Arthritis - Osteoarthritis

Arthritis - Osteoarthritis

1 Overview

Summary and Quick Facts

  • Along with cardiovascular disease, osteoarthritis causes more disability than any medical condition among the elderly.
  • Upon reading this protocol, you will learn about the critical medical factors of osteoarthritis and about some underappreciated, yet potentially dangerous side effects of drugs often used to treat osteoarthritis pain. Additionally, you will discover several natural treatment strategies that have been shown to help support joint structure and function to provide more than just pain relief.
  • Treatments generally begin with the least invasive options. Natural compounds like undenatured type-II collagen and methylsulfonylmethane (MSM) modulate fundamental aspects of osteoarthritis pathology, while others such as krill oil and Boswellia serrata target inflammatory pathways that can contribute to pain, swelling and joint degradation.

What is Osteoarthritis?

Osteoarthritis is a degenerative joint disease that typically affects weight-bearing joints and hands. This disease is caused by the loss of protective cartilage in joints. There is no cure for osteoarthritis, and treatments generally aim to reduce load (losing weight to remove stress from joints), improve joint support, and relieve pain.

Pain relief often comes from non-steroidal anti-inflammatory drugs (NSAIDs); however, some people are not aware that excessive use of NSAIDs can cause liver and kidney damage. NSAIDs also cannot help with rebuilding damaged joint cartilage and are purely palliative.

Natural interventions such as undenatured type-II collagen and methylsulfonylmethane (MSM) may help manage osteoarthritis causes and symptoms.

What are the Risk Factors for Osteoarthritis?

  • Advanced age
  • Female gender
  • Obesity
  • Intense joint wear-and-tear (high-impact sports, physical labor)
  • Joint trauma
  • Family history

What are the Signs and Symptoms of Osteoarthritis?

  • Joint pain

What are the Conventional Medical Treatments for Osteoarthritis?

Note: Treatments generally begin with the least invasive options. If the disease does not respond, then more aggressive approaches can be considered.

  • Physical therapy/exercise
  • Acetaminophen or NSAIDs
  • Corticosteroid and hyaluronic acid injections
  • Opioids
  • Joint-replacement surgery

What are Emerging Therapies for Osteoarthritis?

  • Tanezumab is an antibody against nerve growth factor (which plays a significant role in pain transmission) that can reduce pain intensity
  • Stem cell treatment
  • Hormone replacement therapy for postmenopausal women
  • Apitherapy (treatment with bee venom, alone or in combination with acupuncture)

What Dietary and Lifestyle Changes Can Help Osteoarthritis?

  • Exercise, at least 30 minutes of walking 3 days per week

What Natural Interventions May Help Osteoarthritis?

  • Glucosamine. Glucosamine is a component of glycosaminoglycans and proteoglycans, which help provide cartilage the flexibility it needs to function. Glucosamine has been shown to reduce the severity of osteoarthritis symptoms.
  • Chondroitin. This complex sugar molecule is found in connective tissue and contributes lubrication to cartilage. Chondroitin has been shown to reduce pain and increase joint function in patients with osteoarthritis.
  • Hyaluronic acid. Hyaluronic acid is a building block for cartilage. When administered orally or intra-articularly, hyaluronic acid has demonstrated pain relief and increased functionality in patients with osteoarthritis.
  • Sulfur compounds such as methylsulfonylmethane (MSM) and keratin. These compounds can reduce pain and inhibit the degenerative quality of osteoarthritis. Both MSM and keratin treatments have been shown to relieve pain and improve joint functionality.
  • S-adenosylmethionine (SAMe). SAMe may stimulate the production of cartilage, leading to reduced pain and stiffness in patients with osteoarthritis.
  • Proteolytic enzymes. Various proteolytic enzymes, including bromelain, have been shown to reduce pain and increase functionality in osteoarthritis. A supplement containing bromelain was more effective than the NSAID diclofenac in a clinical trial.
  • Undenatured type-II collagen. The gradual destruction of joint cartilage exposes collagen, causing an immune response and inflammatory attack on the joint. Treatment with undenatured collagen may help reduce this inflammation and induce tolerance, leading to enhanced daily activities in patients with osteoarthritis.
  • Other anti-inflammatory options are soy and avocado oil, omega-3 fatty acids, curcumin, ginger, Korean angelica, vitamin D, and green tea, among others.

2 Introduction

Osteoarthritis is a very common degenerative joint disease and a leading cause of disability. Affecting over 20 million in the U.S. alone, this progressive disease is characterized by structural damage and functional impairment within joints (CDC 2012; NIH MedlinePlus 2012; Mayo Clinic 2012; Seed 2011; Lawrence 2008; Lane 2011).

Many interrelated factors – such as obesity and oxidative stress – work together in osteoarthritis to cause progressive, degenerative changes in weight-bearing joints including the knees, neck, lumbar spine, and hips, as well as the hands. A multifactorial approach is best when targeting osteoarthritis management (Ziskoven 2011; Busija 2010).

Conventional medical treatment focuses upon reducing load (e.g. weight loss) and improving joint support (i.e. enhancing muscle strength), as well as treating the pain and stiffness of osteoarthritis with acetaminophen and other NSAID drugs.

However, these drugs expose arthritis sufferers to the risks of liver and kidney damage (Woodcock 2009). In addition, these drugs often offer only incomplete/ partial relief (Vista 2011; Bijlsma 2011), and treatment with acetaminophen and NSAIDs fails to help the body rebuild damaged joint cartilage (Kapoor 2011).

On the other hand, natural compounds like undenatured type-II collagen and methylsulfonylmethane (MSM) modulate fundamental aspects of osteoarthritis pathology, while others such as krill oil and Boswellia serrata target novel inflammatory pathways that can contribute to pain, swelling and joint degradation (Min 2006; Wang 2004; Palmieri 2010; Gregory 2008; Deutsch 2007; Sengupta 2010; Sengupta 2011).

Upon reading this protocol, you will learn about the critical medical factors of osteoarthritis, as well as learn about some underappreciated, yet potentially dangerous side effects of drugs often used to treat osteoarthritis pain. Additionally, you will discover several natural treatment strategies that have been shown to help support joint structure and function to provide more than just pain relief.

3 Understanding Osteoarthritis

Normal Joint Anatomy and Function

The bones of the human skeletal system are connected by a complex series of joints, which connect two or more bones and allow for a wide variety of movements that would otherwise be impossible (Briant 2008).

In order to facilitate smooth joint movement, the surfaces of joints are lined by a low-friction, load-distributing, wear-resistant tissue called articular cartilage, which is composed of 65 to 80 percent water, collagen (fibrous proteins), proteoglycans, and chondrocytes (cells that produce cartilage) (Pearle 2005). In adults, damaged cartilage has a very limited capacity for self-healing due to blood supply limitations, and the relatively poor capacity of resident chondrocytes to migrate and proliferate (Henrotin 2009).

Joints can be classified as synovial, fibrous, or combination joints, based on the presence or absence of a synovial membrane and the amount of motion that occurs in the joint.

Normal synovial joints allow a significant amount of motion the articular surface. These joints are composed of the following:

  • Articular cartilage
  • Subchondral bone
  • Synovial membrane
  • Synovial fluid
  • Joint capsule

Normal articular surface of synovial joints consists of articular cartilage surrounded by proteoglycans and collagen. The cartilage protects the underlying subchondral bone by distributing large loads, maintaining low contact stresses, and reducing friction.

Synovial fluid supplies nutrients to the articular cartilage; it also absorbs shock from slow movements, as well as the elasticity required to absorb shock from rapid movements.

Osteoarthritis Onset and Progression

Osteoarthritis (OA) can occur in any freely moving joint in the body, but it most commonly affects load- and stress-bearing joints like the knees, lumbar spine, and hips (Lawrence 2008).

At the onset of OA, where cartilage cells depart from their normal pattern of growth and differentiation, the outermost layer of articular cartilage begins to soften as its protein structure degrades. As OA progresses, this loss of protein content becomes more rapid, affecting deeper and deeper layers of cartilage (Pearle 2005). Eventually, the entire protective layer of cartilage is destroyed as the chondrocytes become completely overwhelmed and unable to reverse the tissue damage.

Because cartilage does not contain free nerve endings, joint destruction is typically not associated with pain until it is considerably advanced. This is a major reason why OA tends to be diagnosed so late in the disease process (Bijlsma 2011; Felson 2005).

With a majority of the protective cartilage now gone, the raw surfaces of the bones become exposed to gradual bone-on-bone erosion. This process inevitably leads to the destruction/deformation of nearly all the joint structures involved in movement, and is often accompanied by chronic inflammation in and around the joint space (i.e., synovial membrane) (Pearle 2005).

In many cases, the bone destruction caused by OA is followed by “remodeling”, which is characterized by bone spurs that grow along the joint margins. Although these bony outgrowths are believed to stabilize the injured joint by increasing bone surface area, they are also a significant source of pain, as joint movement causes them to rub against adjacent bones, nerves, and/or soft tissue (Mayo Clinic 2009; Pearle 2005). The intensity of symptoms can vary significantly, ranging from mild to severe (Strand 2011).

The pain caused by OA is typically worsened upon physical activity. As the disease progresses, however, patients may begin to report pain even when resting. Complaints of stiffness tend to occur more frequently in the morning, and often resolve shortly after awakening. However, any period of prolonged inactivity can cause this stiffness, which is sometimes referred to as “inactivity gelling” (Kalunian 2012b).

In cases of advanced OA, patients often report both physical and psychosocial disability. In fact, along with cardiovascular disease, OA causes more disability than any medical condition among the elderly (Hunter 2009).

4 Osteoarthritis Causes and Risk Factors

Osteoarthritis (OA) arises as a result of a complex interplay of factors such as aging, mechanical forces, joint integrity, local inflammation, genetics, and congenital abnormalities (Kalunian 2012a; Bijlsma 2011).

Risk factors for osteoarthritis include (Seed 2011; Busija 2010):

  • Advanced age
  • Female gender
  • Obesity (see below)
  • History of physical labor
  • High-impact sports
  • Joint trauma
  • Family history

Obesity and Osteoarthritis

Because obesity increases the load and stress on many joints, it appears to be one of the most influential risk factors contributing to the development or advancement of osteoarthritis (OA) (Busija 2010). However, studies of obese patients have identified a high prevalence of OA in non-weight bearing areas (e.g., finger joints) as well (Rai 2011).

Data reveal that fat tissue is a major source of catabolic and pro-inflammatory mediators (i.e., cytokines, chemokines, and adipokines), which are implicated in the process of OA (Rai 2011). In addition, obese patients tend to experience insulin resistance and increased glucose load, which may also contribute to the chronic inflammation and cartilage degradation of OA (Sowers 2010).

Since OA has been linked not only to obesity, but also to other cardiovascular risk factors (e.g., diabetes, dyslipidemia, hypertension, and insulin resistance), researchers have proposed that it might be related to a much larger group of risk factors, called “metabolic syndrome” (Velasquez 2010; Katz 2010).

Recent studies have shown that physical activity and diet programs (alone or in combination) are associated with a reduction in pain, as well as functional improvement among overweight or obese adults with OA (Brosseau 2011). In cases where patients are too obese to engage in physical activity, bariatric surgery has also been correlated with improvements in pain and function among patients with OA of the hip and knee (Gill 2011).

Metabolic Factors Associated with Osteoarthritis

Several interrelated metabolic factors also contribute to osteoarthritis onset and progression; chief among which are inflammation, mitochondrial dysfunction, and oxidative stress.

  • Inflammation – Osteoarthritis (OA), like many other age-related diseases, is tied to excessive inflammation (Goldring 2011).

    Over-indulgence in foods rich in pro-inflammatory omega-6 fatty acids and insufficient intake of foods rich in anti-inflammatory omega-3 fatty acids characterizes the dietary pattern of most modern, industrialized nations.

    Arachidonic acid (an omega-6 fatty acid) is the raw material used by the body to synthesize numerous inflammatory mediators, including leukotriene B4, prostaglandin E2, and thromboxane A2, all of which contribute to pain, swelling, and joint destruction (see figure 1) (Liagre 2002; Devillier 2001; Kawakami 2001).

  • Mitochondrial dysfunction – Mitochondria are the power cores of our cells; they generate the energy that cells need to function. With age, mitochondrial function deteriorates, leading to a variety of negative consequences (Vaamonde-Garcia 2012; Cillero-Pastor 2008; Blanco 2004).

    In the case of OA, dysfunctional mitochondria conspire with inflammation to augment joint destruction. One study found that the inflammatory propensity of chondrocytes was amplified when their mitochondria were dysfunctional. Specifically, mitochondrial dysfunction in chondrocytes is associated with increased reactive oxygen species production and activation of the “master-regulator” of inflammation, nuclear factor-kappa B (Nf-kB) (Vaamonde-Garcia 2012).

    Fortunately, adhering to a plant-based diet rich in dietary antioxidants, reduced in saturated fat, and balanced in omega-6 and omega-3 fats, such as the Mediterranean diet (see Nutritional Interventions section below) may be an effective means of targeting several of the metabolic imbalances that affect OA.

  • Oxidative stress - Oxidative stress, which is caused by free radicals, is known to be a factor in cartilage destruction and inflammation. These reactive molecules are also involved in pain perception (Ziskoven 2010).

Hormones and Osteoarthritis

After the age of 50, more women are affected by osteoarthritis (OA) than men (Bijlsma 2011); this female preponderance suggests that hormone abnormalities may influence the progression and development of the disease (Tanamas 2011).

The link between hormones and OA is further supported by evidence linking hormone (e.g., estrogen) deficiencies to an increased risk of osteoarthritis (Parazzini 2003).

In addition, some evidence suggests that hormone replacement therapy can relieve symptoms of OA, especially among postmenopausal women (Song 2004). As a result, Life Extension encourages OA patients to test for hormone deficiencies and correct them when identified.

Further reading is available in the Female Hormone Restoration protocol.

(Aldamiz-Echevarria 2007; Wixted 2010; Simopoulos 2011; Schror 2011; Bengmark 2006; Murias 2004; Oz 2008; Keicher 1995; Prasad 2004; Safayhi 1992)

5 Diagnosis

Osteoarthritis (OA) is diagnosed based upon medical history and clinical examination (Busija 2010).

Radiographic imaging can aid in the diagnosis of OA. It involves the identification of a variety of anatomic abnormalities such as joint space narrowing, bone spurs, and joint bone deformity (Murphy 2012). However, since many patients with joint abnormalities do not develop symptoms, a diagnosis of OA cannot be made solely upon the basis of positive radiographic images. Likewise, patients with symptoms of OA may not display radiographic evidence (Bijlsma 2011).

A newer method of imaging called delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) provides information about cartilage quality and may offer an improved means of diagnosing OA in the early stages (Siversson 2012). This method involves the intravenous injection of a negatively charged contrast agent, which then diffuses into articular cartilage over at least two hours. An increased concentration of contrast agent (in positively charged areas on the MRI scan) would be indicative of articular cartilage damage in that specific region (Taylor 2009).

6 Conventional Treatment Options

Since there is no cure for ostheoarthritis (OA), most available treatments are aimed at controlling pain and maintaining joint function (Kapoor 2011). If OA pain is unable to be controlled with less invasive measures like physical therapy and exercise, treatment options ranging anywhere from intermittent use of analgesics to total joint replacement surgery are available (Strand 2011).

Physical Therapy/ Exercise

In most cases, ostheoarthritis (OA) treatment should begin with the safest and least invasive therapies (e.g., exercise) (Sinusas 2012). This is because physical activity is associated with significant health benefits among OA patients (e.g., preventing obesity, conserving physical function, and contributing to normal joint health) (Egan 2010).

Exercise programs consisting of muscle strengthening and range-of-motion movements are associated with significant improvements in OA symptoms (Sinusas 2012). Similarly, aerobic activity can reduce pain and disability in people with OA of the knee (Jansen 2011).

In patients who are either unable or unwilling to participate in vigorous exercise, walking for approximately 30 minutes per day, at least 3 days per week, can contribute to a reduction of OA symptoms (Ng 2010).

Pharmacologic Treatment and Other Therapies

Acetaminophen. Acetaminophen is usually the first-line pharmacologic therapy in conventional medicine for ostheoarthritis (OA) (Lim 2011; Woodcock 2009). If acetaminophen is unsuccessful, the next pharmacological treatment level varies depending upon patient-specific factors (e.g., treatment success), but usually involves the use of one or more of the following options (Lim 2011; Scheiman 2010; Howes 2011):

  • Topical non-steroidal anti-inflammatory drugs (NSAIDs)
  • Topical capsaicin
  • Oral NSAIDs
  • Intra-articular corticosteroid and hyaluronic acid injections
  • Opioids

The Potentially Lethal Side Effects of Over-the-Counter Pain Medications

In an effort to relieve suffering, many ostheoarthritis (OA) patients turn to non-prescription over-the-counter (OTC) analgesics such as acetaminophen, aspirin, and other non-steroidal anti-inflammatory drugs (NSAIDs) (Hersh 2007). However, since these drugs do not require a prescription, patients may incorrectly assume that they do not need to be as careful about safety as they would with a prescription analgesic. Therefore, it is important for patients to become educated about serious adverse side effects that can occur with popular non-prescription OTC analgesics (Wilcox 2005).

Acetaminophen is one of the most widely used analgesics in the United States. In 2008, approximately 25 billion doses of acetaminophen were sold in the US alone (FDA 2009). Unintentional acetaminophen overdose is responsible for approximately 15,000 hospitalizations each year, and is the leading cause of acute liver failure in the US (Woodcock 2009).

Patents taking acetaminophen should follow these recommendations (Saccomano 2008):

  • Do not to exceed a maximum dose of 4 grams/day
  • Remember that many prescription pain medications also contain acetaminophen
  • Recognize that acetaminophen is also called APAP, paracetamol, and acetyl-para-aminophenol
  • Do not use with other NSAIDs (without medical consultation), which increase the risk of kidney toxicity
  • Do not take with alcohol, which significantly increases the risk of liver toxicity
  • For those taking acetaminophen for pain relief, aggressive supplementation with hepato-protective nutrients such as N-acetyl-cysteine (NAC) and milk thistle extract may provide a means of reducing drug-induced liver damage (Abenavoli 2010; Bajt 2004).

NSAIDs such as ibuprofen and naproxen are also associated with significant adverse effects such as gastrointestinal bleeding, peptic ulcer disease, high blood pressure, edema (i.e., swelling), kidney disease, and heart attack (Peterson 2010). For example, long-term use of NSAIDs can lead to impaired glomerular filtration, renal tubular necrosis, and eventual chronic renal failure by disrupting prostaglandin synthesis, which can impair renal perfusion (Weir 2002). Even in NSAID users without overt kidney dysfunction, subclinical irregularities in kidney function are often observed (Ejaz 2004).

Aspirin (a type of NSAID) is commonly used to treat minor aches and pains, as well as being recommended at low doses for heart protection and stroke prevention. Aspirin irreversibly inhibits an enzyme called cyclooxygenase-1 (COX-1) in platelets, which is why it poses a greater risk of bleeding (i.e., hemorrhage) than other NSAIDs (Hersh 2007). Therefore, patients taking aspirin should avoid the simultaneous use of anticoagulant drugs and/or alcohol (without talking to their doctor first). Aspirin can also cause mild side effects such as heartburn, nausea, vomiting, stomach ache, ringing in the ears, hearing loss, and rash (NIH 2011).

7 Novel and Emerging Therapies

Tanezumab

Tanezumab is an antibody that targets nerve growth factor (NGF), which plays a significant role in pain transmission (Cattaneo 2010). Among patients with osteoarthritis (OA) of the knee, tanezumab was associated with a significant reduction in pain intensity (Felson 2011). However, in June 2010, the FDA put all trials of tanezumab on hold because a significant number of patients taking this drug experienced an unusually rapid progression of joint bone necrosis (Lane 2010). Some researchers claim this bone necrosis occurred because of overuse of the joint (due to the potent analgesic effect of tanezumab). However, the FDA is waiting for more information on the exact cause of this adverse effect before allowing trials to continue (Wood 2010; Lane2010).

Stem Cells

Stem cells are renewable, unspecialized precursor cells that can transform into specialized cell types (Vrtovec 2013; Singh 2016). Embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells have all been investigated for their regenerative potential in osteoarthritis. Of these, mesenchymal stem cell therapy is considered the most promising. Mesenchymal stem cells can be isolated from adipose tissue, bone marrow, umbilical cord, and other sites (Burke 2016; Freitag 2016; Filardo 2013; Richardson 2016).

Mesenchymal stem cells derived from bone marrow can be delivered as a simple concentrate that can be prepared on-site. Such preparations include mesenchymal stem cells in addition to several other types of cells from bone marrow. Therefore, it can be difficult to pinpoint exactly which types of cells are responsible for the effects of the procedure. This technique has the added value of convenience, as it can be performed during a single office visit. In another approach, stem cells are isolated from bone marrow and cultured to generate specific cell types. Both types of stem cell preparations can be delivered by injection or during surgery (Filardo 2016; Burke 2016).

Adipose-derived mesenchymal stem cells are readily available, as they can be obtained by less invasive measures than bone marrow, including liposuction. Adipose tissue also contains connective tissue abundant in stromal vascular fraction, a rich source of stem cells. Adipose-derived stem cells are generally less efficient than bone marrow-derived stem cells in stimulating cartilage synthesis, but adipose taken from near the knee appear to be suitably efficacious in this regard and warrant further study (Filardo 2016; Burke 2016; Koga 2008; Jang 2015). Multiple trials using adipose-derived mesenchymal stem cells have reported positive clinical results in osteoarthritis, including decreased pain and improved function. Improved cartilage status as verified by arthroscopy and MRI has also been observed, implying the treatment resulted in cartilage regeneration (Koh 2015; Michalek 2015; Burke 2016; Pak 2016).

Individual patient characteristics appear to influence the outcomes of mesenchymal stem cell therapy in osteoarthritis, as better clinical results have been observed in younger individuals, and those with lower BMI, smaller areas of cartilage degradation, and earlier stage of osteoarthritis progression. Studies have not reported any major adverse events associated with mesenchymal stem cell harvest or therapy, and most studies report some clinical benefit (Filardo 2013; Filardo 2016). Nevertheless, the effectiveness of stem cell therapy for osteoarthritis has not been conclusively established.

Apitherapy

Apitherapy, the use of bee venom for medicinal purposes, including relieving joint pain, can be dated back to at least the 5th century BC (Alqutub 2011). More recently, there have been numerous anecdotal reports of bee stings dramatically improving symptoms of OA (Mayo Clinic 2009b). Bee venom, when combined with acupuncture for the treatment of OA of the knee, was associated with a substantial analgesic effect compared to traditional (needle-only) acupuncture (Kwon 2001). Researchers believe that the anti-inflammatory characteristics of bee venom can be attributed to mellitinin, a component of bee venom that is one hundred times stronger than the inflammation-reducing hormone cortisone (Alqutub 2011).

8 Nutritional Interventions

Targeted nutritional interventions contain a variety of biologically active compounds known to positively influence cartilage degradation in osteoarthritis (OA). Unlike medications, nutritional interventions don’t typically cause side effects, which may explain why nearly one out of every five OA patients uses alternative methods (Ameye 2006).

Joint Structure Support

Glucosamine – Glucosamine is a component of larger compounds called glycosaminoglycans and proteoglycans, which help trap water in the matrix of cartilage, providing it with the flexibility and resilience it needs to function properly (Sanders 2011). In laboratory models, glucosamine has been shown to possess both anti-inflammatory and disease modifying effects in OA (Aghazadeh-Habashi 2011). In addition, researchers believe that glucosamine may repair cartilage by stimulating synthesis of chondrocytes (Fouladbakhsh 2012). Glucosamine also plays a crucial role in maintaining joint lubrication (Sanders 2011).

Commercial glucosamine preparations consist of either glucosamine hydrochloride or glucosamine sulfate (Miller 2011a). When compared to placebo, high-quality clinical data indicate that glucosamine sulfate is superior for relieving the severity of OA symptoms (Herrero-Beaumont 2007).

Although there remains some controversy in the conventional medical community over the effectiveness of glucosamine for osteoarthritis, most published studies show that glucosamine sulfate is effective and studies that have found otherwise have been limited by methodological flaws and dosing/ formulation inconsistencies (Bijlsma 2011; Aghazadeh-Habashi 2011). Since glucosamine offers promise as structural support in osteoarthritis, additional research is planned (Seed 2011).

Because cartilage takes time to synthesize, and glucosamine is only one of its structural components, experts recommend up to 8 weeks of initial therapy before making an assessment concerning efficacy (Sanders 2011).

Chondroitin – Chondroitin sulfate is a complex sugar molecule found in connective tissue such as bone, cartilage, tendons, ligaments, and skin (Martel-Pelletier 2015). Complexes of chondroitin sulfate in cartilage create a gel-like material and contribute to water retention, lubrication, and resiliency. One study found that cartilage samples from arthritic joints had lower concentrations of chondroitin sulfate than samples from healthy joints (Ishimaru 2014). In laboratory studies, chondroitin sulfate reduced inflammation and promoted a healthy balance between breakdown and new formation of bone and cartilage (Martel-Pelletier 2015; Henrotin 2014). Laboratory studies of cartilage-producing cells suggest chondroitin and glucosamine sulfates may work synergistically to protect cartilage (Calamia 2014).

Randomized controlled clinical trials show 800 mg to 1200 mg per day of chondroitin sulfate can prevent progression of cartilage loss and reduce pain in patients with OA of the knee (Kahan 2009; Wildi 2011; Zegels 2013). Chondroitin sulfate also decreased pain and improved function in patients with OA of the hand (Gabay 2011). A meta-analysis of clinical studies determined chondroitin sulfate is effective for improving measures of pain and functioning with little risk of adverse side effects in patients with OA (Singh 2015). It is worthwhile to note that findings from a meta-analyses show two or more years of daily use may be needed before a beneficial effect on cartilage protection is seen (Lee 2010). Clinical research has demonstrated that treatment of osteoarthritic joints with the combination of glucosamine and chondroitin sulfates can relieve pain, improve function, and enhance joint structure (Hochberg 2016; Raynauld 2016).

Chondroitin sulfate appears to relieve pain more effectively and has a better safety profile than NSAIDs (Henrotin 2014; Hochberg 2013). A randomized controlled trial compared 1200 mg per day of chondroitin sulfate to 200 mg per day of celecoxib (Celebrex) in 138 patients with OA of the knee. After two years of treatment, the two treatment groups experienced similar reductions in swelling and symptoms such as knee pain and stiffness; however, MRI measurements showed that those taking chondroitin sulfate had significantly less cartilage volume loss (Pelletier 2016). In a randomized clinical trial with 605 participants with OA of the knee, a group receiving a combination of 800 mg of chondroitin sulfate plus 1500 mg of glucosamine sulfate daily had less joint space narrowing after two years than groups receiving placebo or either supplement alone (Fransen 2015).

Hyaluronic acid - Hyaluronic acid (HA) is secreted by chondrocytes and used as a basic building block for cartilage synthesis. Researchers believe that HA is useful in the management of OA because it interferes with pain mediators and decreases the production of key enzymes (i.e., metalloproteinases) responsible for digesting and destroying healthy cartilage tissue (Palmieri 2010). Hyaluronic acid intra-articular injections are used to treat OA of the knee. It has been linked to improvements in pain and functional status among OA patients (Iannitti 2011), especially when combined with other treatment strategies (Palmieri 2010).

Hyaluronic acid is typically administered intra-articularly; however, HA is absorbed orally much more efficiently when formulated with a phospholipid (Huang 2007).

Findings from an experimental trial show that orally administered hyaluronic acid improved the prognosis of horses that underwent joint surgery. In a blinded, placebo-controlled experiment involving 48 thoroughbreds, 30 days of post-operative use of oral hyaluronic acid significantly improved outcomes (McIlwraith 1991; Bergin 2006).

In a randomized, placebo-controlled, double-blind study of 20 human patients with OA of the knee, subjects received 80 mg of a specially formulated, orally ingested hyaluronic acid supplement called Hyal-Joint™ or a placebo daily for eight weeks. The treatment group had a greater magnitude of improvement in bodily pain and social functioning (Kalman 2008).

Sulfur Compounds – Sulfur containing compounds, such as Methylsulfonylmethane (MSM), are commonly found in fruits, vegetables, grains, as well as the human body (AMR 2003). Experts believe that these compounds may reduce peripheral pain and inhibit the degenerative changes of OA by stabilizing cell membranes and scavenging free radicals that can lead to inflammation. In clinical trials, MSM was able to reduce both pain and swelling among OA patients. It is well tolerated and not associated with any significant side effects (Gregory 2008). Another study found that patients with OA of the knee taking MSM for 12 weeks demonstrated an improvement in pain and physical function (Debbi 2011).

Keratin is another sulfur-rich compound (Hill 2010) that supports joint health by supplying building blocks for joint repair, stimulating antioxidant enzymes, and acting as an antioxidant itself (Quaglini 2010; Aitken 2010). In a clinical evaluation, supplementation with solubilized keratin relieved OA pain more than placebo (Aitken 2010).

S-Adenosylmethionine - S-Adenosylmethionine (SAMe) is naturally occurring within the body and has been reported to possess both anti-inflammatory and analgesic effects. Clinical trials have shown that SAMe can reduce pain, stiffness, and increase functioning among patients with OA (Hardy 2003; Kim 2009). Moreover, SAMe has been found to be as effective - yet safer – than NSAIDs in the treatment of OA in some populations (Soeken 2002). SAMe may achieve this by stimulating the production of cartilage through one of these potential mechanisms: modulating cellular growth/survival signals within joints, reducing inflammatory mediators, and/or increasing the production of antioxidants like glutathione (Hosea 2008). SAMe is not found in food (Rutjes 2009).

Anti-inflammatory Nutrients

Omega-3 Fatty Acids – Omega-3 fatty acid supplementation is generally recommended for individuals consuming a typical Western diet (high in pro-inflammatory omega-6 fatty acids) (Simopoulos 2006; Knott 2011). Increased levels of omega-6 fatty acids have been linked to the destruction of bone and cartilage among OA patients; supplementation with omega-3 fatty acids can combat this effect (see figure 1) (Knott 2011). Omega-3 fatty acids have also been shown to reduce the amounts of certain proteins that are important in the pathology of OA (Zainal 2009). In the clinical setting, the combination of omega-3 fatty acids with glucosamine was more effective at reducing morning stiffness and pain than glucosamine alone (Gruenwald 2009).

Krill - Krill are cold water, shrimp-like crustaceans that are rich in omega-3 fatty acids (AMR 2010). In OA patients or those with related inflammatory conditions, supplementation with 300 mg of krill oil daily for seven days reduced C-reactive protein (CRP) – a marker of inflammation – by more than 15% compared to placebo. By day 30, the reduction doubled to more than 30%. Additionally, seven days of krill oil treatment reduced pain nearly 30%, stiffness more than 20%, and functional impairment almost 23% (Deutsch 2007).

Undenatured Type-II Collagen – Undenatured Type-II Collagen (UC-II) has received considerable attention as a therapeutic agent in OA (Crowley 2009). Recent discoveries have revealed that gradual destruction of joints in OA leads to the exposure of joint collagen, which triggers an immune response that launches an autoimmune-like inflammatory attack on the joint (Heinegard 2011). UC-II functions as a “switch” to turn off this immune response. It does so by inducing what immunologists call specific oral tolerance—the desensitization of immune response to specific agents via an orally administered intervention (Gupta 2009). Among OA patients, UC-II has been shown to significantly enhance daily activities and is not generally associated with any side effects (Crowley 2009).

Soy and Avocado Oil – Avocado and soy unsaponifiable (ASU) mixtures may stimulate collagen synthesis and promote cartilage repair, as well as reduce circulating levels of pro-inflammatory cytokines, which are implicated in the pathology of OA (Kucharz 2003; Priotta 2010). A review of four clinical studies involving ASU treatments among OA patients found evidence for its use in reducing pain and improving function (Christensen 2008). Among OA patients, ASU also significantly reduces the need to take NSAIDs (Long 2001). ASU mixtures have been recommended by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) for the symptomatic treatment of OA (Henrotin 2008).

Curcumin – Curcumin is a natural plant phenolic compound that has been shown to possess potent anti-inflammatory and antioxidant properties (Singh 2007). Research suggests that curcumin may represent a viable alternative to NSAIDs, and that it may complement the activity of some OA drugs (Henrotin 2010; Lev-Ari 2006). Curcumin’s effectiveness in OA may be due to its ability to attenuate nuclear factor kappa B (Nf-kB) signaling, reduce the production of inflammatory mediators (Mathy-Hartert 2009; Henrotin 2010), and interfere with cartilage destruction (Mathy-Hartert 2009). Curcumin has been recommended for the long-term complementary management of OA (Belcaro 2010a; Belcaro 2010b).

GingerZingiber officinale (i.e., ginger) is related to curcumin. It has traditionally been used for a wide variety of medicinal purposes due to its antioxidant, antimicrobial, and anti-inflammatory properties (Butt 2011). Evidence suggests that ginger supplementation may reduce the subjective experience of pain, especially with respect to OA (Terry 2011). Clinical research has demonstrated that oral ginger extract can improve OA symptoms, and may be as effective as ibuprofen (Haghighi 2005). Interestingly, when applied topically in the form of a warm compress, ginger promotes relaxation and analgesia (Therkleson 2010).

Boswellia - Boswellia serrata is a tree commonly found in the hilly areas of India (Clayton 2007). In the last two decades, the use of gum resins extracted from this tree has become popular among Western cultures (Abdel-Tawab 2011). This is because it is reported to possess beneficial anti-inflammatory, anti-arthritic, and analgesic properties (Clayton 2007). Specifically, compounds in boswellia such as 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) are inhibitors of the inflammatory enzyme 5-lipoxygenase (5-LOX) (Siddiqui 2011).

One of the first high-quality clinical studies involving the use of Boswellia serrata extract for the treatment of OA of the knee found that it was associated with a reduction in pain and swelling, as well as an improvement in function and range of movement. In addition, Boswellia serrata extract was well tolerated, and thus recommended for patients with OA of the knee (Kimmatkar 2003). Boswellia serrata extract has not only been shown to be clinically efficacious for reducing the symptoms of OA (e.g., pain and function), but also appears to be able to fortify cartilage against damage and promote its repair (Sengupta 2010; Sengupta 2011).

Korean Angelica - Decursinol is a medicinal compound found in the roots of the Korean flower Angelica gigas Nakai (Korean angelica) (Song 2011). It has been widely utilized in traditional Asian medicine as a treatment for pain associated with various conditions (e.g., arthritis) (Kim 2009). Laboratory evidence shows that an active constituent derived from Korean Angelica inhibits activation of nuclear factor-kappa B (Nf-kB) (Kim 2006). Decursinol may also act within the central nervous system to relieve pain (Choi 2003). One study found that co-administration of decursinol and acetaminophen resulted in synergistic pain-relieving effects. The authors of this study attributed the analgesic effect of decursinol to its ability to reduce the activity of the pro-inflammatory enzyme cyclooxygenase (Seo 2009).

Proteolytic enzymes – Numerous clinical studies have evaluated the efficacy of various preparations of proteolytic enzymes for conditions ranging from rheumatoid arthritis and muscular pain, to kidney disease and chronic airway disorders (Nakamura 2003; Ritz 2009). In one trial among 80 patients with OA of the knee, proteolytic enzymes were found to be as effective as the NSAID diclofenac for relieving pain and improving function (Singer 1996). Some early trials indicate that the proteolytic enzyme bromelain may be effective for relieving OA pain (Brien 2004).

One study reported that a supplement containing bromelain (90 mg, three times daily) was as effective as diclofenac (50 mg, twice daily) in improving the symptoms of osteoarthritis of the knee. Patients reported comparable reductions in joint tenderness, pain and swelling, and improvement in range of motion at the end of the study. The investigators found bromelain to be as good as diclofenac on a standard pain assessment scale and to be better than the drug in reducing pain at rest (by 41% for bromelain versus 23% for the drug), improving restricted function (by 10% for bromelain versus 0% for the drug), being rated by more patients in improving symptoms (24% for bromelain versus 19% for the drug), and being evaluated by more physicians as having good efficacy (51% for bromelain versus 37% for the drug). In summary, the investigators determined bromelain to be an effective and safe alternative to NSAIDs such as diclofenac for painful osteoarthritis (Akhtar 2004).

Experts generally advise consuming enteric-coated bromelain supplements to benefit from its anti-inflammatory effects.

Vitamin D - Vitamin D is a prohormone version of an important hormone called 1,25-dihydroxycholecalciferol or 1,25-dihydroxy vitamin D, also known as calcitriol (Dusso 2005). Vitamin D, once converted into calcitriol, inhibits inflammation by regulating some of the genes responsible for producing pro-inflammatory mediators (i.e., cytokines) (Manson 2010). Evidence suggests that patients with osteoarthritis have lower blood levels of vitamin D than healthy controls (Muraki 2011); this was especially true of younger osteoarthritis patients (i.e., <60) in one study (Heidari 2011).

Life Extension recommends routine vitamin D deficiency testing for all individuals with pain complaints. If vitamin D levels are low, vitamin D supplementation may result in significant improvements in pain (Selfridge 2010). Life Extension suggests that blood levels of 25-hydroxyvitamin D should be kept between 50 and 80 ng/mL for optimal health.

Antioxidants

Oxidative stress is involved in OA-associated inflammation and pain (Ziskoven 2011). Researchers have found that damaged human chondrocytes release free-radicals, which can exacerbate joint destruction (Rosenbaum 2010). Therefore, OA patients should maintain an adequate intake of antioxidants such as astaxanthin and vitamin C (Nakao 2010; Breidenassel 2011); especially since antioxidant-deficient diets may increase the risk of OA (Rosenbaum 2010).

Green Tea Extracts – Epigallocatechin gallate (EGCG), the major and most biologically active component of green tea, was shown in an in vitro study to protect human chondrocytes from inflammatory damage (Akhtar 2011). This may be due to EGCG’s ability to inhibit the expression of inflammatory mediators (e.g., COX-2 and nitric oxide) (Rosenbaum 2010). However, EGCG is only one of several green tea polyphenols (GTPs). A GTP mix has shown promise for managing symptomatic OA. An expert review on green tea’s role in OA theorizes that GTP mixtures may be beneficial when used in combination with traditional OA treatments (Katiyar 2011).

Additional Support

The following list of additional treatment options may be useful for managing the symptoms of OA.

  • Acupuncture – Among OA patients, acupuncture is able to decrease pain levels and increase quality of life estimates. Experts believe that acupuncture achieves its analgesic effect by stimulating the body’s natural opioid system and reducing the release of stress hormones (Sanders 2011).
  • Boron - Boron is an essential nutrient for healthy bones and joints. Evidence suggests that it is safe and effective for the treatment of OA (Newnham 1994).
  • Niacinamide – Niacinamide, a form of vitamin B3, has been shown to reduce inflammation, decrease consumption of anti-inflammatory medications, and increase joint mobility in OA patients (Jonas 1996). One hypothesis suggests that it may have achieved these effects by modulating inflammatory pathways of joint destruction (McCarty 1999).
  • Mineral Complex – In a clinical study among OA patients, aquamin F (a seaweed-derived mineral mixture) was associated with an increased range of motion and walking distance. Its use in OA may also result in a decreased need for NSAIDs (Frestedt 2009). Most high quality multivitamins contain adequate concentrations of minerals.
  • Mitochondrial Support – Resveratrol, and theoretically other nutrients that support mitochondrial health like coenzyme Q10 (CoQ10) and pyrroloquinoline quinone (PQQ), may be able to ease inflammation and oxidative stress in chondrocytes. Mitochondrial dysfunction can increase inflammation in these cells, potentially impairing cartilage and joint function in OA (Vaamonde-Garcia 2012).
  • Topical olive oil – In 2012, a four-week long clinical trial compared topical virgin olive oil to topical piroxicam, an NSAID, among thirty women aged 40 – 85 with osteoarthritis of the knee. From week two through four, those randomized to the olive oil treatment reported less pain and greater physical function than those using piroxicam (Bohlooli 2012).
  • Gamma linolenic acid - GLA, a plant-derived omega-6 fatty acid, plays an important role in modulating inflammation throughout the body, especially when incorporated into the membranes of immune system cells (Johnson 1997; Ziboh 2004). It was noted that GLA regulates the inflammatory "master molecule" nuclear factor-kappa B (Nf-kB), preventing it from switching on genes for inflammatory cytokines in cell nuclei (Chang 2010). While GLA has been shown to be effective among rheumatoid arthritis patients (Soeken 2004), more research is needed to determine its effectiveness in OA.

Abdel-Tawab M, Werz O, Schubert-Zsilavecz M. Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data. Clin Pharmacokinet. 2011;50(6):349-69.

Abenavoli L, Capasso R, Milic N, et al. Milk thistle in liver diseases: past, present, future. Phytother Res. 2010 Oct;24(10):1423-32.

Aghazadeh-Habashi A, Jamali F. The glucosamine controversy; a pharmacokinetic issue. J Pharm Pharm Sci. 2011;14(2):264-273.

Aitken R. Technical Summary of Cynatine® FLX Clinical Trial. 2010. Data on file.

Akhtar N, Haqqi TM. Epigallocatechin-3-gallate suppresses the global interleukin-1beta-induced inflammatory response in human chondrocytes. Arthritis Res Ther. 2011;13(3).

Akhtar NM, Naseer R, Farooqi AZ, Aziz W, Nazir M. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee—a double-blind prospective randomized study. Clin Rheumatol. 2004 Oct;23(5):410-5.

Aldámiz-Echevarría L, Prieto JA, Andrade F, et al. Arachidonic acid content in adipose tissue is associated with insulin resistance in healthy children. J Pediatr Gastroenterol Nutr. 2007 Jan;44(1):77-83.

Alqutub AN, Masoodi I, Alsayari K, Alomair A. Bee sting therapy-induced hepatotoxicity: A case report. World J Hepatol. 2011;3(10):268-270.

Alternative Medicine Review. Methylsulfonylmethane (MSM). Monograph. Altern Med Rev. 2003;8(4):438-441.

Ameye LG, Chee WS. Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence. Arthritis Res Ther. 2006;8(4).

AMR (Alternative Medicine Review). Krill oil. Monograph. Altern Med Rev.2010;15(1):84-86.

Bajt ML, Knight TR, Lemasters JJ et al. Acetaminophen-induced oxidant stress and cell injury in cultured mouse hepatocytes: protection by N-acetyl cysteine. Toxicol Sci. 2004 Aug;80(2):343-9. Epub 2004 Apr 28.

Belcaro G, Cesarone MR, Dugall M, et al. Efficacy and safety of Meriva(R), a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patients. Altern Med Rev. 2010;15(4):337-344.

Belcaro G, Cesarone MR, Dugall M, et al. Product-evaluation registry of Meriva(R), a curcumin-phosphatidylcholine complex, for the complementary management of osteoarthritis. Panminerva Med. 2010;52(2 Suppl 1):55-62.

Bengmark S. Curcumin, an atoxic antioxidant and natural NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases. JPEN J Parenter Enteral Nutr. 2006 Jan-Feb;30(1):45-51.

Bergin BJ, Pierce SW, Bramlage LR, Stromberg A. Oral hyaluronan gel reduces post operative tarsocrural effusion in the yearling Thoroughbred. Equine Vet J. 2006 Jul;38(4):375-8.

Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet. 2011;377(9783):2115-2126.

Blanco FJ, López-Armada MJ, and Maneiro E. Mitochondrial dysfunction in osteoarthritis. ondrion. 2004 Sep;4(5-6):715-28. Epub 2004 Oct 1.

Bohlooli S, Jastan M, Nakhostin-Roohi B, et al. A pilot double-blinded, randomized, clinical trial of topical virgin olive oil versus piroxicam gel in osteoarthritis of the knee. J Clin Rheumatol. 2012 Mar;18(2):99-101.

Breidenassel C, Valtuena J, Gonzalez-Gross M, et al. Antioxidant vitamin status (A, E, C, and beta-carotene) in European adolescents - the HELENA Study. Int J Vitam Nutr Res. 2011;81(4):245-255.

Briant P, Andriacchi T. (2008) Chapter 6: Joint Biomechanics: The Role of Mechanics in Joint Pathology (pg. 107). In: Gary Firestein (Ed.), Kelley's Textbook of Rheumatology (8th ed.). Saunders, An Imprint of Elsevier.

Brien S, Lewith G, Walker A, et al. Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies. Evid Based Complement Alternat Med. 2004 Dec;1(3):251-257.

Brosseau L, Wells GA, Tugwell P, et al. Ottawa Panel evidence-based clinical practice guidelines for the management of osteoarthritis in adults who are obese or overweight. Phys Ther. 2011;91(6):843-861.

Burke J, Hunter M, Kolhe R, Isales C, Hamrick M, Fulzele S. Therapeutic potential of mesenchymal stem cell based therapy for osteoarthritis. Clinical and translational medicine. Dec 2016;5(1):27.

Busija L, Bridgett L, Williams SR, et al. Osteoarthritis. Best Pract Res Clin Rheumatol. 2010;24(6):757-768.

Butt MS, Sultan MT. Ginger and its health claims: molecular aspects. Crit Rev Food Sci Nutr. 2011;51(5):383-393.

Calamia V, Mateos J, Fernandez-Puente P, Lourido L, Rocha B, Fernandez-Costa C, . . . Blanco FJ. A pharmacoproteomic study confirms the synergistic effect of chondroitin sulfate and glucosamine. Scientific reports. Jun 10 2014;4:5069.

Cattaneo A. Tanezumab, a recombinant humanized mAb against nerve growth factor for the treatment of acute and chronic pain. Curr Opin Mol Ther. 2010;12(1):94-106.

Centers for Disease Control and Prevention. Arthritis. Meeting the Challenge of Living Well At A Glance 2012. Updated 4/12/2012. Available at: http://www.cdc.gov/chronicdisease/resources/publications/aag/arthritis.htm#aag. Accessed 5/7/2012.

Chang CS, Sun HL, Lii CK, Chen HW, Chen PY, Liu KL. Gamma-linolenic acid inhibits inflammatory responses by regulating NF-kappaB and AP-1 activation in lipopolysaccharide-induced RAW 264.7 macrophages. Inflammation. 2010 Feb;33(1):46-57.

Choi SS, Han KJ, Lee JK, et al. Antinociceptive mechanisms of orally administered decursinol in the mouse. Life Sci. 2003 Jun 13;73(4):471-85.

Christensen R, Bartels EM, Astrup A, Bliddal H. Symptomatic efficacy of avocado-soybean unsaponifiables (ASU) in osteoarthritis (OA) patients: a meta-analysis of randomized controlled trials. Osteoarthritis Cartilage. 2008;16(4):399-408.

Cillero-Pastor B, Caramés B, Lires-Deán M, et al. Mitochondrial dysfunction activates cyclooxygenase 2 expression in cultured normal human chondrocytes. Arthritis Rheum. 2008 Aug;58(8):2409-19.

Clayton JJ. Nutraceuticals in the management of osteoarthritis. Orthopedics. 2007;30(8):624-9.

Crowley DC, Lau FC, Sharma P, et al. Safety and efficacy of undenatured type II collagen in the treatment of osteoarthritis of the knee: a clinical trial. Int J Med Sci. 2009;6(6):312-321.

Debbi EM, Agar G, Fichman G, et al. Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: a randomized controlled study. BMC Complement Altern Med. 2011;11:50.

Deutsch L. Evaluation of the effect of Neptune Krill Oil on chronic inflammation and arthritic symptoms. J Am Coll Nutr. 2007;26(1):39-48.

Devillier P. [Pharmacology of non-steroidal anti-inflammatory drugs and ENT pathology]. Presse Med. 2001 Dec 22-29;30(39-40 Pt 2):70-9.

Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. American Journal of Physiology - Renal Physiology. July 1, 2005 2005;289(1):F8-F28.

Egan BA, Mentes JC. Benefits of physical activity for knee osteoarthritis: a brief review. J Gerontol Nurs. 2010;36(9):9-14.

Ejaz P, Bhojani K, Joshi VR. NSAIDs and kidney. J Assoc Physicians India. 2004 Aug;52:632-40.

Felson DT. Osteoarthritis in 2010: New takes on treatment and prevention. Nat Rev Rheumatol. 2011;7(2):75-6.

Felson DT. The sources of pain in knee osteoarthritis. Curr Opin Rheumatol. 2005 Sep;17(5):624-8.

Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee surgery, sports traumatology, arthroscopy: official journal of the ESSKA. Aug 2013;21(8):1717-1729.

Filardo G, Perdisa F, Roffi A, Marcacci M, Kon E. Stem cells in articular cartilage regeneration. Journal of orthopaedic surgery and research. 2016;11:42.

Food and Drug Administration (FDA). Acetaminophen: background and overview. Meeting material from the June 29, 2009, joint meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Advisory Committee and Nonprescription Drug Advisory Committee. Silver Spring, MD, 2009.

Fouladbakhsh J. Complementary and Alternative Modalities to Relieve Osteoarthritis Symptoms: A review of the evidence on several therapies often used for osteoarthritis management. Orthop Nurs. 2012;31(2):115-121.

Fransen M, Agaliotis M, Nairn L, Votrubec M, Bridgett L, Su S, . . . Day R. Glucosamine and chondroitin for knee osteoarthritis: a double-blind randomised placebo-controlled clinical trial evaluating single and combination regimens. Annals of the rheumatic diseases. May 2015;74(5):851-858.

Freitag J, Bates D, Boyd R, Shah K, Barnard A, Huguenin L, Tenen A. Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy - a review. BMC musculoskeletal disorders. 2016;17:230.

Frestedt JL, Kuskowski MA, Zenk JL. A natural seaweed derived mineral supplement (Aquamin F) for knee osteoarthritis: a randomised, placebo controlled pilot study. Nutr J. 2009;8:7.

Gabay C, Medinger-Sadowski C, Gascon D, Kolo F, Finckh A. Symptomatic effects of chondroitin 4 and chondroitin 6 sulfate on hand osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial at a single center. Arthritis and rheumatism. Nov 2011;63(11):3383-3391.

Gill RS, Al-Adra DP, Shi X, Sharma AM, Birch DW, Karmali S. The benefits of bariatric surgery in obese patients with hip and knee osteoarthritis: a systematic review. Obes Rev. 2011;12(12):1083-1089.

Goldring MB and Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol. 2011 Sep;23(5):471-8.

Gregory PJ, Sperry M, Wilson AF. Dietary supplements for osteoarthritis. Am Fam Physician. 2008;77(2):177-184.

Gruenwald J, Petzold E, Busch R, et al. Effect of glucosamine sulfate with or without omega-3 fatty acids in patients with osteoarthritis. Adv Ther. 2009 Sep;26(9):858-71.

Gupta RC, Canerdy TD, Skaggs P, et al. Therapeutic efficacy of undenatured type-II collagen (UC-II) in comparison to glucosamine and chondroitin in arthritic horses. J Vet Pharmacol Ther. 2009;32(6):577-584.

Haghighi M, Khalvat A, Toliat T, Jallaei S. Comparing the effects of ginger (zingiber officinale) extract and ibuprofen on patients with osteoarthritis. Archives of Iranian Medicine. 2005;8(4):267–271.

Hardy ML, Coulter I, Morton SC, et al. S-adenosyl-L-methionine for treatment of depression, osteoarthritis, and liver disease. Evid Rep Technol Assess. 2003;64:1-3.

Heidari B, Heidari P, and Hajian-Tilaki K. Association between serum vitamin D deficiency and knee osteoarthritis. Int Orthop. 2011 Nov;35(11):1627-31.

Heinegard D, Saxne T. The role of the cartilage matrix in osteoarthritis. Nat Rev Rheumatol. 2011;7(1):50-56.

Henrotin Y and Dubuc JE. Cartilage repair in osteoarthritic patients: utopia or real opportunity? 1000 Med Rep. 2009 Nov 26;1. pii: 88.

Henrotin Y, Clutterbuck AL, Allaway D, et al. Biological actions of curcumin on articular chondrocytes. Osteoarthritis Cartilage. 2010;18(2):141-149.

Henrotin Y. Avocado/soybean unsaponifiable (ASU) to treat osteoarthritis: a clarification: Osteoarthritis Cartilage. 2008 Sep;16(9):1118-9; author reply 1120. Epub 2008 Mar 4.

Henrotin Y, Marty M, Mobasheri A. What is the current status of chondroitin sulfate and glucosamine for the treatment of knee osteoarthritis? Maturitas. Jul 2014;78(3):184-187.

Herrero-Beaumont G, Ivorra JA, Del Carmen Trabado M, et al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator. Arthritis Rheum. 2007;56(2):555-567.

Hersh EV, Pinto A, Moore PA. Adverse drug interactions involving common prescription and over-the-counter analgesic agents. Clin Ther. 2007;29(97):2477-97.

Hill P, Brantley H, Van Dyke M. Some properties of keratin biomaterials: kerateines. Biomaterials. 2010;31(4):585-593.

Hochberg M, Chevalier X, Henrotin Y, Hunter DJ, Uebelhart D. Symptom and structure modification in osteoarthritis with pharmaceutical-grade chondroitin sulfate: what's the evidence? Current medical research and opinion. Mar 2013;29(3):259-267.

Hochberg MC, Martel-Pelletier J, Monfort J, Moller I, Castillo JR, Arden N, . . . Pelletier JP. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Annals of the rheumatic diseases. Jan 2016;75(1):37-44.

Hosea Blewett HJ. Exploring the mechanisms behind S-adenosylmethionine (SAMe) in the treatment of osteoarthritis. Crit Rev Food Sci Nutr. 2008;48(5):458-463.

Howes F, Buchbinder R, Winzenberg TB. Opioids for osteoarthritis? Weighing benefits and risks: a Cochrane Musculoskeletal Group review. J Fam Pract. 2011;60(4):206-212.

Huang SL, Ling PX, Zhang TM. Oral absorption of hyaluronic acid and phospholipids complexes in rats. World J Gastroenterol. 2007;13(6):945-949.

Hunter DJ, McDougall JJ, Keefe FJ. The symptoms of osteoarthritis and the genesis of pain. Med Clin North Am. 2009;93(1):83-100.

Iannitti T, Lodi D, Palmieri B. Intra-articular injections for the treatment of osteoarthritis: focus on the clinical use of hyaluronic acid. Drugs R D. 2011;11(1):13-27.

Ishimaru D, Sugiura N, Akiyama H, Watanabe H, Matsumoto K. Alterations in the chondroitin sulfate chain in human osteoarthritic cartilage of the knee. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. Feb 2014;22(2):250-258.

Jang Y, Koh YG, Choi YJ, Kim SH, Yoon DS, Lee M, Lee JW. Characterization of adipose tissue-derived stromal vascular fraction for clinical application to cartilage regeneration. In vitro cellular & developmental biology. Animal. Feb 2015;51(2):142-150.

Jansen MJ, Viechtbauer W, Lenssen AF, Hendriks EJ, de Bie RA. Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic review. J Physiother. 2011;57(1):11-20.

Johnson MM, Swan DD, Surette ME, et al. Dietary supplementation with gamma-linolenic acid alters fatty acid content and eicosanoid production in healthy humans. J Nutr. 1997 Aug;127(8):1435-44.

Jonas WB, Rapoza CP, and Blair WF. The effect of niacinamide on osteoarthritis: a pilot study. Inflamm Res. 1996 Jul;45(7):330-4.

Kahan A, Uebelhart D, De Vathaire F, Delmas PD, Reginster JY. Long-term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trial. Arthritis and rheumatism. Feb 2009;60(2):524-533.

Kalman DS, Heimer M, Valdeon A, Schwartz H, Sheldon E. Effect of a natural extract of chicken combs with a high content of hyaluronic acid (Hyal-Joint) on pain relief and quality of life in subjects with knee osteoarthritis: a pilot randomized double-blind placebo-controlled trial. Nutr J. 2008 Jan 21;7:3.

Kalunian K. Clinical manifestations of osteoarthritis. In: UpToDate, Tugwell P., Romain P. (Eds), UpToDate, Waltham, MA, 2012. Available at: http://www.uptodate.com/contents/clinical-manifestations-of-osteoarthritis?source=search_result&search=Clinical+manifestations+of+osteoarthritis&selectedTitle=1%7E150

Kalunian K. Risk factors for and possible causes of osteoarthritis. In: UpToDate, Tugwell P., Romain P. (Eds), UpToDate, Waltham, MA, 2012a. Available at: http://www.uptodate.com/contents/risk-factors-for-and-possible-causes-of-osteoarthritis?source=search_result&search=Risk+factors+for+and+possible+causes+of+osteoarthritis&selectedTitle=1%7E150

Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7(1):33-42.

Katiyar SK, Raman C. Green tea: a new option for the prevention or control of osteoarthritis: Arthritis Res Ther. 2011 Aug 10;13(4):121.

Katz JD, Agrawal S, Velasquez M. Getting to the heart of the matter: osteoarthritis takes its place as part of the metabolic syndrome. Curr Opin Rheumatol. 2010;22(5):512-519.

Kawakami M, Matsumoto T, Tamaki T. Roles of thromboxane A2 and leukotriene B4 in radicular pain induced by herniated nucleus pulposus. J Orthop Res. 2001 May;19(3):472-7.

Keicher U, Koletzko B, and Reinhardt D. Omega-3 fatty acids suppress the enhanced production of 5-lipoxygenase products from polymorph neutrophil granulocytes in cystic fibrosis. Eur J Clin Invest. 1995 Dec;25(12):915-9.

Kim J, Lee EY, Koh EM, et al. Comparative clinical trial of S-adenosylmethionine versus nabumetone for the treatment of knee osteoarthritis: an 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV study in Korean patients. Clin Ther. 2009;31(12):2860-2872.

Kim JH, Jeong JH, Jeon ST, et al. Decursin inhibits induction of inflammatory mediators by blocking nuclear factor-kappaB activation in macrophages. Mol Pharmacol. 2006 Jun;69(6):1783-90.

Kimmatkar N, Thawani V, Hingorani L, Khiyani R. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee--a randomized double blind placebo controlled trial. Phytomedicine. 2003;10(1):3-7.

Knott L, Avery NC, Hollander AP, Tarlton JF. Regulation of osteoarthritis by omega-3 (n-3) polyunsaturated fatty acids in a naturally occurring model of disease. Osteoarthritis Cartilage. 2011;19(9):1150-1157.

Koga H, Muneta T, Nagase T, Nimura A, Ju YJ, Mochizuki T, Sekiya I. Comparison of mesenchymal tissues-derived stem cells for in vivo chondrogenesis: suitable conditions for cell therapy of cartilage defects in rabbit. Cell and tissue research. Aug 2008;333(2):207-215.

Koh YG, Choi YJ, Kwon SK, Kim YS, Yeo JE. Clinical results and second-look arthroscopic findings after treatment with adipose-derived stem cells for knee osteoarthritis. Knee surgery, sports traumatology, arthroscopy: official journal of the ESSKA. May 2015;23(5):1308-1316.

Kucharz EJ. Application of avocado/soybean unsaponifiable mixtures (piascledine) in treatment of patients with osteoarthritis. Ortop Traumatol Rehabil. 2003;5(2):248-251.

Kwon YB, Kim JH, Yoon JH, et al. The analgesic efficacy of bee venom acupuncture for knee osteoarthritis: a comparative study with needle acupuncture. Am J Chin Med. 2001;29(2):187-199.

Lane NE, Brandt K, Hawker G, et al. OARSI-FDA initiative: defining the disease state of osteoarthritis. Osteoarthritis Cartilage. 2011;19(5):478-482.

Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med. 2010;363(16):1521-1531.

Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58(1):26-35.

Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis. Rheumatology international. Jan 2010;30(3):357-363.

Lev-Ari S, Strier L, Kazanov D, et al. Curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in osteoarthritis synovial adherent cells. Rheumatology (Oxford). 2006 Feb;45(2):171-7. Epub 2005 Oct 25.

Liagre B, Moalic S, Vergne P, et al. Effects of alumina and zirconium dioxide particles on arachidonic acid metabolism and proinflammatory interleukin production in osteoarthritis and rheumatoid synovial cells. J Bone Joint Surg Br. 2002 Aug;84(6):920-30.

Lim AY, Doherty M. What of guidelines for osteoarthritis? Int J Rheum Dis. 2011;14(2):136-144.

Long L, Soeken K, Ernst E. Herbal medicines for the treatment of osteoarthritis: a systematic review. Rheumatology. 2001;40(7):779-793.

Manson JE. Pain: sex differences and implications for treatment. Metabolism. 2010;59(1):S16-20.

Martel-Pelletier J, Farran A, Montell E, Verges J, Pelletier JP. Discrepancies in composition and biological effects of different formulations of chondroitin sulfate. Molecules. Mar 06 2015;20(3):4277-4289.

Mathy-Hartert M, Jacquemond-Collet I, Priem F, Sanchez C, Lambert C, Henrotin Y. Curcumin inhibits pro-inflammatory mediators and metalloproteinase-3 production by chondrocytes. Inflamm Res. 2009;58(12):899-908.

Mayo Clinic Letters. I accidentally disturbed a beehive in my yard and was stung extensively. It was a frightening experience, but it amazingly seems to have cured my arthritis. Is there any medical basis for this? Mayo Clin Health Lett. 2009;27(2):8.

Mayo Clinic. Bone spurs. Sometimes, a source of pain. Mayo Clin Health Lett. 2009;27(6):7.

Mayo Clinic. Osteoarthritis. Available at: http://www.mayoclinic.com/health/osteoarthritis/DS00019. Accessed 5/7/2012.

McCarty MF, Russell AL. Niacinamide therapy for osteoarthritis--does it inhibit nitric oxide synthase induction by interleukin 1 in chondrocytes? Med Hypotheses. 1999;53(4):350-360.

McIlwraith CW, Foerner JJ, Davis DM. Osteochondritis dissecans of the tarsocrural joint: results of treatment with arthroscopic surgery. Equine Vet J. 1991 May;23(3):155-62.

Michalek J, Moster R, Lukac L, et al. Autologous adipose tissue-derived stromal vascular fraction cells application in patients with osteoarthritis. Cell transplantation. Jan 20 2015.

Miller KL, Clegg DO. Glucosamine and chondroitin sulfate. Rheum Dis Clin North Am. 2011;37(1):103-118.

Min SY, Park KS, Cho ML, et al. Antigen-induced, tolerogenic CD11c+,CD11b+ dendritic cells are abundant in Peyer’s patches during the induction of oral tolerance to type II collagen and suppress experimental collagen induced arthritis. Arthritis Rheum. 2006 Mar;54(3):887-98.

Muraki S, Dennison E, Jameson K, et al. Association of vitamin D status with knee pain and radiographic knee osteoarthritis. Osteoarthritis Cartilage. 2011 Nov;19(11):1301-6.

Murias M, Handler N, Erker T, et al. Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationship. Bioorg Med Chem. 2004 Nov 1;12(21):5571-8.

Murphy L, Helmick CG. The impact of osteoarthritis in the United States: a population-health perspective. Am J Nurs. 2012;112(3 Suppl 1):S13-19.

Nakamura S, Hashimoto Y, Mikami M, et al. Effect of the proteolytic enzyme serrapeptase in patients with chronic airway disease. Respirology. 2003 Sep;8(3):316-20.

Nakao R, Nelson OL, Park JS, Mathison BD, Thompson PA, Chew BP. Effect of astaxanthin supplementation on inflammation and cardiac function in BALB/c mice. Anticancer Res. 2010;30(7):2721-2725.

National Institutes of Health. Aspirin: AHFS Consumer Medication Information. PubMed Health [Internet]. Bethesda (MD): National Library of Medicine (US); [Last updated March 2011; Accessed April 2012]

Newnham RE. Essentiality of boron for healthy bones and joints. Environ Health Perspect. 1994;7:83-85.

Ng NT, Heesch KC, Brown WJ. Efficacy of a progressive walking program and glucosamine sulphate supplementation on osteoarthritic symptoms of the hip and knee: a feasibility trial. Arthritis Res Ther. 2010;12(1):12.

Oz HS and Chen TS. Green-tea polyphenols downregulate cyclooxygenase and Bcl-2 activity in acetaminophen-induced hepatotoxicity. Dig Dis Sci. 2008 Nov;53(11):2980-8. Epub 2008 Mar 29.

Pak J, Lee JH, Kartolo WA, Lee SH. Cartilage Regeneration in Human with Adipose Tissue-Derived Stem Cells: Current Status in Clinical Implications. BioMed research international. 2016;2016:4702674.

Palmieri B, Lodi D, Capone S. Osteoarthritis and degenerative joint disease: local treatment options update. Acta Biomed. 2010;81(2):94-100.

Parazzini F. Menopausal status, hormone replacement therapy use and risk of self-reported physician-diagnosed osteoarthritis in women attending menopause clinics in Italy. Maturitas. 2003;46(3):207-12.

Pearle AD, Warren RF, Rodeo SA. Basic science of articular cartilage and osteoarthritis. Clin Sports Med. 2005;24(1):1-12.

Pelletier JP, Raynauld JP, Beaulieu AD, Bessette L, Morin F, de Brum-Fernandes AJ, . . . Martel-Pelletier J. Chondroitin sulfate efficacy versus celecoxib on knee osteoarthritis structural changes using magnetic resonance imaging: a 2-year multicentre exploratory study. Arthritis research & therapy. Nov 03 2016;18(1):256.

Peterson K, McDonagh M, Thakurta S, et al. Drug Class Review: Nonsteroidal Antiinflammatory Drugs (NSAIDs): Final Update 4 Report. National Institute of Health (NIH) PubMed Health. Bethesda (MD): National Library of Medicine (US).

Prasad NS, Raghavendra R, Lokesh BR, et al. Spice phenolics inhibit human PMNL 5-lipoxygenase. Prostaglandins Leukot Essent Fatty Acids. 2004 Jun;70(6):521-8.

Priotta M. Arthritis disease - the use of complementary therapies. Aust Fam Physician. 2010 Sep;39(9):638-40.

Quaglini M. Evaluation of the efficacy of a food supplement to strengthen hair growth. 2010. Data on file.

Rai MF, Sandell LJ. Inflammatory mediators: tracing links between obesity and osteoarthritis. Crit Rev Eukaryot Gene Expr. 2011;21(2):131-142.

Raynauld JP, Pelletier JP, Abram F, Dodin P, Delorme P, Martel-Pelletier J. Long-Term Effects of Glucosamine and Chondroitin Sulfate on the Progression of Structural Changes in Knee Osteoarthritis: Six-Year Followup Data From the Osteoarthritis Initiative. Arthritis care & research. Oct 2016;68(10):1560-1566.

Richardson SM, Kalamegam G, Pushparaj PN, et al. Mesenchymal stem cells in regenerative medicine: Focus on articular cartilage and intervertebral disc regeneration. Methods (San Diego, Calif.). Apr 15 2016;99:69-80.

Ritz B. Multi-Center Study Evaluating the Efficacy of Wobenzym(R)N in Treating Knee Osteoarthritis (Clinical Trial). Study First Received: September 9, 2009. ClinicalTrials.gov processed this record on April 24, 2012.

Rosenbaum CC, O'Mathuna DP, Chavez M, Shields K. Antioxidants and antiinflammatory dietary supplements for osteoarthritis and rheumatoid arthritis. Altern Ther Health Med. 2010;16(2):32-40.

Rutjes AW, Nuesch E, Reichenbach S, Juni P. S-Adenosylmethionine for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2009;7(4).

Saccomano S, Deluca DA. Too toxic. Nurs Manage. 2008;39(9):32A-H.

Safayhi H, Mack T, Sabieraj J, et al. Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase. J Pharmacol Exp Ther. 1992 Jun;261(3):1143-6.

Sanders M, Grundmann O. The use of glucosamine, devil's claw (Harpagophytum procumbens), and acupuncture as complementary and alternative treatments for osteoarthritis. Altern Med Rev. 2011;16(3):228-238.

Scheiman JM, Sidote D. Which NSAID for your patient with osteoarthritis? J Fam Pract. 2010;59(11):E1-6.

Schror K. Pharmacology and cellular/molecular mechanisms of action of aspirin and non-aspirin NSAIDs in colorectal cancer. Best Pract Res Clin Gastroenterol. 2011 Aug;25(4-5):473-84.

Seed SM, Dunican KC, Lynch AM. Treatment options for osteoarthritis: considerations for older adults. Hosp Pract. 2011;39(1):62-73.

Selfridge NJ. Vitamin D and Pain: Making Sense of It All. Alternative Medicine Alert. 2010;13(7):77-78.

Sengupta K, Kolla JN, Krishnaraju AV, et al. Cellular and molecular mechanisms of anti-inflammatory effect of Aflapin: a novel Boswellia serrata extract. Mol Cell Biochem. 2011;354(1-2):189-97.

Sengupta K, Krishnaraju AV, Vishal AA, et al. Comparative efficacy and tolerability of 5-Loxin and Aflapin Against osteoarthritis of the knee: a double blind, randomized, placebo controlled clinical study. Int J Med Sci. 2010;7(6):366-77.

Seo YJ, Kwon MS, Park SH, et al. The analgesic effect of decursinol. Arch Pharm Res. 2009;32(6):937-43.

Siddiqui MZ. Boswellia serrata, a potential antiinflammatory agent: an overview. Indian J Pharm Sci. 2011 May;73(3):255-61.

Simopoulos AP. Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother. 2006;60(9):502-507.

Simopoulos AP. Evolutionary aspects of diet: the omega-6/omega-3 ratio and the brain. Mol Neurobiol. 2011 Oct;44(2):203-15. Epub 2011 Jan 29.

Singer F and Oberleitner H. [Drug therapy of activated arthrosis. On the effectiveness of an enzyme mixture versus diclofenac]. Wien Med Wochenschr. 1996;146(3):55-8.

Singh A, Singh A, Sen D. Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010–2015). Stem Cell Research & Therapy. 2016;7:82.

Singh JA, Noorbaloochi S, MacDonald R, Maxwell LJ. Chondroitin for osteoarthritis. The Cochrane database of systematic reviews. Jan 28 2015;1:Cd005614.

Singh S. From Exotic Spice to Modern Drug? Cell. 2007;130(5):765-768.

Sinusas K. Osteoarthritis: diagnosis and treatment. Am Fam Physician. 2012;85(1):49-56.

Siversson C, Chan J, Tiderius CJ, et al. Effects of B1 inhomogeneity correction for three-dimensional variable flip angle T1 measurements in hip dGEMRIC at 3 T and 1.5 T. Magn Reson Med. 2012;67(6):1776-81.

Soeken KL, Lee WL, Bausell RB, Agelli M, Berman BM. Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. J Fam Pract. 2002;51(5):425-430.

Soeken KL. Selected CAM therapies for arthritis-related pain: the evidence from systematic reviews. Clin J Pain. 2004 Jan-Feb;20(1):13-8.

Song YJ, Lin SQ, Wu ZH, Weng XS, Qiu GX, Chen FL. [Effect of combined continued hormone replacement therapy on knee osteoarthritis symptom of postmenopausal women]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2004;26(5):571-5.

Sowers MR, Karvonen-Gutierrez CA. The evolving role of obesity in knee osteoarthritis. Curr Opin Rheumatol. 2010;22(5):533-537.

Strand V, Bloch DA, Leff R, Peloso PM, Simon LS. Safety issues in the development of treatments for osteoarthritis: recommendations of the Safety Considerations Working Group. Osteoarthritis Cartilage. 2011;19(5):493-499.

Tanamas SK, Wijethilake P, Wluka AE, et al. Sex hormones and structural changes in osteoarthritis: a systematic review. Maturitas. 2011;69(2):141-156.

Taylor C, Carballido-Gamio J, Majumdar S, Li X. Comparison of quantitative imaging of cartilage for osteoarthritis: T2, T1rho, dGEMRIC and contrast-enhanced computed tomography. Magn Reson Imaging. 2009;27(6):779-784.

Terry R, Posadzki P, Watson LK, Ernst E. The use of ginger (Zingiber officinale) for the treatment of pain: a systematic review of clinical trials. Pain Med. 2011;12(12):1808-1818.

Therkleson T. Ginger compress therapy for adults with osteoarthritis. J Adv Nurs. 2010;66(10):2225-2233.

Vaamonde-García C, Riveiro-Naveira RR, Valcárcel-Ares MN, et al. Mitochondrial dysfunction increases the inflammatory responsiveness to cytokines in normal human chondrocytes. Arthritis Rheum. 2012 May 1. doi: 10.1002/art.34508. [Epub ahead of print]

Velasquez MT, Katz JD. Osteoarthritis: another component of metabolic syndrome? Metab Syndr Relat Disord. 2010;8(4):295-305.

Vista ES, Lau CS. What about supplements for osteoarthritis? A critical and evidenced-based review. Int J Rheum Dis. 2011;14(2):152-158.

Vrtovec B, Poglajen G, Haddad F. Stem cell therapy in patients with heart failure. Methodist DeBakey cardiovascular journal. Jan-Mar 2013;9(1):6-10.

Wang Y, Prentice LF, Vitetta L, Wluka AE, Cicuttini FM. The effect of nutritional supplements on osteoarthritis. Altern Med Rev. 2004;9(3):275-296.

Weir MR. Renal effects of nonselective NSAIDs and coxibs. Cleve Clin J Med. 2002;69 Suppl 1:SI53-8.

Wilcox CM, Cryer B, Triadafilopoulos G. Patterns of use and public perception of over-the-counter pain relievers: focus on nonsteroidal antiinflammatory drugs. J Rheumatol. 2005;32(11):2218-24.

Wiley-Blackwell (2011, September 6). Chondroitin sulfate improves hand function, relieves morning stiffness caused by osteoarthritis, study finds. ScienceDaily. Accessed April 24, 2012, from http://www.sciencedaily.com-/releases/2011/09/110906085340.htm

Wixted JJ, Fanning P, Rothkopf I, et al. Arachidonic acid, eicosanoids, and fracture repair. J Orthop Trauma. 2010 Sep;24(9):539-42.

Wood JN. Nerve Growth Factor and Pain. New England Journal of Medicine. 2010;363(16):1572-1573.

Woodcock J. A difficult balance--pain management, drug safety, and the FDA. N Engl J Med. 2009;361(22):2105-7.

Zainal Z, Longman AJ, Hurst S, et al. Relative efficacies of omega-3 polyunsaturated fatty acids in reducing expression of key proteins in a model system for studying osteoarthritis. Osteoarthritis Cartilage. 2009;17(7):896-905.

Zegels B, Crozes P, Uebelhart D, Bruyere O, Reginster JY. Equivalence of a single dose (1200 mg) compared to a three-time a day dose (400 mg) of chondroitin 4&6 sulfate in patients with knee osteoarthritis. Results of a randomized double blind placebo controlled study. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. Jan 2013;21(1):22-27.

Ziboh VA, Naguwa S, Vang K, et al. Suppression of leukotriene B4 generation by ex-vivo neutrophils isolated from asthma patients on dietary supplementation with gammalinolenic acid-containing borage oil: possible implication in asthma. Clin Dev Immunol. 2004 Mar;11(1):13-21.

Ziskoven C, Jager M, Kircher J, et al. Physiology and pathophysiology of nitrosative and oxidative stress in osteoarthritic joint destruction. Can J Physiol Pharmacol. 2011;89(7):455-466.

Ziskoven C, Jäger M, Zilkens C, et al. Oxidative stress in secondary osteoarthritis: from cartilage destruction to clinical presentation? Orthop Rev (Pavia). 2010 Sep 23;2(2):e23.