. These results were derived using a meta-analyses and meta-regression. The figures presented help significantly in the interpretation of the data given that most readers will not understand the statistical methods used. As with the other article (Ann Intern Med 2005; 142: 765-775), the limitations of this study relate primarily to the quality of the primary data which, for the most part, is not very good. Nevertheless, the message to the clinician is clear; well designed and professionally supervised programs are more likely to be effective than programs than do not meet these qualifications. Again, this is far from the recommendation clinicians oftentimes make to their patients of remaining physically active despite chronic low back pain.

– Graciela S. Alarcon, MD

ON FIBROMYALGIA: more on accupuncture

A randomized clinical trial of acupuncture compared with sham acupuncture in fibromyalgia.NP Assefi, KJ Sherman, C Jacobsen, J Goldberg, WR Smith, D BuchwaldAnn Intern Med 2005 7;143(1):10-9

This study was conducted in 100 adult community dwellers with Fibromyalgia (FM). They were randomized to receive either real or sham acupuncture (biw) for 12 weeks. The diagnosis of FM was “confirmed” by a coordinator trained in the assessment of tender points (records were not reviewed and interviews not conducted to rule other disorders). The primary outcome measure was pain (10 cm. VAS); secondary outcomes included fatigue, sleep, well being and function. Patients continued any previous FM-related treatments they were on at the time of the study (acupuncture as an “adjunct” therapy study). Patients were told they had one in four probability of being assigned to a treatment that “could be effective”. Of the 100 patients randomized, four never rstarted treatment but almost all who started it, completed the study. Neither the primary nor the secondary outcomes studied were significantly different in the acupuncture group vs the sham acupuncture group (these results contrast with recently published data on the value of acupuncture in knee OA) . Given that in the clinical setting, acupuncture is used in combination with herbal, dietary and massage therapies, the possibility that acupuncture could in fact work if used in that manner cannot be ruled. However, the data regarding these other therapies for FM pain have been mixed. To date the most successful programs for FM include a combined approach of limited pharmacologic treatment and a structured exercise program. Acupuncture does not seem to be an integral and essential part of this treatment paradigm, as this study suggests.

--Graciela S. Alarcon, MD

This study is another among a mixed bag of results on treatments for Fibromyalgia. In this study, sham (fake) accupuncture was no better than "true" accupuncture. I think the take home message is this: if accupuncture works for you, do it. However, it is always better to use a combination approach. Wether or not it includes accupuncture, depends on the individual.

Ricardo Pocurull, MD

Woman Complains about Doctor's telling her she is fat

Woman Files Complaint After Doctor Tells Her She's Obese
Attorney General Recommends Doctor Take Education Course
POSTED: 4:48 pm EDT August 22, 2005
ROCHESTER, N.H. -- The state is investigating a Rochester doctor because a patient complained that he bluntly told her she needed to lose weight.
Dr. Terry Bennett said that he's outraged by what he calls a baseless complaint. A patient was apparently insulted when Bennett told her that she was obese and could only get healthier by losing weight.
"It's an epidemic in the United States, and it's croaking us," Bennett said.
Bennett said that it's a lecture he gives to many of his overweight patients.
"It's your weight, ... and there's dozens of programs," Bennett said. "You don't have to come in here. You can join Jenny Craig. You can go see Weight Watchers."
Bennett said he tells obese patients that their weight is bad for their health and their love lives. But the lecture drove one patient to write a letter to the Board of Medicine, which has passed on the complaint to the Attorney General's Office.
"Did I sleep with somebody? Did I give somebody drugs? Was I careless? No. End of story," Bennett said. "That should have been the end of it."
Now, other overweight patients are coming to Bennett's defense.
"What really makes me angry is he told the truth," patient Mindy Haney said. "How can you punish somebody for that?"
Haney said that Bennett has helped her lose more than 150 pounds, but, at first, she didn't want to listen.
"I have been in this lady's shoes. I've been angry and left his practice. I mean, in-my-car-taking-off angry," Haney said. "But once you think about it, you're angry at yourself, not Dr. Bennett. He's the messenger. He's telling you what you already know."
Haney is so upset at the complaint that she has started a petition demanding that the attorney general be fired. So far, she's gathered 100 signatures.
Bennett said that the Attorney General's Office tried to get him to settle the matter by agreeing to attend a medical education course, which he refused.
"I'm sorry," Bennett said. "If she's watching, I'm devoutly sorry to have offended you. I didn't mean to offend you. I meant to tell you the truth. And that's what I tried to do."
The Board of Medicine would not comment on the case, but Vice President Kevin Costin said, "Physicians have to be professional with patients and remember everyone is an individual. You should not be inflammatory or degrading to anyone."
Bennett said that he thinks his apology should be enough.
Copyright 2005 by TheWMURChannel. All rights reserved. This material may not be published, broadcast, rewritten or redistributed

Dangers from NSAIDs: GI bleeds

NEW YORK (Reuters Health) Aug 24 - Approximately one third of all hospitalizations and deaths related to gastrointestinal bleeding can be attributed to the use of nonsteroidal anti-inflammatory agents (NSAIDs) or aspirin, results of a population-based observational study in Spain suggest. Up to one third of these incidences may be related to low-dose aspirin.
To estimate the mortality risk caused by GI complications from NSAID use, Dr. Angel Lanas, a gastroenterologist at University Hospital in Zaragoza, and his associates evaluated data from 2001 for 26 Spanish hospitals. Data included hospitalizations related to peptic-ulcer disease or complications such as bleeding or perforation, as well as drug use during the month prior to hospitalization.
They report their findings in the American Journal of Gastroenterology for August.
A total of 8010 serious GI events were reported, and among these, the mortality rate was 5.7%. Although hospitalizations were six times more likely to be due to upper GI complications rather than those in the lower GI tract, the percentage of deaths was similar (5.7% versus 5.3%, respectively).
The authors report that the proportion of complications and deaths attributed to NSAID and aspirin use was 36.3%. They also note that nearly 90% of deaths occurred in patients older than 60 years old.
To extrapolate the impact of aspirin and NSAID use on the general population of Spain, Dr. Lanas' group obtained data from 197 hospitals representative of all the hospitals in the Spanish National Health System.
Their results suggest that the mortality rate resulting from NSAID- or aspirin-related GI complications was between 21.0 and 24.8 cases per million inhabitants. This translates to 24.4 to 28.8 deaths per million prescriptions, and a maximum of 15.3 cases per 100,000 NSAID users.
The investigators note that mortality rates due to NSAID-associated GI events is similar to that for deaths associated with occupational activities, and is equivalent to more than 50% of AIDS deaths in 2001 in Spain.
According to the authors, these results highlight "the importance of taking ever-greater steps to research new and better alternatives to treat pain and inflammation in the elderly, to heighten physician and public awareness of the associated problems of NSAID therapy, and to educate them on the use of appropriate prevention strategies."
Dr. Byron Cryer, from the Dallas VA Medical Center, agrees with this conclusion. He writes in a related editorial: "Although clinically significant GI events with NSAIDs are uncommon, as a result of the vast numbers of patients who take these medications, when assessed by percentages these complications remain a significant public health concern."
Am J Gastroenterol 2005;100:1685-1695.

Patients on antimalarials at risk for myopathy

Aug 22, 2005
Janis Kelly

"The prevalence of antimalarial myopathy is higher than previously recognized when the muscle-enzyme determination is used as a screening method. When a persistent muscle-enzyme disturbance is observed, a clinical and electromyographic study should be performed periodically to detect earlier the development of a clinical myopathy," say the researchers, led by Dr Enrique Casado (Parc Tauli University Hospital, Barcelona).
Muscle-enzyme changes in 18% of patients
This prospective study included all patients with rheumatic diseases taking antimalarials over a three-year period. Serum muscle enzymes were measured at inclusion and every six months thereafter. Patients who had muscle-enzyme disturbances at any point were further assessed with muscle strength electromyography (EMG) and muscle biopsy. The study included 111 patients taking chloroquine and eight taking hydroxychloroquine.
Antimalarial myopathy was defined as the presence of the specific ultrastructural microscopic findings associated with persistent muscle-enzyme disturbances, regardless of clinical symptoms.
Clinical antimalarial myopathy was defined as the presence of antimalarial myopathy associated with an objective muscle weakness, through direct examination of proximal and distal muscles of upper and lower limbs and neck flexor muscles.
Casado reported that 22 patients (18.5%) had persistent muscle-enzyme disturbances. These involved lactate dehydrogenase (LDH) in 19/22 patients, creatine kinase in 7/22 patients, and aldolase in 3/22 patients. Although LDH is not specific for muscle disease, levels normalized in all of the patients who stopped antimalarial drug therapy.
Fifteen patients were biopsied. Light microscopy showed antimalarial myopathy in 3/15. Electron microscopy showed antimalarial myopathy in all 15 patients.
Of these 15 patients, 11 had myopathy at the time they entered the study, and four developed myopathy during follow-up. Eight of 15 patients with biopsy-proven myopathy also had muscle weakness, for a prevalence rate of 6.7%, and all eight also had myopathy on electromyography.
"Antimalarial myopathy was demonstrated in 12.6% of the patients included in the study," Casado writes. Thirteen patients were being treated with chloroquine and two with hydroxychloroquine.
The authors note that the incidence of myopathy was much higher in their study than in previous studies, but they point out that this study was prospective and also used a sensitive screening test: muscle-enzyme changes. Earlier studies were smaller, retrospective, and uncontrolled, and no other prospective data on the incidence of antimalarial myopathy have been published, they add.
Casado emphasizes that antimalarial myopathy diagnosis should be confirmed by biopsy. "In these cases an ultrastructural examination is absolutely mandatory to detect the characteristic tissue deposits that confirm the diagnosis of an antimalarial myopathy, since light microscopy has numerous false negatives (80% in our series)."
May be masked by musculoskeletal symptoms
Myopathy is a recognized toxic effect of antimalarials, along with retinal problems. These toxicities occur with long-term administration of the drugs and stem from accumulation of intracellular deposits, mainly in the retina and muscle, the authors explain.
The muscle toxicity may be difficult to spot in patients who already have musculoskeletal symptoms, they comment. In this study, patients were being treated with antimalarials for rheumatoid arthritis (69 patients), palindromic rheumatism (14), Sjörgen's syndrome (11), systemic lupus erythematosus (9), undifferentiated connective tissue diseases (7), psoriatic arthritis (4), and other rheumatic conditions (5).
"Initial symptoms of muscular injury are characteristically mild. However, painless proximal weakness in both upper and lower extremities may become more severe in time," the authors write. "In many cases, this clinical feature is masked by the musculoskeletal manifestations of the underlying disease, which could explain why the diagnosis of antimalarial myopathy is usually difficult and often delayed."
Source
Casado E, Gratacos J, Tolosa C, et al. Antimalarial myopathy: an underdiagnosed complication? Prospective longitudinal study of 119 patients. Ann Rheum Dis 2005; DOI:10.1136/ard.2004.023200. Available at: http://ard.bmjjournals.com.

Trial shows short-term benefit of corticosteroid injection for sciatica

Aug 22, 2005
Allison Gandey
Southampton, UK - Overturning previous findings of no demonstrable advantage of epidural steroids, the Wessex Epidural Steroids Trial (WEST) study group reports first-time positive results in its large randomized controlled trial. In an advance access paper published online July 19, 2005 in Rheumatology, the group reports that epidural corticosteroids offer short-term relief of symptoms in patients with sciatica at three weeks [1]. But they also point out that the injections did not offer any medium- or long-term benefit in terms of symptoms, function, return to work, or the need for surgery. "Traditionally sciatica has been considered to be a self-limiting condition by many clinicians. However, our results suggest that this is not the case, as most patients had significant pain and disability at the end of the study," comment the researchers, led by Dr Nigel Arden (University of Southampton, UK). "The majority of patients in this pragmatic study had been in pain for over three months at the time of referral to secondary care and can therefore be defined as suffering from chronic pain."

"Many clinicians involved in low-back pain and sciatica treatment were waiting for the complete report of this very interesting study," Dr Jean-Pierre Valat (Hôpital Trousseau, Tours, France) told rheumawire. Approached for comment because he has led previous studies in this area, Valat says that he has been waiting on the WEST results since preliminary findings were first presented at the American College of Rheumatology meeting in 2002. "The results presented here seem quite different from those shown at the ACR meeting, as the improvement with epidural steroid injection reaches here a clear statistical significance at week three on leg pain and function."
Common treatment for sciatica
In their paper, Arden and colleagues define sciatica as unilateral, well-localized leg pain in the dermatomal distribution of the sciatic nerve that normally radiates to the foot or toes. It is often associated with numbness or paresthesia. They write that sciatica was initially thought to occur as a result of a prolapsed lumbar vertebral disk causing compression of the nerve root, leading to neural ischemia, edema, and eventually chronic inflammation, scarring, and perineural fibrosis. But it is now believed that sciatica can occur in the absence of direct nerve-root compressionpossibly as a result of the release of phospholipase A2 and other proinflammatory agents from a damaged disk, leading to nerve-root inflammation and edema.
The premise behind epidural injections is that the corticosteroid will reduce perineural inflammation and stop perineural fibrosis and therefore prevent chronic pain. Valat points out that steroid injections are an easy outpatient technique very commonly used to treat sciatica. "It is safe compared with high-dose NSAIDs or opioids," he added.
The trial involved 228 patients and lasted 12 months. Participants from four secondary pain-care clinics in the Wessex region had a clinical diagnosis of unilateral sciatica lasting one to 18 months. They were randomized to either three lumbar epidural steroid injections of triamcinolone acetonide or interligamentous saline injections at intervals of three weeks. The main outcome measure was the Oswestry low-back pain disability questionnaire (ODQ).
Arden and his team found that at three weeks, the epidural-steroid-injections group demonstrated a transient benefit over the placebo group. They report that patients achieved a 75% improvement in ODQ, 12.5% vs 3.7%, with a number needed to treat of 11.4. They observed no benefit of treatment from six to 52 weeks. The group also found that injections did not improve physical function, hasten return to work, or reduce the need for surgery. And there was no benefit of repeated vs single injection.

Injections appear to be justified when analgesics prove insufficient
Commenting on the study, Valat said, "The use of epidural injections seems justified for the management of acute sciatica when simple analgesics are not sufficient. This large pragmatic study demonstrates a short-term benefit useful in clinical practice."

The researchers say that despite a thorough search for clinical predictors of response, they were unable to identify any. "We conclude that there is no simple, clinically identifiable group of patients with sciatica that can be identified as being appropriate for an epidural steroid injection."
Valat explained that in his group's previous work, which, unlike this study, did not find a significant benefit of treatment, a different comparator was used [2]. "We used epidural saline injections, which is probably not an inactive treatment," Valat told rheumawire. He notes that in a previous New England Journal of Medicine study, Carette et al had also used epidural saline as a comparator yet had found a statistically significant effect of epidural steroid injections on leg pain at week six, but not at further evaluation [3]. "The comparator used by Ardeninterligamentous salineis probably a much better one," Valat said. "The aim of epidural steroid injections is to obtain a symptomatic short-term effect on pain and disability, and it is achieved in the present study."

Sources
Arden NK, Price C, Reading I, et al. A multicentre randomized controlled trial of epidural corticosteroid injections for sciatica: The WEST study. Rheumatology 2005; DOI: 10.1093/rheumatology/kei028. Available at: http://intl-rheumatology.oxfordjournals.org.
Valat JP, Giraudeau B, Rozenberg S, et al. Epidural corticosteroid injections for sciatica: A randomised, double blind, controlled clinical trial. Ann Rheum Dis 2003; 62:639-643.
Carette S, Leclaire R, Marcoux S, et al. Epidural corticosteroid injections for sciatica due to herniated nucleus pulposus. N Engl J Med 1997; 336:1634-1640.

Jury Finds Merck at Fault in Texas Man's Death

JANGLETON, Texas (Reuters) Aug 19 - A jury in the first civil trial against Merck & Co.'s popular painkiller Vioxx on Friday found the pharmaceutical company liable for the 2001 death of a Texas man, awarding his widow a total of more than $250 million.
The 12-member jury in Texas state court awarded a $24 million penalty to the widow of Robert Ernst for mental anguish and loss of companionship and $229 million in punitive damages.
Merck shares fell $1.41, or about 4.6 percent, to $29.00. Merck's options trading volume spiked up as the verdict was announced.
"Everyone knew this was a hard case going in. The jurisdiction in which it was tried is very plaintiff friendly," said Brett Gallagher, a senior portfolio manager. "It probably was the most expected outcome, and now unfortunately the uncertainty drags on."
Plaintiff's lawyer Mark Lanier said he expects Texas law limiting punitive damages would reduce that $229 million award.
"Merck sure ought to come to the table and accept its responsibility," he said.
Merck immediately said it would appeal the decision.
"There is no reliable scientific evidence that shows Vioxx causes cardiac arrhythmia, which an autopsy showed was the cause of Mr. Ernst's death," Merck attorney Jonathan Skidmore said.
Ernst, a Walmart employee, was a long distance runner who often competed in marathons.

Some Glucosamine Products Get Absorbed Poorly

Aug 18, 2005
Janis Kelly
Boston, MA - Osteoarthritis (OA) patients in large numbers began taking glucosamine supplements in the wake of randomized studies showing delayed radiographic progression with glucosamine compared with placebo [1,2]. Subsequent studies cast some doubt on this effect [3], and Dr Beth Anne Biggee (Tufts-New England Medical Center, Boston, MA) and colleagues have now published data showing that the amount of glucosamine in the serum after oral dosing is far below that needed for the chondroprotective mechanisms proposed to account for glucosamine's apparent benefits in OA [4].
My knowledge of the way that chondroitin sulfate is formed has made me highly skeptical that providing glucosamine orally can have any direct function on cartilage.
Senior author Dr Jeremiah E. Silbert (Harvard Medical School and Brigham and Women's Hospital, Boston, MA) tells rheumawire that the data were not a complete surprise.
"My knowledge of the way that chondroitin sulfate is formed has made me highly skeptical that providing glucosamine orally can have any direct function on cartilage. We have previously published two articles showing that mouse chondrocytes in culture and human chondrocytes in culture make their own glucosamine from glucose, with less than 0.2% coming from glucosamine added to the culture medium at the levels we find in serum," says Silbert, who has spent most of his research career studying glucosamine and chondroitin sulfate.
1500 M oral glucosamine, but only 11.5 M gets into serum
In this study 18 OA patients fasted overnight, then took 1500 M of commercial glucosamine sulfate. Silbert's team then used a new high-sensitivity method to measure glucosamine concentrations in serum samples drawn at baseline and every 15 to 30 minutes over three hours and additionally from two subjects at five hours and eight hours. The new method measures serum glucosamine concentrations as low as 0.5 M, much lower than possible in previous studies.
Biggee et al found that none of the subjects had detectable glucosamine levels at baseline. Of the 18 patients, 17 had detectable glucosamine after taking the oral supplement. Serum concentrations began to rise within 30 to 45 minutes after dosing and reached maximums of 1.9 to 11.5 M after 90 to 180 minutes.
"This maximum concentration of 11.5 M has previously been shown to contribute less than 2% of the galactosamine incorporated into chondroitin sulfate in incubations of glucosamine with cultured human chondrocytes and is a much lower concentration than the glucosamine concentrations claimed by other investigators to have various significant in vitro effects," the authors write.
They add, "This raises questions regarding current biologic rationales for glucosamine usage that were based on in vitro effects of glucosamine at much higher concentrations."
The extra amount is changing the miniscule into miniscule-plus-an-additional-miniscule and would still be far below any concentration that has been shown to have an effect on chondrocytes.
"The amounts in the serum are far lower than the amounts used experimentally by others to show effects. It is possible that there could be these other effects, but they need to be demonstrated at the concentrations found in serum to have validity. I doubt that this will be seen, but I keep an open mind," Silbert says.
The data also show an interesting divergence between subjects who had previous exposure to glucosamine and those who were glucosamine-naïve. Those who had previously used glucosamine had significantly faster appearance of glucosamine in the serum after oral ingestion, slower rate of rise to serum maximum levels, and higher serum maximum levels.
Silbert speculates that previous chronic glucosamine usage has modified liver cells in some undefined way, perhaps causing low-level liver damage, so that the uptake of glucosamine is lessened, which then allows more to spill out into the peripheral circulation. "However," he points out, "the extra amount is changing the miniscule into miniscule-plus-an-additional-miniscule and would still be far below any concentration that has been shown to have an effect on chondrocytes."
Sources
Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year randomized, placebo-controlled, double-blind study. Arch Intern Med 2002; 162:2113-2123.
Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomized, placebo-controlled clinical trial. Lancet 2001; 357:251-256.
Hughes R, Carr A. A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatology 2002; 41:279-284.
Biggee BA, Blinn C, McAlindon TE, et al. Low levels of human serum glucosamine after ingestion of glucosamine sulphate relative to capability for peripheral effectiveness. Ann Rheum Dis; DOI:10.1136/ard.2005.03 6368. Available at http://ard.bmjjournals.com.