Kerry Bone Co-Founder and Director Research & Development MediHerb Adjunct Associate Professor, University of New England, Australia
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Topics Covered
Defining osteoarthritis (OA) and its prevalence Risk factors and OA Pathophysiology and pain in OA OA, AGEs and circulation Rational OA therapy versus NSAIDs Boswellia and Willow Bark Nutrition and OA Herbal protocols for OA Case histories
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Defining Osteoarthritis
Osteoarthritis (OA) has been defined as the failed repair of damage caused by excessive mechanical stress on joint tissues1
All joint structures are affected, but the major hallmarks are the destruction of articular cartilage and changes in the subchondral bone
Historically OA was called “osteoathrosis”, a term implying the absence of inflammation
1 Van Weeren PR, de Grauw JC. Vet Clin North Am Equine Pract 2010; 26(3): 619-642
New Insights for Preventing and Managing Osteoarthritis
However, high-sensitive assays (such as for C-reactive protein, CRP) demonstrates that low-grade inflammation is present and that synovial tissue is also involved in the pathology1
A recent review highlighted that while the OA process (attempted healing) may cause joint pain, it is often successful in leading to a stable, painless joint2
1 Heinegård D, Saxne T. Nat Rev Rheumatol 2011; 7(1): 50-56 2 Brandt KD, Dieppe P, Radin E. Med Clin N Am 2009; 93(1): 1-24
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Prevalence of OA
Clinically-diagnosed OA occurs in more than 50% of adults older than 65 years and in more than 30% aged 45 to 64 years1
According to Access Economics about 1 in 10 Australians suffer from OA2
1 Valdes AM, Spector TD. Best Pract Res Clin Rheumatol 2010; 24(1): 3-14 2 www.arthritis.org.au
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Risk Factors in OA
New Insights for Preventing and Managing Osteoarthritis
Risk Factors in OA Widely accepted risk factors are: • Age • Obesity • Joint injury • Genetics (39 to 65% in twin studies) • Gender • Joint misalignment • Metabolic disorders
However, the robustness of many of these is still debated
Felson DT. Radiol Clin North Am 2004; 42(1): 1-9 Lohmander LS, Felson D. Osteoarthritis Cartilage, 2004; 12(Suppl A): S49-S52 Dawson J, Juszczak E, Thorogood M et al. J Epidemiol Community Health 2003; 57(10): 823-830 Cheung PP, Gossec L, Dougados M. Best Pract Res Clin Rheumatol 2010; 24(1): 81-92
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Pathophysiology of OA: Cartilage The precise mechanisms behind cartilage
degradation are still unclear. Early on there is an increase of water and a decrease of proteoglycans (aggrecans) and type II collagen
The predominant enzymes responsible for cartilage matrix degradation in OA are the matrix metalloproteinases (MMPs) and aggrecanases
Later cartilage mineralisation (predominantly calcium pyrophosphate and phosphate) occurs and could accelerate inflammation
Umlauf D, Frank S, Pap T et al. Cell Mol Life Sci 2010; 67(24): 4197-4211
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Pathophysiology of OA: Synovium Synovial inflammation (synovitis) occurs in early OA
but can be subclinical. It is possibly induced by cartilage matrix degradation
It becomes more extensive as OA progresses, with synovial hypertrophy and hyperplasia occurring
There are increased numbers of immune cells, such as activated B cells and T lymphocytes
In turn, the synovitis may contribute to the progression of cartilage degradation
Martel-Pelletier J, Pelletier JP. Eklem Hastalik Cerrahisi 2010; 21(1): 2-14 Attur M, Samuels J, Krasnokutsky S et al. Best Pract Res Clin Rheumatol 2010; 24(1): 71-79
New Insights for Preventing and Managing Osteoarthritis
Pathophysiology of OA: Subchondral Bone The degeneration and erosion of cartilage has
recently been challenged as the primary pathological event in OA
Subchondral bone is suggested to play a key role: after all the disease was originally called osteoarthritis because of the prominence of the bone reaction
The subchondral bone plate is in direct contact with the cartilage and could influence its degradation
Evidence from humans and animal models has shown that subchondral bone alterations may precede cartilage degeneration
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Pathophysiology of OA: Subchondral Bone There is also increasing evidence that bone marrow
lesions (BMLs) and bone cysts have an important role in the pathogenesis of knee OA
BMLs are strongly associated with radiological progression of knee OA and BML enlargement predicts increased cartilage loss, and the reverse
Martel-Pelletier J, Pelletier JP. Eklem Hastalik Cerrahisi 2010; 21(1): 2-14 Tat SK, Lajeunesse D, Pelletier JP et al. Best Pract Res Clin Rheumatol 2010; 24(1): 51-70
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Pathophysiology of OA
Attur M, Samuels J, Krasnokutsky S et al. Best Pract Res Clin Rheumatol 2010; 24(1): 71-79
New Insights for Preventing and Managing Osteoarthritis
The common observation that chronic OA patients can experience flare-ups speaks to it being an inflammatory disease
Inflammation seems to be a very early event in OA, perhaps elicited by the initial traumatic injury
Elevated levels of CRP can be observed well before clinical disease
Inflammation and its triggers directly affect synovial cells (fibroblasts and macrophages), as well as cartilage chondrocytes, causing them to produce cytokines, particularly interleukin (IL)-1β and later tumour necrosis factor (TNF)-α. (The macrophage is a key inflammatory cell in OA)
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Inflammation in OA
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Inflammation in OA
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New Insights for Preventing and Managing Osteoarthritis
Pain in OA Cartilage is aneural, hence cannot be the tissue
that directly generates pain In contrast subchondral bone, synovium, marginal
periosteum, ligaments and the joint capsule are all richly innervated
But rarely can the precise tissue origin of pain be identified in the individual patient and many people with severe radiographic changes are asymptomatic
Imaging studies at the knee joint have shown a correlation between pain and both synovitis and subchondral bone changes Brandt KD, Dieppe P, Radin E. Med Clin N Am 2009; 93(1): 1-24
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Joint Stress or Susceptibility? Is OA a Systemic Disease? While the OA definition links it to mechanical stress,
the predisposition and responses to such stress could be more important to chronic disease and pain development
One study found that OA is more widespread in the body than is apparent from clinical studies1
This is consistent with other data suggesting that OA is a disease that is primarily dependant on systemic predisposition to a particular type of bone response to mechanical stress
Generalised OA is a strong predictor of disease progression2
1 Rogers J, Shepstone L, Dieppe P. Arthritis Rheum 2004; 50(2): 452-457 2 Cheung PP, Gossec L, Dougados M. Best Pract Res Clin Rheumatol 2010; 24(1): 81-92
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Advanced Glycation End Products
New Insights for Preventing and Managing Osteoarthritis
AGEs and OA Increased severity of OA correlates with higher
cartilage advanced glycation end product (AGE) levels1
AGEs in cartilage trigger AGE receptors (RAGE) on chondrocytes and fibroblast-like synoviocytes to increase catabolic activity eg production of cytokines and matrix degrading enzymes, which degrade and breakdown cartilage2
1 DeGroot J, Verzijl N, Wenting-van Wijk MJ et al. Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum 2004; 50(4): 1207-1215
2 Steenvoorden MM, Huizinga TWJ, Verzijl N et al. Activation of receptor for advanced glycation end products in osteoarthritis leads to increased stimulation of chondrocytes and synoviocytes. Arthritis Rheum 2006; 54(1): 253-263
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OA and Insulin Resistance Insulin resistance (IR) predisposes to an increased
incidence of AGEs Current information suggests that OA shares a
similar biochemical and inflammatory profile to metabolic syndrome1
Analysis of the National Health and Nutrition Examination Survey III data (7714 people) revealed that OA is associated with an increased prevalence of metabolic syndrome, particularly in younger people2
1 Katz JD, Agrawal S, Velasquez M. Curr Opin Rheumatol 2010; 22(5): 512-519 2 Puenpatom RA, Victor TW. Postgrad Med 2009; 121(6): 9-20
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OA and Circulation Growing evidence from epidemiological studies
suggests that OA is linked to primary cardiovascular (CV) disease
A high prevalence of cardiovascular risk factors and vascular comorbidity have been described in OA
Factors strongly associated include hyperlipidaemia and hypertension
A higher risk of cardiovascular death is associated with widespread OA and one large study found that men with OA in any finger joint were 40% more likely to die from cardiovascular disease Kornaat PR, Sharma R, van der Geest RJ et al. Skeletal Radiol 2009; 38(12): 1147-1151 Conaghan PG, Vanharanta H, Dieppe PA. Ann Rheum Dis 2005; 64(11): 1539-1541
New Insights for Preventing and Managing Osteoarthritis
OA, Circulation and Subchondral Bone One recent review suggested there is mounting
evidence that a microvascular pathology plays a key role in the initiation and/or progression of OA
Disruption of microvascular blood flow in subchondral bone may reduce nutrient diffusion to articular cartilage in OA
Ischaemia in subchondral bone due to microthrombi may produce osteocyte death, bone resorption and articular damage in OA
Findlay DM. Vascular pathology and osteoarthritis. Rheumatology 2007; 46(12): 1763-1768
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NSAIDs Are Deadly
In the often-cited NEJM study it was estimated that the number of hospitalisations in the United States for serious gastrointestinal complications from NSAIDs was at least 103,000 patients per year
It was also estimated in the same study that 16,500 NSAID-related deaths occurred every year in the United States. This figure was similar to the number of deaths per year from AIDS
Wolfe M, Lichtenstein D, Singh G. NEJM 1999; 340: 1888
New Insights for Preventing and Managing Osteoarthritis
NSAIDs In Crisis Not surprisingly physicians, breathed a sigh of relief
when the selective COX inhibitors were released on the market. Yes they were expensive, but they were seen as lifesavers
Unfortunately this euphoria was short-lived. In 2004 rofecoxib (Vioxx) was withdrawn from the US market, shortly followed by valdecoxib (Bextra) in 2005
This was because both drugs were linked to unacceptably high risks of heart attacks and strokes. But we now know that this problem is not just confined to selective NSAIDs
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NSAIDs In Crisis One systematic review and meta-analysis included
23 observational studies of the impact of NSAID use on heart attack rates
Apart from rofecoxib (RR 1.33) the other NSAIDs with a significantly increased risk were diclofenac (RR 1.40) and indomethacin (RR 1.30)
There was no protective effect observed from any of the NSAIDs studied
1 McGettigan P, Henry D. JAMA 2006; 296(13): 1633-1644
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NSAIDs In Crisis
Do They Even Work Long-term?
NSAIDs have also taken a hammering concerning their clinical efficacy
A meta-analysis and systematic review of 23 clinical trials including more than 10,000 patients found that NSAIDs as a whole (including selective COX-2 inhibitors) were ineffective for long-term pain relief in osteoarthritis of the knee1
1 Bjordal JM, Ljunggren AE, Klovning A et al. BMJ 2004; 329: 1317-1322
New Insights for Preventing and Managing Osteoarthritis
A placebo-controlled, crossover trial in 30 patients with knee OA found that 8 weeks of Boswellia extract (1000 mg/day, 40% boswellic acids) significantly (p<0.001) reduced the pain index from 2.7 to 0.26 and the swelling index from 1.1 to zero1
Another trial in 66 patients with knee OA found that Boswellia extract (1000 mg/day, 40% boswellic acids) was as effective as valdecoxib (10 mg/day) over 6 months2
1 Kimmatkar N, Thawani V, Hingorani L et al. Phytomedicine 2003; 10(1): 3-7 2 Sontakke S, Thawani V, Pimpalkhute S et al. Indian J Pharmacology 2007; 39(1): 27-29
Boswellia: The Clinical Evidence
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However, while Boswellia had a slower onset of action (about 1 month), its effect persisted after discontinuation of therapy (unlike valdecoxib)
This suggests it could be disease modifying In a 2008 trial, 75 patients with knee OA received
either two doses of a specialised Boswellia extract (100 or 280 mg/day of a AKBA-enriched extract) or a placebo for 90 days1
1 Sengupta K, Alluri KV, Satish AR et al. Arthritis Res Ther 2008; 10: R85
Boswellia: The Clinical Evidence
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Symptom alleviation was faster in the higher dose group (as early as 7 days) and significantly better than placebo and MMP-3 in synovial fluid was significantly and substantially reduced in both Boswellia groups
A 2010 trial compared the specialised extract above at 100 mg/day with 100 mg/day of a similar extract (but with enhanced bioavailability) and a placebo over 90 days in 60 patients with knee OA1
Clinical results were remarkable, the WOMAC pain subscale fell from 45.0 to 13.9 in patients taking the enhanced extract (p<0.0001)
1 Sengupta K, Krishnaraju AV, Vishal AA et al. Int J Med Sci 2010; 7(6): 366-377
Boswellia: The Clinical Evidence
New Insights for Preventing and Managing Osteoarthritis
In a randomised, open, single-dose, two-way crossover study, 12 healthy male volunteers received 786 mg of Boswellia extract either with or without a standard high-fat meal1
Plasma concentrations of boswellic acids were measured up to 60 hours after the oral dosing
Administration in conjunction with a high-fat meal led to a substantial improvement in the bioavailability of the boswellic acids
For example, the maximum concentration for AKBA was 6.0 ng/mL for the fasted conditions versus 28.8 ng/mL with food
This means that Boswellia is best taken with meals, especially those containing some animal or vegetable fat
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Boswellia Complex Each tablet contains: Boswellia serrata (Boswellia) extract 1.9 g equivalent to dry gum oleoresin standardised to contain boswellic acids 180 mg Curcuma longa (Turmeric) extract 2.0 g equivalent to dry rhizome standardised to contain curcuminoids 70.4 mg Apium graveolens (Celery) extract 1.0 g equivalent to dry fruit Zingiber officinale (Ginger) extract 300 mg equivalent to dry rhizome
Dosage: 1 tablet 2 to 4 times per day
New Insights for Preventing and Managing Osteoarthritis
Willow Bark What is It? Many Willow Bark species are used therapeutically
especially Salix alba, S. daphnoides and S. purpurea They all contain derivatives of salicylic acid, mainly
salicin Clinical trials have found that a high potency Willow
Bark extract standardised for salicin has significant analgesic activity, but with fewer side effects than conventional NSAIDs
In fact it acts quite differently to NSAIDs: Willow Bark is NOT a herbal aspirin
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A Large-Scale Study A large-scale study found that Willow Bark when
tested in a clinical setting had a superior safety and efficacy profile compared to NSAIDs
This was presented at a Berlin conference in early 2004 and involved 922 physicians and 4,731 patients in Germany1
1 Werner G, Scheithe K. Congress Phytopharmaka and Phytotherapy. Berlin, February 26-28, 2004
Willow Bark
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A Large-Scale Study Over 6 to 8 weeks, patients with arthritis or back
pain took various doses of Willow Bark extract (an average of around 3 tablets per day) and rated their pain intensity from 1 to 10 (with 10 representing pain of the highest intensity)
Most of the patients had previously been taking NSAIDs, but had generally discontinued these because of either a lack of efficacy or side effects
Willow Bark
New Insights for Preventing and Managing Osteoarthritis
Willow Bark: Clinical Trials A Large-Scale Study During the observation period, only 15.5% needed
supplementary antirheumatic drugs in addition to their Willow Bark
Average pain intensity reduced from 6.4 to 3.7 points in the first 4 weeks of treatment and had fallen further to 2.7 after 8 weeks, with 97% of patients reporting a reduction in pain and 18% reporting no pain at all
Side effects were judged as minor and occurred in only 1.3% of patients. These were mainly abdominal pain or an allergic skin rash
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MediHerb Saligesic
A high potency Willow Bark extract in tablet form phytoequivalent to the extract proven in clinical trials
Each tablet contains 400 mg of extract with 60 mg of salicin, corresponding to 8 g of bark
Dose is 2 to 4 tablets per day
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Nutrition and OA
Low dietary vitamin C intake was associated with increased risk of progression, but not incidence of knee OA
Suboptimal selenium intake has been linked to worse OA and early onset of the disease
A low dietary intake and serum level of vitamin D was associated with progression of knee OA, other results have been controversial
No relationship has been found for dietary vitamins E, B1, B6, niacin and folate Zhang Y, Jordan JM. Clin Geriatr Med 2010; 26(3): 355-369 Cheung PP, Gossec L, Dougados M. Best Pract Res Clin Rheumatol 2010; 24(1): 81-92
New Insights for Preventing and Managing Osteoarthritis
Previous slides propose that microcirculatory and CV factors may predispose to OA
This was supported by a UK study in female twins that found a strong protective effect on radiographic hip OA for “Allium” consumption (Odds Ratio 0.70)
Non-citrus fruit was also protective (OR 0.56)
Williams FM, Skinner J, Spector TD et al. Dietary garlic and hip osteoarthritis: evidence of a protective effect and putative mechanism of action. BMC Musculoskelet Disord 2010; 11: 280
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Herbs for OA Therapeutic Strategy: Goals, Actions and Herbs The herbal approach regards OA not as a focal joint
disease, but a systemic disorder. Emphasis is placed on an alkaline-forming diet
Herbs which make the body more alkaline are a key part of the support of OA, and the main herb in this category is Celery Seed. This is considered to increase the excretion of acidic metabolites in the urine. It probably also has anti-inflammatory activity. Another herb used for OA in this category is Dandelion Leaves
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Herbs for OA
Therapeutic Strategy: Goals, Actions and Herbs Depuratives, which are believed to aid in the
clearance of metabolic waste from the body, are often recommended. These include Burdock and Yellow Dock, but the key herb is Nettle Leaf which has recently been found to also have anti-inflammatory activity in arthritis
Bladderwrack is used for obese patients with arthritis because of its thyroid-stimulating activity, but may also have other effects
New Insights for Preventing and Managing Osteoarthritis
Herbs for OA Therapeutic Strategy: Goals, Actions and Herbs St John’s Wort is used where nerve
entrapment is present. Because of its positive effect on the nervous system, particularly in cases of depression, it can also help to compensate for negative psychosocial factors and improve sleep quality
Anti-inflammatory herbs are often used and these include Boswellia, Ginger and Turmeric. Herbs which may modify cytokines and other inflammatory processes, eg Rehmannia, Bupleurum and Boswellia and those working on NFκB like Feverfew should be considered
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Herbs for OA Therapeutic Strategy: Goals, Actions and Herbs Willow Bark is the key analgesic herb The importance of improving the circulation to
affected joints has long been recognised and traditional support such as Prickly Ash can be supplemented with modern support such as Garlic, Ginkgo and Celery Seed
Herbs to benefit the microcirculation are also relevant, such as Grape Seed and Pine Bark extracts (sources of OPCs), Bilberry, Gotu Kola and Ginkgo
Gotu Kola should be considered as a long-term management to improve viability of chondrocytes
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Herbs for OA
Example Liquid Formula
Celery Seed 1:2 35 mL Nettle Leaf 1:2 35 mL Ginger 1:2 10 mL Turmeric 1:1 30 mL
110 mL
Dosage: 8 mL with water twice per day
New Insights for Preventing and Managing Osteoarthritis
Boswellia Complex tablets (3 to 4 per day) with a possible loading dose
Additional Support (as required)
Saligesic tablets (2 to 4 per day) especially if pain is a substantial feature
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Herbs for OA
Additional Support (as required)
Herbs for circulation, especially Garlic tablets (1 to 2 per day) and Ginkgo Forte tablets (2 to 3 per day) or PhytoRegenex tablets (2 to 3 per day) if there are general symptoms of circulatory deficiency
St John’s Wort tablets (3 to 4 per day) if nerve entrapment is present
Gotu Kola 1:1 liquid (4 mL 1 to 2 times per day) for repair and healing or Tissue Regenex tablets (3 to 4 per day)
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Case History A Case of Small Joint OA
This disorder can be very difficult to treat and is quite stubborn, presumably because of its hereditary aspect
The following 58-year-old female patient had quite advanced disease with large deformities on all of her fingers, marked stiffness and moderate pain
New Insights for Preventing and Managing Osteoarthritis
The patient was initially prescribed the following liquid:
Ginger 1:2 15 mL Celery Seed 1:2 50 mL Nettle Leaf 1:2 35 mL
100 mL
Dosage: 8 mL with water twice per day Boswellia Complex tablets at 2 per day were also included
Case History
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Progress was initially steady but not dramatic
In the following 6 months 2 Saligesic tablets per day were added and the patient reported a big improvement in her pain and stiffness, despite being more active than usual
