Osteoarthritis is the most common form of arthritis, affecting millions of people, and nearly twice as many women as men, particularly after age 45. Osteoarthritis is a complex disease, as it turns out, involving a growing body of evidence demonstrating the role of systemic factors such as genetics; growth factors; hormonal influences; microcirculation problems; nutrient deficiencies; bone density issues; and, of course, biomechanical factors such as muscle weakness, obesity, and joint laxity.
There are several newer discussions and hypotheses in the literature that offer potential new insights into the pathophysiology of osteoarthritis. One of these is the role of the estrogen receptor in chondrocytes and the potential role of estradiol in decreasing interleukin–1B induced nitrous oxide protein expression (Annals of the Rheumatic Diseases 2005;64:1539–1541). Another is the hypothesis that progressive osteoarthritis is an atheromatous vascular disease of subchondral bone. This line of thinking will likely be linked to studies of statins on the prevention and treatment of osteoarthritis in order to examine this hypothesis (Annals of the Rheumatic Disease 2004;63:544–548). Yet another recent discussion in the literature is that osteoarthritis may be an more an issue of growth problems than degeneration, that there is a dysregulated tissue turnover, with the balance in favor of growth. There is production of new tissue in the presence of existing tissue, but it occurs in the wrong place and at the wrong time.
New therapies may then focus on a more systemic and whole-system approach, looking more closely at what factors may underlie the numerous elements potentially involved.
In my own clinical search and attempts to help more of my patients, almost exclusively women, I have become increasingly frustrated with the limitations of botanical anti-inflammatories (e.g., ginger, curcumin, bromelain, Boswellia, devil's claw) and nutraceuticals that stimulate the production of proteoglycan synthesis (e.g., glucosamine or chondroitin sulphate, MSM, SAMe). Not to say that these interventions have no value; in my experience, they often can – just not consistently adequate and not often enough.
Some of the following abstracts have appeared in my previous columns, but in an effort to provide a focused resource for clinicians and those who suffer with osteoarthritis, this current column attempts to highlight some newer research, newer thinking, and promising new approaches to the treatment of osteoarthritis. Clearly, despite a plethora of over-the-counter, prescription, and nutraceutical/botanical analgesic therapies, there is still a need for safe and effective treatments, not only for pain relief but for long-term management to alter the course of the degenerative osteoarthritic process.
Flavonoid Mixture and Osteoarthritis of the Knee
A proprietary mixture of flavonoids (baicalin and catechin) known as flavocoxid (Limbrel) was tested against naproxen, a conventional non-steroidal anti-inflammatory drug for the management of moderate osteoarthritis (OA) of the knees. A 4-week, multicenter, double-blind, controlled pilot study was conducted in patients who had grade 2 to 3 OA of a knee. Subjects were randomly assigned to either flavocoxid 500 mg twice daily or naproxen 500 mg twice daily. One hundred three individuals were randomized to the trial. Two failed to complete the study, both in the naproxen arm, and one presumably due to side effects of upper gastrointestinal discomfort.
Both the flavocoxid and naproxen groups showed significant and similar reduction in the signs and symptoms of knee OA (p < 0.001) of approximately 85% from baseline for all four measurements. There were no statistically significant differences in the two groups with respect to any of the measurable outcomes.
Comment: Flavocoxid is considered a prescription medical food, a category considered distinct from drugs and supplements. It is a concentrated > 90% pure standardized blend of baicalin, a flavonoid extracted from Scutellaria baicalensis, and a catechin from Acacia catechu. It has been previously determined that mixtures of baicalin and catechin possessed significant COX-1, COX-2, and 5-LOX inhibitory activity. Practitioners are familiar with other plants and plant extracts possessing significant anti-inflammatory activity, so this should be no surprise. However, this is the first formal clinical trial investigating flavocoxid. A 30-day therapeutic trial of an herbal product demonstrating similar results to a common pharmaceutical analgesic, and on average 85 % improvement in signs and symptoms of knee OA, is a great sign for practitioners and patients.
Levy R, Saikovsky R, Shmidt E, et al. Flavocoxid is as effective as naproxen for managing the signs and symptoms of osteoarthritis of the knee in humans: a short-term randomized, double-blind pilot study. Nutr Res. 2009;29:298–304.
Seaweed Supplement for Knee Osteoarthritis
This small, double-blind, placebo-controlled pilot study investigated a supplement from seaweed (Aquamin) on symptoms of moderate to severe OA of the knees in 22 subjects. Measurements assessed included walking distance, range of motion, pain, and joint mobility of the knee in those individuals who were withdrawing from NSAIDs. Eight subjects were given 2400 mg/day of Aquamin and 14 given placebo for up to 12 weeks.
Fourteen individuals completed the study, and analysis showed that there were no significant differences in pain and joint mobility scores, but did show small but statistically significant improvements in passive and active extension, and improved walking distance in the Aquamin group, but not the placebo group. There was a 50% reduction in NSAID use in the Aquamin group, although it should be noted that the Aquamin did not eliminate the NSAID use altogether.
Comment: Aquamin is a calcium- and magnesium-rich seaweed derived from the red algae Lithothamnion coralliodes. It also contains some trace minerals, including manganese, selenium, zinc, phosphorus, potassium, sulfur, iron, boron, sodium, cobalt, and copper. Many minerals have been shown to have some anti-inflammatory effects, including magnesium, boron, and manganese, all of which are found in Aquamin, although in quite small amounts. Calcium, comprising about 34% of the Aquamin formula, has been shown to have a role in OA symptoms and in particular, reducing the pain in OA of the knee and/or hip. Whether it due to the calcium, one or more of the other minerals, or a phytonutrient ingredient in the product, this study suggests that Aquamin is a potential treatment for moderate to severe OA of the knee, especially able to reduce the use of NSAIDS, and improve walking distance and range of motion.
Frestedt J, Kuskowski M, Zenk J. A natural seaweed derived mineral supplement (Aquamin F) for knee osteoarthritis: A randomised, placebo controlled pilot study. Nutr J. 2009;8:7.
Pine Bark Extract (Pycnogenol) and Osteoarthritis of the Knee
The purpose of this study was to evaluate the effects of Pycnogenol in reducing symptoms of osteoarthritis (OA) in a double-blind, placebo-controlled, randomized trial. One hundred patients older than 25 were suffering from mild OA (stage I or II) in at least one knee and mild to moderate pain for at least 3 months prior to the study, and/or morning knee stiffness and/or knee crepitus.
The main outcome criteria were reduction of symptoms of OA using the Western Ontario and McMaster (WOMAC) Osteoarthritis Index scores and reduction of pain using a visual analogue scale (VAS). The secondary outcome was a decrease in the use of analgesics. Study subjects were randomly assigned to Pycnogenol 50 mg TID or placebo (14 men and 36 women in the Pycnogenol group, and 18 men and 32 women in the placebo group). Patients were allowed to continue with their current medication (NSAIDs or analgesics) and to change medication as needed, but were required to report dosage or frequency changes at each visit. Patients were evaluated at baseline, 3 months, and 4 weeks after completing the treatment. The WOMAC questionnaire for pain, stiffness, and daily activities was completed by the patient every 2 weeks during the study, whereas the VAS for pain was filled in by each patient weekly.
Results: The WOMAC-A score, summarizing pain scores, improved significantly in the Pycnogenol group (p = 0.0004) over the time of the study. The statistical difference for pain reduction compared to baseline in the Pycnogenol group was evident after weeks 8,12 and 14 (p < 0.001). The difference between treatment group and placebo was near statistical significance at week 8 (p = 0.08).
The WOMAC-B score, analyzing stiffness, showed statistically significant improvement (p = 0.01) in the Pycnogenol groups versus baseline after weeks 8,12, and 14. Statistically significant differences between treatment group and placebo group were observed at weeks 8 and 12 (p < 0.05).
The WOMAC score in regard to the ability to perform daily activities improved significantly versus baseline in the Pycnogenol group at weeks 8,12, and 14 (p < 0.01). The change in the placebo group was not significant, and the difference between the Pycnogenol and placebo groups was not significant.
Pain scores by VAS were somewhat higher in the placebo group than the Pycnogenol group at baseline, although this difference was not significant. After treatment for 4 weeks, the treatment group reported less pain when compared to placebo, and pain continued to diminish until month 3. The correlation of decreased pain over time was statistically significant (p < 0.04) for the Pycnogenol group, but poor for the placebo group (p < 0.17). Only a marginal significance was seen between Pycnogenol versus placebo at weeks 4 (p = 0.08) and 8 (p = 0.07).
Patients in the Pycnogenol group were able to reduce their use of analgesics or NSAIDs at a higher percentage than those in the placebo group. Ten percent of placebo group patients had to increase their dose of analgesics, whereas no higher doses were needed in the Pycnogenol group.
Comment: I'm encouraged to see this study and am looking forward to using this in patients with milder to moderate OA symptoms, especially of the knees. Pycnogenol is a special standardized extract from the bark of the French maritime pine. It is composed of polyphenols, several phenolic acids, catechins, taxifolin and procyanidins. In laboratory research, Pycnogenol selectively inhibits matrix metalloproteinases (MMPs). MMPs are one of the inflammatory responses in arthritic joints induced by interleukin-1. The matrix-degrading activity contributes to the loss of cartilage and is associated with chronic inflammation. Other in vitro research has shown that Pycnogenol inhibits other inflammatory cells and specifically inhibits COX1 and COX2. The observation of these previously observed anti-inflammatory effects, as a background to the current study, contributes a body of information that enables us to have another viable alternative treatment in early OA of the knee, as well as an approach to reducing the use of analgesics and NSAIDs in pain management.
Cisar P, Jany R, Waczulikova I, et al. Effect of pine bark extract (Pycnogenol) on symptoms of knee osteoarthritis. Phytother Res. 2008;22:1087–1092.
Curcumin and Knee Osteoarthritis
One hundred and seven patients with primary osteoarthritis of the knee were studied, including those with knee pain on a scale of 5 to 10 in intensity; radiographic osteophytes; and at least one of the following features: age >50, morning stiffness <30 minutes in duration, and crepitus on motion. The majority of the individuals were overweight women with a BMI >25. Participants were asked to discontinue their knee pain medications and were randomized to either ibuprofen 400 mg twice daily or Curcuma domestica extract, 500 mg four times daily for 6 weeks.
Fifty-two patients received C. domestica extracts and 55 received ibuprofen, with 45 patients in the curcuma and 46 patients in the ibuprofen group completing the study. The mean scores of pain on level walking, pain on stairs, and functions of the knee were significantly improved when compared with the baseline values in both groups. There were no significant differences in those measurements between the patients receiving ibuprofen and C. domestica extracts, except pain on stairs was more favorable with curcumin, and a there was greater degree of moderate to high satisfaction with treatment in the curcumin group than the ibuprofen group (90.1% vs. 82.8%). There was a bit better compliance with the ibuprofen at twice daily than the curcumin four times daily, but no patients reported dissatisfaction in the curcumin group.
Comment: Curcumin has exhibited various pharmacologic activities in previous reports and studies, including anti-inflammatory and antioxidant properties. Curcumin's anti-inflammatory mechanisms include those affecting lipoxygenase, cyclooxygenase, and phospholipase. Curcumin also has been shown to inhibit the secretion of collagenase, elastase, and hylauronidase; inhibit the activation of free-radical activated transcription factors such as nuclear factor kappa B; reduce the proinflammatory cytokines such as tumor necrosis factor alpha, interleukin 1B, and interleukin 8; and have antioxidant properties by inhibiting nitric oxide synthase production. At least six other studies of curcumin in humans reveal that it has anti-inflammatory activity. Dosage ranges from 1125 mg/day up to 8000 mg per day. New products have emerged in the marketplace that are phytosome preparations of curcumin, asserting superior absorption, dose delivery, and anecdotal reports of improved benefits in pain relief.
Kuptniratsaikul V, Thanakhumtorn S, Chinswangwatanakul P, et al. Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis. J Alt Complement Med. 2009;15(8):891–897.
Rosa Canina Fruits (Hyben Vital) for Osteoarthritis
This double-blind, placebo-controlled, crossover study examined the effect of Hyben Vital, a herbal remedy made from a subspecies of Rosa canina (rose hips). One hundred twelve patients – 71 women and 41 men with an average age of 64 – were enrolled and randomized to receive either Hyben Vital 5 g daily or a placebo for 3 months, and then crossed over immediately. Joint pain and stiffness were measured on a 5-point scale; and mood, sleep quality, and energy were assessed and recorded.
The group that took the placebo first (group A) showed significantly more improvement with Hyben Vital than from the placebo for pain and stiffness. The group that received the Hyben Vital first (group B) revealed a similar positive effect to that of group A, and also a similar positive effect from the placebo. When comparing responders with nonresponders, the first 3 months of active treatment (group A) showed a response rate of 66% compared with that of group B of 36%. These data indicate that Hyben Vital reduces the symptoms of pain and stiffness of osteoarthritis.
Comment: One might ask, how is this working? Earlier experiments have demonstrated that Hyben Vital reduces the migration of neutrophils and monocytes and decreases C-reactive protein concentrations in patients with osteoarthritis. Another possible consideration is that Rosa canina powder contains vitamin C. However, there are only 26 mg in 5 g of Hyben Vital, so I doubt that this little amount of vitamin C had sufficient antioxidant benefits to reduce joint pain and stiffness. Three randomized trials done by the Danish manufacturer of Hyben-Vital, also known as Litozin, included a total of 306 osteoarthritis patients who were given rosehip powder or placebo for 3 to 4 months at a dose of 5 g per day. The pain-score changes were significantly greater in the rosehip group than in the placebo group, and effectiveness was similar in all 3 trials. In those trials, the pain-reducing ability of rosehip powder was greater in those anticipating knee or hip surgery. It should be noted that the rosehip powder used in these studies, and in the current study in this abstract, is derived from a chemotype that grows in a particular area of Denmark. The company holds a patent on it for use in osteoarthritis, and it is unclear whether other rosehip products are effective for this use.
Rein E, Kharazmi A, Winther K. A herbal remedy, Hyben Vital (stand. Powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis- a double-blind, placebo-controlled, randomized trial. Phytomedicine. 2004;11:383–391.
High Triterpene Shea Nut Extract Offers a Promising New Approach
I have recently been introduced to a new product, shea nut extract, for the treatment of osteoarthritis. Shea nuts have been used in food and Traditional African Medicine for generations, particularly West Africa. A Danish company has developed a method to greatly concentrate and enhance the triterpenes found in shea nut, yielding a 70% triterpene extract. This high triterpene shea nut extract was allowed into the US in 2004 by the FDA and designated as a new dietary ingredient.
My interest in this product is spurred by the multiple mechanisms in which these triterpenes seem to affect the joint: regulating cytokines; reducing TNF-a, IL-6, and osteocalcin; improving circulation of the joint matrix; slowing inflammatory bone loss; reducing cartilage destruction; and restoring collagen.
In one randomized placebo-controlled trial, 117 patients with radiographic and clinical evidence of osteoarthritis of the knee or hip were given shea nut extract or placebo for 15 weeks. (Cheras PA, Myers SP, Outerbridge K, Nielsen G. Randomised placebo controlled trial on the safety and efficacy of BSP-201 in osteoarthritis. Australian Centre for Complementary Medicine Education and Research [ACCMER]. Sept. 4, 2007.) TNF-alpha reduced 17.9% overall and 23.9% in the group with elevated levels. IL-6 fell by 30.9%; C-reactive protein reduced by 20.6%; CTX-II, a cartilage marker, fell by 28.7% in patients with elevated levels vs. an increase in placebo of 17.6%; and osteocalcin reduced by 9.2% in the elevated group, indicating bone repair mechanisms.
Animal studies are also being conducted by the manufacturers of high-triterpene shea nut extract showing comparable anti-inflammatory effects with ibuprofen but no adverse effects as often seen in ibuprofen. Other studies are in development, and I look forward to those publications.
I have surveyed some retailers and consumers in the natural-products market who have been aware of and using high-triterpene shea nut extract for several months and been pleased to hear of the consistently positive anecdotal reports. For practitioners, shea nut extract yielding 70% triterpenes is available as BSP 201. I look forward to increasing my own clinical usage of this product and hope to see the same positive results in my patients. With its multiple mechanisms of actions, early research, and anecdotal reports, shea nut extract leaves me optimistic.
Estrogen Therapy for Osteoarthritis of the Hip
A systematic review summarized the evidence on the association between exogenous hormone use and osteoarthritis. Nineteen studies on the exogenous use of hormone use were identified in a Medline search up to March 2008. Limited evidence was seen for a protective effect of unopposed estrogen use for incidence of hip /joint replacement. There was also a trend for radiological osteoarthritis of the knee. Conflicting evidence was observed for combination estrogen/progesterone hormone replacement therapy (HRT) use with distal interphalangeal X-ray–confirmed osteoarthritis, "any joint" osteoarthritis, and the knee. There was a significant protective effect of long-term unopposed estrogen therapy for hip osteoarthritis, and limited evidence for a significantly increased risk of HRT for clinical hip osteoarthritis. While a relationship between the exogenous hormone use and osteoarthritis was not clearly observed in this review, yet a protective effect of unopposed estrogen use for hip osteoarthritis was, this relationship of estrogen and OA is considered to be complex. Given that the incidence of osteoarthritis rises significantly in women after age 50 but not in men, this does suggest an association between hormonal changes at menopause and osteoarthritis.
De Klerk B, Schiphof D, Groeneveld J, et al. Limited evidence for a protective effect of unopposed oestrogen therapy for osteoarthritis of the hip: a systematic review. Rheumatology. 2009;48(2):104–112.
Treatments for osteoarthritis are many and varied, ranging from those that focus on reducing numerous inflammatory mechanisms to those that stimulate chondrocytes, improve joint stability, and enhance the joint microcirculation. Natural therapies, over-the-counter medications, and prescription pharmaceuticals need to keep expanding beyond treatments based on inflammatory mechanisms. Some of the therapies discussed above offer further options in treatment, and will hopefully lead to more research in natural therapies, as well as conventional treatments with a better safety profile and more effective results.
Disclosures: Dr. Tori Hudson is the co-owner and director of education and research for Vitanica. She also serves on several scientific advisory boards, including Integrative Therapeutics Inc., Nordic Naturals, Natural Health International, Biogenesis, and BSP Pharma. firstname.lastname@example.org