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The integrated treatment of postmenopausal osteoarthritis.

Epidemiology

Primary osteoarthritis (OA) is common, costly, and crippling. Postmenopausal OA is associated with degeneration, commonly found in hands, knees, and hips. Contributing factors include metabolic, genetic, epigenetic, inflammatory, and mechanical factors. The significance of these interactions is incalculable, but not inconsequential.

In 2009, 40 to 50 million US adults were diagnosed with arthritis. (1) In 2003, the arthritides accounted for 1% of the gross domestic product, or nearly $81 billion in medical expenditures and $47 billion in lost earnings. (2) The incidence of OA increases with age, rising from 27% in those under 70 years old to 44% in those over 80 years old. Obesity confers the highest lifetime risk. (3)

Body mass index (BMI) >27 kg/[m.sup.2] is associated with increased risk for knee OA in a cohort of 3585 persons >55 years old. (3) High heels may increase risk of OA due to increased force across the knee joints. (4)

BMI [greater than or equal to]] 32 kg/[m.sup.2] is associated with 2 to 3 times the risk for total hip replacement in a study of 1,152,006 Norwegians aged 18 to 67 years. (5) 41% of people over age 40 have hand OA; women are more affected than men. (6)

Signs and Symptoms

The symptoms of OA include slowly developing arthralgia, stiffness after stillness, increasing pain as the day progresses, and weakness. Full range of motion is initially uncomfortable and eventually limited. Signs of OA in the hands include limited closure, bony enlargement of distal and proximal interphalangeal joints, carpometacarpal squaring, limited thumb extension, thenar wasting, and thumb in palm formation. In knees, flexion and then extension are limited and motion is often painful and crepitant. Popliteal cysts, cool effusions, vastus medialis obliquus wasting, and valgus or varus deformities can be seen. In the hip, pain is often limited to the groin, inner thigh, or knee alone. Internal rotation is often uncomfortable and limited. Psoas contractures and limited abduction can be seen. X-ray findings can be deceiving! Horrible bone-on-bone osteoarthritis can be seen in an absolutely asymptomatic weight-bearing joint.

Conventional Treatment

Treatments for OA in all sites include weight management, exercise, analgesics, selective and nonselective nonsteroidals (sNSAIDs/nsNSAIDs), topical pharmaceuticals, bracing, special shoes, electrical stimulation, laser therapy, manipulative therapy, physical and occupational therapy, intra-articular steroids, mobility aids (cane, walker, wheel chair), viscosupplementation, arthroscopy, and partial or total joint arthroplasty.

Acetaminophen is weakly analgesic, and narcotics should be reserved for brief perisurgical periods. (7) Although NSAIDs are strongly recommended, all NSAIDs increase risk of gastrointestinal bleeding. Both sNSAIDs and nsNSAIDs, excluding aspirin, increase risk of stroke, and myocardial infarction. (7) NSAIDs should be used sparingly and for short duration and may be used in concert with acetaminophen. Oral NSAIDs (both types) should not be used in any patient over 75 years of age, as they may cause sodium retention, reduce glomerular filtration and worsen hypertension even with short-term use. (7,8) Tramadol provides some relief but its use is limited because of frequent adverse reactions. Topical capsaicin and NSAIDs are modestly efficacious and safe. (8) Manipulative therapies should be offered only as adjunct to exercise. (7)

Hands

Few high-quality randomized controlled trials (RCTs) on hand OA exist. Expert opinion and our clinical experience support the following: evaluation of independent daily living activities, joint protection, work simplification instruction, thermal modalities, and splinting. Intraarticular injection therapies are not recommended in the hand. (7)

Knees

There are data both supporting and refuting patellofemoral bracing, electrical stimulation, wedged insoles, acupuncture, manual therapy, and shoe modifications. (7,9-11)

Intra-articular steroids provide brief pain relief and should be used sparingly if at all. Acute adverse reactions are rare but include increased serum glucose, avascular necrosis, acute synovitis, acute calcium pyrophosphate deposition, infection, tendinopathy, and periarticular calcifications. Long-term adverse reactions include capillary fragility, tissue atrophy, joint destruction, and cartilage degeneration. (12) The common practice of combining intra-articular steroids and local anesthetic causes chondrocyte death. (13) The American Academy of Orthopedic Surgeons (AAOS) does not recommend intraarticular steroid injections, but the American College of Rheumatology does. (7,9)

Intra-articular viscosupplementation with hyaluronic acid has been recommended for patients with mild to moderate knee OA who have failed conservative treatment, but its efficacy is unproven and it is falling out of favor. (5,7,9,12,14) Partial meniscectomy for torn meniscus may be considered, if conservative measures fail, but it is possible to live with a torn meniscus if activity is judicious. (9)

Hips

Intra-articular steroids can be used, but expensive imaging is needed for proper needle placement and they are not that helpful for ordinary OA. Hyaluronic acid has not been approved for use in the hip. Arthroscopy can be helpful in cases of torn labrum. (15) Severe OA of the hip may be tolerated well for years, unlike severe knee OA, which is less tolerated.

Exercise

Exercise must be part of a conventional or integrative approach to OA, but formulating optimal individualized exercise can be challenging. Supervised group exercise is superior to nonsupervised activity. (16) Tai chi, qi gong, yoga, and Feldenkrais method have shown positive results. In an observational study, Webb showed improvement in multiple gait parameters in community-dwelling adults with OA after participation in twice-weekly Feldenkrais method classes over a 30-week period. (17)

Yoga and tai chi are the only disciplines that have been studied using systematic reviews. Cramer found two high-quality studies recommending yoga for OA pain reduction. (18) Evidence is currently stronger for tai chi. A systematic review of three high-quality RCTs found that tai chi improved gait and reduced stiffness and pain for knee OA patients. (19) Studies have also shown that tai chi increases OA patients' quality of life. (20)

Exercise reduces pain and improves physical strength, balance, metabolism, and mood. Many OA patients view their bodies as a source of pain, discomfort, and sadness. Exercise forms such as tai chi and yoga can provide pleasure and joy.

Mind-Body Medicine

Living with any chronic pain can be devastating emotionally, socially, financially, and spiritually. A truly holistic treatment plan for postmenopausal OA must address the mind-body connection. Many formalized techniques improve pain, hot flashes, cognitive function, insomnia, and quality of life. (21-26) Mindfulness-based stress reduction (MBSR) is one such well-studied system. Designed by Jon Kabat-Zinn, PhD, it teaches somatic awareness and meditation. Ussher found that even 10 minutes of MBSR practice decreased pain compared with controls who read natural history literature. (27) Rosenzweig found that an 8-week course in MBSR had the most significant effect on patients with arthritis and back/neck pain compared with other diseases. While still significant, the MBSR program has less effect on headache and fibromyalgia. Patients with concomitant meditation practice had even greater improvements in pain and quality of life. (28)

Phytochemical and Herbal Treatments

Many phytochemicals and herbs have been studied for OA treatment. This review will focus on epigallocatechin-3-gallate (EGCG), sulforaphane, resveratrol, Curcuma longa, Boswellia serrata, and Harpagophytum procumbens.

EGCG, a phytochemical present in green tea, is being researched intensely for its impact on many conditions, including cerebral hemorrhage, liver disease, infection, cancer, atherosclerosis, inflammatory joint disease, and OA. (29)

Basic scientists are discovering and elucidating the molecular mechanisms of EGCG; however, good clinical RCTs OA studies have not yet been conducted. An in vitro study of EGCG showed 2 important effects in inflamed chondrocytes; inhibition of IL-1, TGF [beta], IL-8, and chemokine ligand 2, as well as reduced neutrophil and monocyte migration. (30) In another in vitro model, EGCG prevented production of IL-6, IL-8, monocyte chemotactic protein-1 (MCP-1), MCP-3, and macrophage inflammatory protein-1 beta (MIP-1b) via NF-[kappa]B in inflamed chondrocytes. (31) The chondroprotective role of EGCG may also be due to increased resistance to metalloproteinases 1, 9, and 13. (32) EGCG may also work on cyclooxygenase 2 (COX-2), prostaglandin E2 (PGE2), TNF[alpha], and advanced glycation end products (AGEs). (33,34) Huang stimulated human synovial fibroblasts with IL-1[beta] and found that the application of EGCG inhibited COX-2, PGE2, and IL-8. (33)

Clearly, human studies are lacking; but, given green tea's safety, it is reasonable to advise drinking high-quality, organic green tea or use a green tea product standardized for EGCG. A rational and well-tolerated starting dose of EGCG is 100 to 300 mg daily.

Curcuma longa is one of the best-studied herbs in the treatment of osteoarthritis. There are abundant in vitro, in vivo, clinical studies, and systematic reviews that support its use. It appears to work by inhibiting IL-1[beta], IL-6, IL-8, NF-[kappa]B, TNF[alpha], MMP-3, MMP-9, MMP13, caspase-3, and COX-2 and enhancing chondrogenesis. (35-41) NF-[kappa]B activation can directly trigger matrix degrading enzymes. Curcumin reduces production of AGEs that lead to chondrocyte destruction. (36) Interestingly, it appears that curcumin and resveratrol synergistically protect chondrocytes by downregulating NF-[kappa]B and reducing pro-inflammatory cytokines. (38,42,43) Shakibaei pretreated in vitro chondrocytes with curcumin, resveratrol, or the combination. He then applied IL-1[beta] and observed the catabolic effects. He found that the combination provided superior protection compared with each phytochemical alone. (42)

Strong in vitro studies of curcumin encouraged in vivo studies for patients with OA. Three well-performed clinical trials support its use in knee OA. Knee OA is easily studied because outcome measures and radiographic features are well characterized. A randomized, double-blind study compared diclofenac 75 mg/d + placebo with diclofenac 75 mg/d + curcumin 1000 mg/d for 3 months. Diclofenac and curcumin demonstrated superiority for decreasing pain and improving function. (44) In an in vivo comparison of boswellia (frankincense) + curcumin (500 mg b.i.d.) with celecoxib 100 mg b.i.d., the herbal formulation outperformed celecoxib on symptom scoring. No safety issues were found with the herbal formulation. (45)

The form of curcumin is critical for absorption. There are multiple proprietary forms of curcumin that enhance absorption. Examples are quality curcumin complexed with phosphatidylcholine, BCM-95 (curcumin with essential oil of curcumin), and curcumin dispersed with colloidal nanoparticles. To date there has not been a study comparing each of these forms with the other, although they each have strong evidence supporting increased absorption. BCM-95 has been shown to have a 6.93-fold increase in absorption compared with standardized curcumin. (46) Curcumin dispersed with colloidal nanoparticles was shown to increase blood concentration levels 27-fold higher compared with plain curcumin. (47) Curcumin complexed with phosphatidylcholine has shown a 29-fold higher blood concentration level. (48) It must be stressed that the absorption research has been performed by industry and each uses different standardized curcumin products as a control.

Curcumin complexed with phosphatidylcholine is the only proprietary form of curcumin that has been studied in patients with osteoarthritis. Belcaro performed a 10-month placebo-controlled study examining clinical efficacy and biometric end points such as IL-1 beta, IL-6, and ESR. It proved superior in WOMAC score (a standardized questionnaire to access pain, stiffness, and physical function), Karnofsky Performance Scale Index, and most biometric end points. (49) We often start with high-quality curcumin, loading doses between 1 and 3g/d in divided doses for 2 weeks, then decrease to efficacy. If patients are allergic to soy, some forms of curcumin cannot be used.

Boswellia serrata is another herb that has many different formulations. Several forms are standardized for boswellic acid, 5-Loxin, and proprietary resins. One of these resins was studied in a double-blind RCT for efficacy of treating OA pain and dysfunction. While the trial was only 30 days, statistically significant improvement was first seen at day 5, indicating that this form of boswellia may be effective for acute pain management. (50) 5-Loxin has also been studied in a similar manner. Sengupta studied 2 different dosages of 5-Loxin (100 mg/d and 250 mg/d) and compared them with placebo and followed patients for 90 days. (51) This study's strength was that it measured MMP-3 from knee synovial fluid before and after treatment. At the dosages of both 100 mg/d and 250 mg/d, 5-Loxin showed significant improvement in pain at 7 days that continued until study's end. On a molecular level, boswellia shows many similarities to curcumin. There appears to be strong inhibition of iNOS, MMP-9, MMP-13, NF-[kappa]B, TNF[alpha], IL-1, IL-2, IL-4, IL-6, and IFN[gamma], and the complement system. (52,53)

The British Medical Journal recently published a systematic review of RCTs studying boswellia in several diseases. It found encouraging evidence that boswellia was an effective and safe treatment for osteoarthritis. (54)

Sulforaphane is another promising phytochemical. It belongs to the isothiocyanate group of organosulfur compounds from sprouted cruciferous vegetable seeds, such as broccoli seeds. Intense research on sulforaphane's antineoplastic, antimicrobial, and anti-inflammatory properties is currently being performed. While no human trials in OA patients have yet been performed, we are beginning to understand molecular mechanisms which suggest that it will be efficacious. Sulforaphane appears to activate the cytoprotective transcription factor Nrf2, downregulate NF-[kappa]B, decrease MMP-1 and MMP-13, and protect against cartilage degradation in a mouse model and in vitro. (55-57)

Harpagophytum procumbens (devil's claw) has a long history of use in traditional Western herbalism for arthritis treatment and an established safety record. (58) In vitro evidence suggests that devil's claw inhibits TNF[alpha], IL-6, IL-1[beta], PGE2, NF-[kappa]B, and COX-2. (59,60) Systematic reviews suggest that a dosage of 60 mg/d harpagoside is effective for knee and hip OA. (61) This bitter herb is also a mild diuretic, mild sedative, and appetite stimulant. We find that it is a good choice for anxious patients with sluggish digestion.

The size and quality of trials evaluating herbal interventions is growing rapidly and reaching wider audiences. One such article appeared in Oxford's Rheumatology in late 2013. In a large randomized, double-blind, parallel-efficacy trial of 440 patients, Chopra compared an Ayurvedic formulation of Tinospora cordifolia, Zingiber officinale, Emblica officinalis, and Boswellia serrata with celecoxib (200 mg daily) and glucosamine (2g daily) and found outcomes equivalent at 6 months for all 3 treatments. (62)

Balneotherapy

Balneotherapy is a traditional term to describe spa therapies that often include mud packs and hyperosmolar mineral bathing. It is an easy-to-follow, low-cost treatment that can be combined with mindfulness-based meditation.

Mud application to the knee was found to be superior to control for WOMAC and pain scoring in a recent meta-analysis of 7 RCTs. (63) The difficulty with this analysis is that the dosage of mud applications and follow-up time period for each study were different. This suggests that a 20-minute application of mud, 5 times weekly for 2 weeks, is effective up to 3 months, although it should be noted that even 3 mud-based therapies combined with mineral bathing over the course of a year have been found to be efficacious. (64) Mud therapy has also been compared with intraarticular hyaluronic acid, yielding equivalent results at 6 months; but mud is safer. (65) In our experience, mud therapy works well for hand and knee OA but is a difficult treatment for hip OA due to the "messiness" factor.

Many of the studies evaluating balneotherapy have been performed at the Dead Sea or thermal spas in Europe. An observational study found that 2 mineral baths within 2 weeks improved gait, pain, and WOMAC scores. (66) Evcik compared mud therapy, mineral bathing, and hot packs applied to the knee for 20 minutes 5 times weekly for 2 weeks and found that all therapies improved WOMAC scores. (67)

In our practice, recreating mineral baths in the patient's own home is highly effective and well tolerated, as patients find it easy and pleasurable. Patients are instructed to purchase bulk Dead Sea salt and use 5 to 7 cups per 52-gallon bathtub. We often start with 3 to 5 baths per week then taper to once weekly when the patient has stabilized. Water temperature may prove important, but has not been well studied in OA.

Vitamin D

Although the prospect seems sensible, it is controversial whether vitamin D status affects OA disease risk or progression. One epidemiological study suggests that low intake and low serum levels of vitamin D each appear to be associated with an increased risk for progression of knee OA. (68) Two RCTs have been performed; one showing benefit in OA patients that had a baseline vitamin D [less than or equal to] 50 nmol/L given 60,000 IU daily for 10 days, then 60,000 IU monthly for 12 months. (69) The other RCT found no benefit in patients who were dose-escalated to serum 25(OH) vitamin D levels of >36 nmol/L and followed for 2 years. (70) It should be noted that both articles had serious limitations in that optimal 25 OH vitamin D levels were never achieved. In clinical practice, we aim to raise patients' serum 25(OH) vitamin D3 levels ~150 nmol/L or 60ng/ml. We base our recommendations on the additional benefits of reducing cancer and osteoporosis risks.

Polyunsaturated Omega-3 Fatty Acids (PUFA-3)

To date, the research supporting the use of long-chain [omega]-3 essential fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is much stronger for inflammatory arthritides such as rheumatoid arthritis. It is a relatively new concept to think about osteoarthritis as an inflammatory process, and thus we have not yet fully explored the use of EPA and DHA for clinical efficacy. From a mechanistic, animal-based model, PUFA-3 decreases IL-1[beta]-mediated cartilage degradation, decreases MMP-2, and improves collagen cross-links. (71,72) In humans, our most compelling evidence was performed during the Multicentre OA Study (MOST). Baker examined plasma omega-6 and omega-3 fatty acid levels in 472 adults considered to be at risk of OA. (73) Knee synovitis seen on MRI was evaluated in relation to serum fatty acids and cartilage morphology. They found that patients with higher omega-6 plasma levels had increased synovitis, low DHA, and patellofemoral cartilage loss. These data are intriguing but inadequate to provide definitive evidence supporting routine supplementation for OA. Despite this, PUFA-3 therapy has been shown to have an NSAID-sparing effect in RA and has collateral heart protection with a high safety profile. (74)

If PUFA-3 is prescribed to patients with OA, caution should be taken if the patient is on blood-thinning medications or has a bleeding disorder. Only fish oil that has been third-party verified to be free of PCBs and heavy metals should be used. In light of the Fukushima accident, fish oil may need additional safety testing.

Glucosamine/Chondroitin

Glucosamine and chondroitin have long been touted as the natural medicine treatment of choice for OA and enjoy more research than any other natural substance. Even after a decade of research, the true efficacy of glucosamine and chondroitin is not clear. Glucosamine appears to work by decreasing IL-1B, NF-[kappa]B, MMP-2, MMP9, and COX-2 and via induction of anabolic mediators such as transforming growth factor (TGF)-[beta]1 and connective tissue growth factor (CTGF). Chondroitin shows similar effects by decreasing IL-1B, NF-[kappa]B, MMP-1, MMP-3, and MMP-13 and conversely increasing type II collagen and proteoglycan synthesis in human articular chondrocytes. (75)

RCTs have conflicting outcomes. Most studies have been small or poorly performed. That said, compelling evidence for the clinical use of glucosamine was recently published by Bertin and Taieb. (76) They analyzed data from 11,772 patients and found that those who used glucosamine took significantly less NSAIDs. If glucosamine and chondroitin allow a patient to decrease intake of a potentially harmful medication, even when true efficacy is not proven, it is reasonable to prescribe them in a clinical setting.

Glucosamine and chondroitin may not be safe for use in patients with chronic liver diseases, although these data are highly circumstantial. (77) We advise caution in treating chronic liver disease patients with glucosamine and chondroitin.

Platelet Rich Plasma (PRP)

It is beyond the scope of this article to fully address the research and impact of platelet rich plasma injection into OA joints. However, given the body of evidence, it should not be overlooked as a safe and effective treatment for many OA patients, especially those facing total joint replacement therapy. The research of PRP is rapidly expanding and has been overall positive. PRP appears to release growth factors that can increase meniscal and chondrocyte growth. (78-80) It has been found in multiple trails to be superior to hyaluronic acid injection for pain, function, and radiographic features. (81,82)

Diet

We often tell our patients that no amount of supplements can compensate for poor diets, no matter what the disease. We have just spent a good deal of time discussing the dietary supplements for OA management in women; now we must turn our attention to diet. Unfortunately, diet is an incredibly difficult subject to study within the current scientific paradigm. If we rely on research alone, we can only make broad statements; for example, a diet low in vitamin K or magnesium or high in soda may contribute to disease progression. (83-85) Our recommendations on diet are therefore based on our collective 31 years of clinical practice. Most patients are prescribed a diet that is more than 90% vegetables, fruits, raw nuts and seeds, eggs, pasture-raised meat, olive oil, grapeseed oil, and coconut oil. A good diet contains less than 10% grains (whole or refined), dairy, sugars, conventionally raised meat, processed meats, and vegetable oils (corn, peanut, etc.). Patients are also advised to eat 3 cups of cruciferous vegetables and 3 cups of dark leafy greens per day. Helping the patient focus on what to eat, rather than foods to avoid, acts to "crowd out" nutrient-poor dietary choices.

While purely anecdotal, a recent patient story illustrates the importance of diet. A 48-year-old, morbidly obese female presented with severe bilateral knee OA looking for alternatives to knee surgery, which was recently discussed as her only option for care. Fatigue and pain precluded exercise. She was prescribed the diet described above. At 6 weeks she was walking without a cane, able to walk up and down stairs, and had enough energy to start a light exercise program. Then one night she succumbed to food cravings and ate an entire pepperoni pizza. Within 12 hours she was unable to get out of bed and photodocumented her knees more than doubling in size. She spent the next 3 days in bed. Needless to say, she returned to her healthful eating routines and has continued to improve.

Conclusion

Osteoarthritis can be devastating and life changing. Integrative and conventional physicians agree on prevention through diet and exercise. We believe that high-quality supplements are crucial for patient safety, strong clinical studies, and limiting the need for potentially dangerous pharmaceuticals. Patient safety is paramount, pharmaceuticals fall short, regenerative techniques are promising but unproven, and surgery should be a last resort.

Integrative physicians believe that Mediterranean/Paleolithic diets provide energy and substrate for patients to exercise and repair their tissues. We attempt to coach patients through the game of life with osteoarthritis, enabling joyful and easy movement. Because OA risk factors are multifactorial, we believe that utilizing multiple therapies is essential and guides our holistic approach of diet, exercise, meditation, modalities, and nutraceuticals. We have shown that there is growing evidence for each of these synergistic interventions. We strongly encourage future research to include study of medical-grade supplements, excluding inferior products to ensure study validity. We would also like to see multifaceted clinical models to evaluate effectiveness of the holistic approach.

by Alena Guggenheim, ND, and Carla Guggenheim, DO, FACP, with thanks to Nicholas Morgan, ND

Notes

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Alena Guggenheim attended Reed College in Portland, Oregon, and graduated with a BA in biology in 2001. In 2007 she graduated from the National College of Natural Medicine with a doctorate in naturopathic medicine. In 2009 she completed a residency through National College of Natural Medicine and the Center For Natural Medicine mentored by Dr. Martin Milner that focused on cardiopulmonary medicine. During her education she participated in research regarding immune modulation with herbs and personality implications on health. In 2011 she began teaching in the Master of Science in Integrative Medicine Research (MSiMR) and Doctorate of Naturopathic Medicine programs at NCNM. She teaches clinical physical diagnosis, rheumatology, microbiology and an integrative modalities course. She also mentors students completing the MSiMR program. Her research focuses on immune modulation by mushrooms.

Dr. Guggenheim maintains a private practice at the Center For Natural Medicine in Portland, the first naturopathic clinic in the country to be a certified Patient Centered Primary Care Home. She provides holistic primary care with a focus on rheumatological diseases such as rheumatoid arthritis and lupus.

Carla Guggenheim, DO, FACP, is a board-certified rheumatologist and fellow of the American College of Physicians. Her undergraduate degree is in dance. She completed her DO degree at Des Moines University in 1988, DO rotating internship and internal medicine residency at Michigan State University in 1992, and rheumatology residency at the University of Iowa in 1994. She is clinical faculty at Michigan State University and National College of Natural Medicine. She is director of the first naturopathic rheumatology residency in the US.

Nicholas Morgan, ND, is a second-year resident at Arthritis Care PC in Lansing, Michigan, where he also founded the Center for Integrative Wellness. He graduated from NUHS in 2011 and is the first naturopathic rheumatology resident in the US. Dr. Morgan's medical interests include arthritis prevention, epigenetics/nutrigenomics, functional medicine, and methylation management. In addition to practicing medicine, he enjoys teaching and public speaking to help increase awareness about the benefits of person-centered health care.
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Author:Guggenheim, Alena; Guggenheim, Carla; Morgan, Nicholas
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Date:Feb 1, 2014
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