Nutraceuticals: joint supplements, fish oils, and others (Proceedings)

"What evidence-based joint supplement, fish oil and probiotic recommendations can be made?"

For joint supplements, the news isn't good. Despite the enthusiasm, and aggressive marketing, not only is compelling evidence for efficacy lacking, there is evidence against efficacy. For example, a recent study in humans1 concluded that, "Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain." This study is available free online for anyone to read and draw one's own conclusions. In veterinary medicine, a recent systematic review of clinical treatments for osteoarthritis in dogs2 concluded that, "A high level of comfort exists for meloxicam that the claimed relationship is scientifically valid and that its use is clinically efficacious for the treatment of osteoarthritis in dogs. A moderate level of comfort exists for carprofen; etodolac; pentosan polysulphate; green-lipped mussels; P54FP; polysulfated glycosaminoglycans; and a combination of chondroitin sulfate, glucosamine hydrochloride, and manganese ascorbate. An extremely low level of comfort exists for hyaluronan." A subsequent (manufacturer-funded) controlled trial3 of pentosan polysulphate (PPS) optimistically concluded that, "PPS administered after stabilization of the cruciate deficient stifle may prove to be a useful adjunctive treatment option, although further studies are necessary to substantiate this claim." – particularly given the result that, "All dogs clinically improved after surgery without differences in lameness score, vertical GRFs, or radiographic progression."

With regard to fish oil, concerns remain for the quality of dietary supplements. Although clients and veterinarians may not be aware of the situation, the contents of dietary supplements are not currently regulated, and can vary widely depending on the manufacturer' standards. Moreover, governmental regulation, oversight, and quality-assurance processes for prescriptions are quite different from those for dietary supplements. Safe preparation, packing, and holding of human dietary supplements is governed by the FDA's "Good Manufacturing Practices" (GMPs). The GMPs applicable to dietary supplements are those used for foods, however, not for drugs. The FDA recently established revised GMP regulations that require dietary supplement manufacturers ". . . to evaluate the identity, purity, strength, and composition of their dietary supplements." Mandatory compliance with these regulations will take effect between June 2008 and June 2010. Veterinarians interested in using fish oils could look for products that are GMP-certified and can demonstrate that they have been stripped of heavy metals, dioxins and halogenated polycarbons.4

Even in this case, the evidence for efficacy for fish oils is limited to a pure formulation called P-OM3 (Lovaza), and marketed as a drug. I this been shown to be effective for treating hypertriglyceridemia in humans at a dose of 4 grams/per day (or about 60 mg/kg body weight for an adult human). Amounts of omega-3 fatty acids in dietary supplements often are much lower. Additionally, a recent study has called the specificity of the effects of fish oil on coronary heart disease risk in humans into question. Cundiff, et al., recently suggested that data supporting the benefits of fish or long-chain omega-3 fatty acid (FA) supplement consumption and coronary heart disease may be confounded by other dietary and lifestyle factors. Using the Diabetic Control and Complications Trial (DCCT) database (n= 1,441), correlations between consumption of omega-3 FAs and saturated FAs to dietary variables (energy, macronutrients, sodium, and cholesterol) and to age, gender, exercise level, and tobacco use were tested. They found that omega-3 FA intake was inversely correlated with consumption of calories, percent calories from total fat, and percent calories from saturated FAs, and directly with dietary fiber intake - a nutrient intake profile associated with a lower CHD risk. Moreover, the higher saturated FA intake associated with not eating fish is itself associated with less exercise and more tobacco use. They concluded that their findings provided evidence that associations observed in studies suggesting a benefit of fish or omega-3 FAs may be due to a convergence of greater fish intakes with an overall healthier dietary pattern rather than with a specific effect of these FAs. Such confounders have not been considered in veterinary medicine to my knowledge.

The evidence for effectiveness for probiotics in dogs and cats also is weak. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. These are a subset of so-called "alimentary pharmabiotics" which are defined as any material with (documented) health benefit that can be mined from host-microbe-dietary interactions in the gut. In addition to live whole organisms (probiotics), alimentary pharmabiotics also include other components of commensal microbiota, including dead organisms, cell proteins, cell wall polysaccharides, probiotic DNA or GMOs that have beneficial effects on the host.

Probiotic science is a relatively young area of scientific investigation. As of March, 2011, there were 6734 "probiotics" publications in the PubMed database, of which 1839 (27%) were reviews. In contrast, there were 531969 "antibiotics" publications, of which 46,110 (9%) were reviews. Thus, the field of probiotics currently has more interest than evidence. In human medicine, great interest in probiotics has been expressed by investigators in Metabolism of dietary compounds in the gut lumen (lactose, lipid, oxalate, indigestible dietary components

     1. Metabolic activity of GI mucosa & liver

     2. Inflammatory bowel diseases, IBS

     3. Allergic diseases

     4. Infections:

          • Infectious diarrhea (acute and antibiotic-associated)

          • Traveler's diarrhea

          • Necrotozing enterocolitis (infants)

          • Helicobacter pylori

          • Respiratory tract, ear, nose, and throat, and urogenital infections

          • Infectious complications in surgically ill patients

One must be cognizant, however, that results obtained with one probiotic strain cannot be extrapolated to other strains, that in vitro and laboratory animal studies often do not translate into clinically relevant outcomes, and that beneficial effects in one particular health area may not translate to any another area. Based on the available clinical research, it appears that certain probiotics may shorten recovery time in dogs with acute, nonspecific, self-limiting diarrhea, and modulate immune responses to vaccination. Further research will undoubtedly clarify the role of probiotic use in veterinary clinical medicine.

The scientific validity of any treatment can be experimentally tested. The US Food and Drug Administration provides us with the appropriate standard—safety and efficacy. Safety means provision of evidence that the treatment does no harm, that the benefits outweigh the risks. A safe therapy is one that does no unacceptable harm. Efficacy means that the treatment does what it claims to do, the likely benefit from the therapy when applied by a competent practitioner to a comparable patient. Safety and efficacy in patients may be assessed using the principles of evidence-based medicine (EBM). EBM is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of EBM integrates an individual's clinical expertise with the best available external clinical evidence from systematic research. Clinical expertise means the proficiency and judgment acquired through experience and practice. Increased expertise leads to more effective and efficient diagnosis, and in more thoughtful and compassionate consideration of individual patients' predicaments, rights, and preferences while making clinical decisions about their care. Current best evidence means clinically relevant research, especially patient-centered clinical research into the safety and efficacy of therapeutic, rehabilitative, and preventive regimens.1

Studies should be examined to determine if they investigated associations between a treatment and an outcome, the efficacy of a treatment, or its effectiveness. Associations include uncontrolled observation of clinical phenomena and results of epidemiologic studies. By themselves they cannot identify cause-effect relationships. For example, associations between smoking and lung cancer subsequently were confirmed in controlled studies, whereas those between β-carotene as a cancer preventative failed to be supported in clinical trials. Efficacy trials are studies where patients are recruited to determine if a treatment works under ideal circumstances, often a controlled clinical trial. Effectiveness studies are designed to determine if a treatment works when it is offered to patients that might accept or reject it as they might ordinarily do in a primary care setting.

For clinicians, EBM provides a mechanism for critical and thoughtful evaluation of current research before applying it to clinical practice. Critical thinking is fostered by comparing and contrasting new information with the generally accepted current standard. It identifies the pertinent questions about the validity and relevance of the information to be answered, and helps determine when facts become outdated (or were never really true in the first place). EBM helps us evaluate evidence about treatments for both relevance and strength. For example, a crucial question posed by EBM is, "In patients with (the problem of interest), does (the proposed therapy), when compared to standard therapy truly lead to an improved outcome (safer and/or more effective)?" The following criteria may be helpful when evaluating the relevance of an article about any therapy:

     1. Can the results be applied to my patients? (considering their species, breed, age, sex, and specific disease problem)

     2. Were all of the clinically relevant outcomes considered? A treatment that changes a "surrogate" physiologic measurement (e.g., blood urea nitrogen in dogs with kidney disease) without influencing an important clinical outcome (survival time, cost of care, etc.) may be of little value, whereas an important clinical outcome improvement may be interesting regardless of its effects on surrogate variables.

     3. Are the likely benefits worth the potential risks and costs?

     4. If the answer to any of these questions was "no," you may prefer to find an article to read that is worthy of your precious time. If all were answered "yes," you may want to proceed to consider these questions:

     5. Are the results of the study valid?

          • Was the assignment of patients to treatments randomized?

          • Were all patients who entered the trial properly accounted for and attributed at its conclusion?

          • Was follow-up complete?

          • Were patients analyzed in the groups to which they were randomized?

          • Were patients, health workers, and study personnel "blind" to treatment?

          • Were the groups similar at the start of the trial?

          • Aside from the experimental intervention, were the groups treated similarly?

     6. What were the results?

          • How large was the treatment effect?

          • How precise was the estimate of the treatment effect?

In addition to the above criteria for published articles, the strength of evidence from books, Web sites, etc., can be rated according to the following scale:

The EBM approach also can enhance the emotional aspects (art) of our practice of medicine; our confidence in our abilities, our compassion and empathy for our clients, and our humility in the presence of the vast complexity of nature. The same questions used to screen an article also can help assess the "emotional efficacy" of a treatment:

     1. Can the results be applied to my patients? (considering my confidence in my own skills and attitudes, and those of my clients)

     2. Were all of the clinically relevant outcomes considered? (what about ease of use, impact on the quality of life of my client and patient?)

     3. Are the likely benefits worth the potential risks and costs?

Information about safety and effectiveness of nutritional therapies may be less readily available than information about some other medical treatments. Research on these therapies is ongoing and continues to grow. Credible information also may be found in scientific research literature obtained through public libraries, university libraries, medical libraries, online computer services, and the US National Library of Medicine (NLM) at the National Institutes of Health (NIH) and their National Center for Complementary and Alternative Medicine. Information about researching alternative therapies can be found here. Useful information to gather for evaluation of novel nutritional therapies includes relevant research, advantages, and disadvantages compared to other treatments, risks, side effects, expected results, and the expected length of treatment. Controlled clinical trials usually provide the best information about a therapy's scientific effectiveness and should be sought whenever possible. Problems still arise, however, because of the difficulties associated with experimentation, such as biologic variability, small sample size, researcher bias, careless interpretation, and use of anecdotal evidence. To guard against these risks, one should assess the following criteria before accepting any scientific conclusion:

     1. The strength of the association

     2. The consistency of the association

     3. The specificity of the association

     4. The temporality of the association (which came first?)

     5. The dose–response relationship of the effect

     6. The biologic plausibility of the effect

Because of the importance of the placebo effect and compassionate belief in the value of the therapy on the outcome of the treatment, the preferred method of testing a treatment is the prospective, blinded, placebo-controlled trial. Such methods are particularly important for evaluation of treatments with potentially large emotional effects to separate the influence of the therapist from the effect of the therapy, and have been applied to surgical and chiropractic procedures and to acupuncture. By carefully considering all new treatments in the light of both the scientific and emotional aspects that comprise clinical medicine, one may be able to provide the best possible overall care for our patients.

References available on request