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?

  • Consume a diet high in omega-3 fatty acids, fiber, and essential vitamins and minerals
  • Limit pro-inflammatory foods high in saturated fat and sugar
  • Target 150 minutes of moderate exercise or 75 minutes of vigorous exercise 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 (OA) is the most common form of arthritis and a common cause of joint pain and disability. It affects over 30 million adults in the United States and more than 300 million people worldwide.1,2 OA is the result of breakdown of cartilage and other joint-associated tissue over time. Cartilage protects and cushions the ends of bones.3 When cartilage in joints deteriorates, bone will rub on bone. OA affects the entire joint, causing changes in the underlying bone, breakdown of the connective tissue that holds the joint together, and inflammation in the lining of the joint.3 Importantly, OA should not be thought of as merely the result of wear and tear on a joint—it involves active biological processes such as inflammation and degradation of the cartilage matrix.4

The joint deterioration associated with OA can cause pain, stiffness, swelling, and loss of flexibility. Advanced OA may lead to reduced mobility and poor quality of life.1,3 In less-advanced cases, OA symptoms can often be managed to some degree with non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. However, long-term use of NSAIDs may have untoward risks of gastrointestinal ulcers and bleeding, cardiovascular problems, and kidney toxicity.5,6 Similarly, long-term or excessive use of acetaminophen (eg, Tylenol) may lead to liver problems in some people,7 and it may not be effective for long-term pain management.8

Many factors contribute to OA onset and progression, including obesity (which promotes systemic inflammation), joint injury, genetics, and advancing age. Therefore, a multifactorial approach is generally required, including weight loss, pain relief, and joint support. Several natural ingredients, such as extracts of Chinese skullcap, white mulberry, and cutch tree, target inflammatory pathways and may help reduce joint pain and swelling and complement medical treatments.

In this protocol you will learn more about the onset and progression of OA, as well as the causes, risk factors, and diagnosis of this condition. You will also discover conventional and emerging treatments, as well as several nutritional supplements and dietary and lifestyle changes that can support optimal joint health and function.

3 Understanding Osteoarthritis

Joint Structure and Function

Joints are where two or more bones meet and consist of the following tissues9:

  • Cartilage – the tissue that covers bones at the joints, which reduces friction during movement.
  • Synovial membranes – secrete synovial fluid to lubricate the joints. Synovial fluid is a clear, sticky, non-Newtonian fluid present in synovial bursa and the joint capsule.
  • Ligaments – bands of connective tissue that connect bone to bone and support the joint.
  • Tendons – connective tissue that connects muscles to bones and facilitates joint movement.

Joints may be fixed, such as those in the skull, in which there is no movement, or mobile, including10:

  • Ball and socket joints – allow for backward, forward, sideways, and rotational movements (eg, shoulder and hip joints)
  • Hinge joints – allow for bending or straightening movements (eg, knee and elbow joints)
  • Pivot joint – allows for limited rotational movements (eg, neck joints)
  • Ellipsoidal joint – allows for any movement but a pivot movement (eg, wrist joint)

Onset and Progression of Osteoarthritis

OA can occur in any joint, but is most common in injured joints or those used for repetitive motions. The knee is the most common joint affected in the lower portion of the body. Other load-bearing joints, such as the spine and hips, are also commonly affected.11 As joint pain develops and progresses, a person affected by OA may make subtle adjustments to their posture and body movements, which can unevenly distribute biomechanical loads on joints, predisposing those joints to OA progression.12

While OA is often described as a degenerative joint disease, it also involves active inflammatory processes and the destruction of joint tissue by proteolytic enzymes.13-15 Normally, cartilage at the end of bones provides cushion and allows for smooth joint motion. As OA worsens, bones of the affected joint weaken and deteriorate, and growths called bone spurs or osteophytes may develop. These outgrowths may help stabilize the joint, but they can also rub on other bones, nerves, and other tissue, causing pain and further damage.16 As joint deterioration continues, local release of inflammatory proteins can recruit more immune cells, which in turn promote further inflammation and joint damage. Indeed, many contemporary research papers describe the progression of OA as an inflammatory, immune-mediated process, at least in part.14,17,18

4 Osteoarthritis Symptoms

Osteoarthritis (OA) symptoms vary, but the most common include joint pain and tenderness that worsens with joint use, reduced mobility, swelling in the joint, joint deformity in advanced joint damage, and occasionally, instability, particularly a buckling of the knee joint. Other signs and symptoms of OA include bone spurs, which may form around the affected joint, and the sensation of grating or popping when the joint is being used.3

Because cartilage does not contain nerve endings, joint damage may not cause pain until OA is in advanced stages.19 OA pain often worsens with physical activity, but people with advanced OA may experience pain even at rest.20 The pain associated with OA may contribute to depression, sleep problems, and generally diminished quality of life in some people.3 Symptoms typically worsen slowly over time.21

While OA can affect any weight-bearing joint, it is most common in joints in the hand, knee, hip, and spine, and less common in the shoulder, elbow, wrist, and ankle. The knee is the most common site of lower-limb disability for adults over age 50.3,22 OA in the hip may manifest as pain or stiffness in the groin, buttocks, or inside of the knee. Pain in the big toe and swelling in the ankles or toes may be symptomatic of OA in the feet, while OA in the fingers may cause swollen, tender, red fingers. A grating sensation in the knee upon movement may be symptomatic of knee OA.21

People with OA experience 30% more falls and have a 20% greater risk of fracture than people without OA. In addition to muscle weakness and impaired balance, which are potential problems associated with OA, some medications used to treat OA symptoms, including pain relievers such as opioids and NSAIDs, can cause dizziness.21,23

5 Diagnosis of Osteoarthritis

Clinical Exam

Diagnosing osteoarthritis (OA) is generally straightforward unless you have unusual symptoms or other health concerns. You doctor will likely not need to order X-rays or other tests. He or she will assess your medical history and ask questions about your symptoms, such as whether you have morning stiffness in the affected joints and how long it typically lasts, and whether your pain is worse when you use the affected joint(s).1,24 During the physical exam, the doctor will examine your joints to assess their range of motion and find signs of joint damage.

Imaging

In less clear cases, some imaging modalities may help confirm suspected OA. Cartilage loss may be visualized on X-ray, which is the type of imaging most widely used to identify OA. Radiographs may show bone spurs or other features of OA, such as a narrowing joint space.25,26

Magnetic resonance imaging (MRI) is utilized in complex cases to detail bone and soft tissue,3 as it can show changes to cartilage and soft tissues, such as ligaments.14 However, according to the Osteoarthritis Research Society International (ORSI), MRI may enable earlier diagnosis of knee OA, prior to radiographically detectable changes. After a literature review including 25 studies, the ORSI concluded that visualization of joint abnormalities on MRI may be useful for early OA diagnosis, although further research is warranted to establish the role of MRI in the routine clinical setting.27,28

Ultrasound can also be used to visualize synovial inflammation and structural changes associated with OA.26 However, ultrasonography has some limitations in the context of OA, including that it cannot assess subchondral bone.

Lab Testing and Blood Work

Blood work is rarely required to diagnose OA. If a diagnosis of OA is not clear, analyzing blood or joint fluid may help rule out other potential causes of joint pain, such as rheumatoid arthritis, gout, or an infection.3

6 Causes and Risk Factors

Many factors contribute to the development of osteoarthritis (OA), including biomechanical factors, genetics, nutritional factors, and bone density. Advancing age, female gender, being overweight, joint injury or repetitive use of the joints, and muscle weakness can all contribute to the development of OA.29

Age

Age is one of the greatest risk factors for the development of OA.4 The prevalence of OA, particularly in the hand, hip, and knee, increases considerably after about age 50.4,30,31

Obesity

Obesity is associated with an increased risk of OA, particularly knee OA.32 Being overweight or obese puts extra stress on joints, which may contribute to joint degeneration. However, as obese individuals also have an increased risk of OA in non-load-bearing joints, some researchers have suggested that an overall increase in chronic inflammation that generally accompanies obesity may contribute to OA.33-36

Gender

Female gender is associated with a greater prevalence and severity of OA. Women have a greater risk of knee, hand, and hip OA compared with men, and they tend to have more severe knee OA.37 The incidence of OA increases around menopause, which may be related to hormonal changes or other factors, such as loss of muscle, bone, or cartilage mass.38

Hormones and Osteoarthritis

There has been much debate about the relationship between hormones and risk of OA. It has been postulated that because estrogen has anti-inflammatory properties at high concentrations, and because estrogen supports bone integrity, the hormonal changes of menopause may contribute to a variety of health problems, including OA. However, observational studies have found inconsistent associations between circulating hormone levels and OA.39 Similarly, available evidence on the effect of hormone replacement therapy (HRT) on OA is mixed.39

A cross-sectional study of over 4,700 women in Korea examined how HRT affects the prevalence of knee OA in women. The researchers found that women receiving hormone therapy had lower prevalence of knee OA compared with women not taking any hormones.40 Additional research—especially randomized controlled trials—is necessary to elucidate the utility of female HRT in the management of OA.39

Repetitive Stress and Occupation

Research suggests repetitive use of a joint may be associated with the development of OA. Knee OA is more frequent in people who squat or kneel often, and hip OA is associated with prolonged lifting and standing. OA of the hand is more frequent in people whose occupations require manual dexterity.38 Highly repetitive, intense physical activity may increase risk of hip and knee OA as well.

Joint Injury or Trauma

Injury to a joint, ligament, or meniscus (a piece of cartilage in the knee that provides cushioning and stability between the shin and thighbone)41 can be associated with the development of posttraumatic OA (ie, OA that develops after an injury).38,42-44

High Bone Density

High Bone density may be a risk factor for OA.45 OA is associated with higher levels of bone density, which may lead to the development of bone spurs. These bony growths damage cartilage and reduce its ability to protect joints.46 In a multi-center observational study of approximately 300 adults with unexplained high bone mass, there was an increased prevalence of knee OA as compared with controls whose bone density was more average.47 Another controlled trial found similar results.48 Further research is required to help us better understand the relationship between bone density and OA, and how this information can be used to manage this condition.

Anatomical Abnormalities

Certain anatomical abnormalities, such as imbalanced or weak muscles, can alter movement at the joint and contribute to the breakdown of cartilage.49 Joint malalignment is also associated with increased structural degradation under stress, which may enhance progression of OA.38

Genetics

Research suggests genes account for up to 60% of hip and hand OA and 40% of knee OA cases.38 However, there is no known single gene responsible for the pathogenesis of this disease. Genes may also operate differently based on a history of trauma or between people of different genders or races and at different body sites.50

Research suggests OA pathogenesis is in part due to genetic factors that influence cartilage structure and bone density.51 Genome studies indicate that mutations in the GDF5 gene, which encodes a growth factor that contributes to bone development, may play a role in OA.52 Other gene variations may cause increased sensitivity to pain, particularly certain variations in the FAAH gene.49 Indeed, the enzyme encoded by the FAAH gene, fatty acid amide hydrolase, is currently an intriguing target for drug development because it breaks down anandamide and other endocannabinoids that have intrinsic pain-relieving properties.

Systemic Inflammation and Osteoarthritis

Inflammation plays an important role in the progression of OA.53 Systemic inflammation tends to increase with age as reflected by increased levels of inflammatory cytokines (proteins that play a role in cell signaling and immunity), such as interleukin-6 (IL-6). Higher blood levels of IL-6 have been associated with progression of knee OA,54 and elevated concentrations of other inflammatory mediators, such as IL-1B, and tumor necrosis factor-alpha (TNF-α),55 have been identified in joints affected by OA.56

Although blood tests are not typically necessary to diagnose OA, assessing circulating levels of C-reactive protein (CRP) can provide insights into the level of inflammation throughout your body. hs-CRP (high sensitivity C-reactive protein), also known as cardiac CRP, is a blood test that measures CRP. Elevated blood levels of hs-CRP are associated with cardiovascular disease, rheumatoid arthritis, and many other inflammatory diseases. Research suggests elevated CRP levels may correlate with symptom severity and functional decline in OA. The association between CRP levels and the extent of joint deterioration observable on X-ray is less consistent.57-59

7 Treatment of Osteoarthritis

Osteoarthritis (OA) treatment is aimed toward improving overall quality of life and physical limitations as much as possible. Unfortunately, there is no cure for OA, and no medical intervention has been approved to stop the progression of the disease. However, integrating medical treatments, including surgery when appropriate, with lifestyle changes such as weight loss and eating a healthy diet may provide relief for some patients.

Several interventions may benefit people with OA, including low-impact physical activity such as biking, swimming, and walking; muscle-strengthening exercises; weight loss; medications; and in some cases, surgery.1 Other conditions that often co-occur with OA, such as depression and insomnia , should also be managed appropriately for best results.

Physical Activity

In most cases, exercise is a first-line management for OA, as it is safe and non-invasive, regardless of disease severity, pain, and joint function.60,61 Physical activity offers many significant health benefits for OA patients, including promoting healthy weight and physical function.62 A regular physical activity program can help reduce stress, relieve pain, improve mood, and support movement.1 See the “Dietary and Lifestyle Considerations” section for more information.

Weight loss

Being overweight is a major risk factor for OA. Being 10 pounds overweight increases the force on the knee while walking by 30‒60 pounds with each step. Overweight women have four times the risk of knee OA as a normal weight woman, and overweight men have a five times greater risk. For a normal-weight woman, approximately 11 pounds of weight loss (2 body mass index [BMI] units) decreases the risk for knee OA by over 50%.63 Conversely, weight gain is associated with an increased risk of OA.64

Weight loss, coupled with exercise, is key to managing obese patients with OA. Losing weight reduces joint loading, which improves symptoms, relieves pain, and improves quality of life in this patient population.65 Greater body weight increases severity of knee OA, and is linked to increased need for hip and knee replacement surgeries.65 Research suggests exercise and weight loss together provide more relief than exercise alone.65 A trial involving over 1,300 people enrolled in an 18-week weight loss program demonstrated, through weight and knee injury assessments, a dose-response relationship between symptoms of knee OA and weight loss, meaning that greater weight loss led to greater reductions in OA symptoms.66

Medications

If pain relief is not achieved through nonpharmacological interventions, oral and topical medications may be used. It is important to note that long-term use of certain medications, including commonly used medications such as ibuprofen or acetaminophen, may have unintended negative health consequences in some people. Systemic medications, including over-the-counter NSAIDs should be used as sparingly as possible and only when symptoms demand it. More information is available in Life Extension’s Acetaminophen and NSAID Toxicity protocol.

Acetaminophen. Acetaminophen (eg, Tylenol) may help temporarily relieve mild-to-moderate OA pain. A review of 13 randomized trials examined the effect of acetaminophen on pain, disability, and quality of life and determined that it has minimal short-term benefits in those with OA.67 Taking more than the recommended dose may cause side effects, such as liver damage.3 A recent literature review of eight cohort studies found a dose-response relationship regarding acetaminophen toxicity, meaning the more you take, the greater the risk of side effects.68 Current best practices are to take acetaminophen at the lowest effective dose and for the shortest possible period of time.69

NSAIDs. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (eg, Advil) and naproxen sodium (eg, Aleve), are a class of drugs used to reduce pain and inflammation by inhibiting the action of COX enzymes, which produce prostaglandins. Prostaglandins keep the lining of the stomach healthy and play a role in pain, inflammation, and fever.70 These medications are currently the cornerstone for relieving OA pain, but they may have side effects including gastrointestinal, renal, and cardiovascular complications.3

In one randomized double-blind trial, 380 patients with OA were given rofecoxib (Vioxx, a selective COX-2 inhibitor) (12.5 or 25 mg/d), celecoxib (Celebrex) (200 mg/d), or acetaminophen (4,000 mg/d). Researchers determined that NSAIDs were better than acetaminophen in relieving moderate-to-severe knee and hip pain, but there appears to be little clinical difference in NSAID effectiveness.71 Ibuprofen and naproxen are effective and have a lower risk of cardiovascular events as compared with diclofenac. Coxibs and nabumetone (Relafen) may have lower risk of GI disturbances.72

Topical NSAIDs. NSAIDs applied topically as a gel may relieve pain effectively with fewer side effects than oral NSAIDs.3 A recent review of 39 randomized, double-blind, placebo-controlled trials with 10,631 participants determined that topical NSAIDs provide good pain relief, with 60% of patients experiencing 50% improvement in pain. Topical diclofenac was equal to oral NSAIDs in knee and hand OA. Risk of toxicity is lower in topical NSAIDs compared with oral formulations due to reduced absorption.73 One of the main risks with oral NSAIDs is gastrointestinal side effects. Topical NSAIDs have been associated with fewer gastrointestinal adverse reactions compared with oral NSAIDs.74

Side Effects of OTC Pain Medications

Non-prescription OTC pain medications are often used by people with OA to relieve pain. However, these medications can have side effects in some people, and may lead to serious health complications. Make sure any medication you take—especially on a long-term basis—is under the guidance of a doctor.

NSAID side effects most commonly involve the stomach and include stomachache, gastritis, ulcers, and stomach or bowel bleeding. NSAIDs may also cause high blood pressure, kidney disease (which may cause swelling of the arms and legs), difficulty concentrating, and balance problems.75,76 Certain NSAIDs, such as diclofenac, increase the risk of heart problems when taken at high doses for a long period of time.70 NSAID toxicity is more common in older people, those with a history of gastrointestinal problems, who also use other medications, and who take high dosages of NSAIDs.77,78

In 2015, the Food and Drug Administration (FDA) strengthened its warning, originally issued in 2005, that NSAID use is associated with the risk of heart attack and stroke, even with short-term use, based on advice of an expert panel that conducted a thorough review of the data regarding the risk of NSAID use. NSAIDs may elevate blood pressure and cause heart failure. The FDA noted that risk of heart attack and stroke increases with higher dosages and longer periods of use, but that the risk may begin even with short-term use and within a few weeks of starting therapy. The risk is greatest in those who already have heart disease, although even those without cardiovascular issues have an increased risk.79,80

A recent longitudinal study examined the risk of cardiovascular disease after NSAID use in people with OA. The risk of developing cardiovascular disease, ischemic heart disease, congestive heart failure, and stroke were estimated for over 7,740 people with OA and 23,000 healthy controls. People with OA had a higher risk of developing heart disease compared with healthy controls. The researchers concluded that NSAID use contributes to the association between OA and cardiovascular disease.81

Those with heart disease should avoid NSAID use, if possible, and anyone who takes these medications should do so under the guidance of a physician. Never take more than one type of NSAID at a time, and try to take the lowest effective dose for the shortest amount of time possible. Work with your doctor to find alternatives to NSAIDs, and seek medical help if you experience symptoms such as shortness of breath, chest pain, or sudden weakness.79

Acetaminophen can cause serious liver damage and is not appropriate for people with liver or kidney problems or those who abuse alcohol.70 While most people recover from acetaminophen overdose, the drug can cause potentially deadly liver injury. Acetaminophen toxicity accounts for 40% of adult cases of liver failure in the developed world.82

People who are considering using NSAIDs to manage their arthritis should talk with their doctor and review Life Extension’s Acetaminophen and NSAID Toxicity protocol for more detailed information on the safe use of these drugs.

Topical capsaicin. Topically applied capsaicin, which is a chili pepper extract, alleviates pain by inhibiting sensory neurons. In one crossover, double-blind, randomized controlled trial involving 100 people with mild/moderate knee OA, patients received either placebo or 0.0125% capsaicin gel applied to the knee three times daily for four weeks. After a one-week washout period, participants then received the other treatment for four weeks. Researchers concluded that capsaicin gel was effective in treating knee OA.83 A review of six studies found that, compared with placebo, topical capsaicin was safe and effective in treating OA of the hand, knee, hip, and shoulder.84

Duloxetine. Duloxetine (Cymbalta) is an antidepressant that may be useful in treating pain.3 In one randomized, double-blind, placebo-controlled trial of 256 patients with knee OA, patients received 60 mg of duloxetine a day or placebo. At week seven, duloxetine dosage was increased to 120 mg a day in a blinded fashion for participants who reported less than 30% pain reduction. Treatment was found to reduce pain and improve function in patients with knee OA.85 In another 10-week randomized, double-blind, placebo-controlled trial, 524 patients with moderate-to-severe knee OA who were taking NSAIDs received 60‒120 mg duloxetine daily. Those who took duloxetine experienced reduced pain and improved function.86

Corticosteroids. Corticosteroids are anti-inflammatories that are either taken orally or injected directly into the joint to help relieve pain. Corticosteroid injections may provide short-term pain relief in patients with knee OA. In a single-blind trial of 150 patients, participants were randomized to receive either corticosteroid injections (40 mg triamcinolone acetonide and 1% lidocaine) or undergo tidal irrigation. Tidal irrigation involves injecting saline fluid in the knee and withdrawing joint fluid from the knee to clear tissue debris, which may reduce inflammation and pain.87 Both procedures relieved pain in the short-term, while tidal irrigation had a longer duration of benefit.88 Intra-articular corticosteroid injections can be used as an adjunct for the short-term treatment of moderate-to-severe pain in people with OA.89

Despite potential short-term benefits, some research suggests that intra-articular corticosteroid injections may be associated with long-term adverse effects, including accelerated OA and joint-related issues. In a report published in the journal Radiology, researchers evaluated the records of 459 patients with knee and hip OA who received at least one intra-articular corticosteroid injection at a hospital in 2018. The researchers noted that 36 adverse joint events in 36 patients were reported, the most common of which was accelerated OA progression (6%), followed by subchondral insufficiency fracture (0.9%), complications of osteonecrosis (0.7%), and rapid joint destruction with bone loss (0.7%). The researchers suggested that patient selection is a key factor associated with outcomes, and some people with recent changes in their joint-related symptoms may not be good candidates for corticosteroid injections. Additional research is needed to more clearly identify those most likely to benefit from intra-articular corticosteroid injections.90

Opioids. Opioids, a class of drugs used to relieve pain, are sometimes used in severe cases of OA. However, there are serious concerns regarding their side effects, including addiction, drowsiness, nausea, and dizziness.91 Opioids are typically used short-term by patients with severe or disabling pain. However, a randomized clinical trial of 240 people with mild-to-moderate back pain and/or hip or knee OA found that using opioids did not result in better pain reduction than non-opioid medications (acetaminophen or NSAIDs) over a one-year period.92 Another analysis of the ability of opioids (including tramadol, hydromorphone, and oxycodone) and NSAIDs (including diclofenac, naproxen, and piroxicam [Feldene]) to reduce knee OA pain suggests there was no significant difference between pain reduction in both drug groups.93 Opioids are generally not recommended for OA treatment except in very carefully selected cases because the risk of harm outweighs the potential benefit.

Surgery

If more conservative treatment options are not successful, surgery may need to be considered. Surgical procedures for OA include realigning the bone, arthroscopy (a surgical procedure in which surgeons can visualize, diagnose, and treat joint problems through a minimally invasive scope), cartilage repair, osteotomy, and arthroplasty.94 If OA has greatly damaged one side of the knee, an osteotomy may be performed, in which bone is added or removed above or below the knee.3

In arthroplasty, or joint replacement surgery, damaged joint surfaces are removed and replaced with plastic or metal joints.3 Arthroplasty is an effective and safe procedure with over 600,000 knee replacements and 300,000 hip replacements performed in the United States each year.95,96 Many joint replacements can be done on an outpatient basis, and long-term outcomes in people who are good candidates are typically quite good. Possible complications include blood clots and infections, and replacements may wear out and need to be replaced over time.3 However, replacements typically last for many years.96 There may also be some stiffness in the joint and numbness around the area of incision following surgery.96

Hip or knee replacement is recommended when pain or stiffness limits daily activities, such as walking and climbing stairs, or when moderate-to-severe pain occurs even at rest, when the joint begins to deform, or other treatments such as medications, physical therapy, other surgeries, or cortisone injections do not improve symptoms.96 Possible surgical candidates have no age or weight restrictions, and total hip and knee replacements, while typically performed on those age 50‒80, have been successfully performed on older and younger people.95,96

Note that improved knee and hip motion is a goal of this surgery, but full motion may not be restored. Physical therapy and rehabilitation will help improve gait and range of motion after surgery. Most people who undergo knee replacement will be able to climb stairs and get into and out of vehicles. Regular low-impact physical activity, such as swimming, biking, and golfing, is an important part of recovery and helps maintain strength and flexibility in the new joint.95,96

Determining which procedure is required may depend on the joint(s) affected, the stage of OA, any patient comorbidities, and age of the patient.94

8 Novel and Emerging Therapies

Regenerative Therapy

Stem cell-based therapies have gained attention for their potential ability to repair and regenerate the structure and function of damaged joint tissue.97 Stem cells are cells that have the potential to develop into many different types of cells in the body. Embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells have all been studied for their potential to treat osteoarthritis (OA). Of these, mesenchymal stem cell therapy is considered to be the most promising in the context of OA.98 Mesenchymal stem cells can develop into skeletal tissue cells, including cartilage and bone.

Mesenchymal stem cells derived from fat (adipose) tissue are obtained by less invasive measures than those required for obtaining stem cells from bone marrow, including liposuction. Several trials using adipose-derived mesenchymal stem cells reported decreased pain and improved function.99 In a recent trial over 1,000 people with knee and hip OA had injections of stromal vascular fraction (containing stem cells) that had been harvested from fat tissue. Approximately three to 12 months after treatment, most patients showed improved clinical outcomes, including improved movement and reduced stiffness and pain.100 In another trial involving 30 elderly people with knee OA, injections with stromal vascular fraction helped reduce pain, improve function, and heal cartilage at the two-year follow-up.101

In one recent report, four people with knee OA had mesenchymal stem cell transplantation in one knee. Three patients had improvements in how many minutes they could walk without pain, and all of them were able to climb more stairs than before. Physical examination demonstrated minor improvements in range of motion.102 In a five-year follow-up of three of these subjects, mild improvements in pain scores persisted. While there was some joint deterioration, the treated knee was still determined to be in better shape than it had been at baseline five years prior.103 In another study of 18 people with knee OA, mesenchymal stem cell injections reduced pain and improved joint function.104

Individual patient characteristics appear to influence the outcomes of mesenchymal stem cell therapy in OA. Better results have been observed in younger individuals, those with lower BMI, smaller areas of cartilage degradation, and earlier stage of OA progression. Studies have not reported any major adverse events associated with mesenchymal stem cell harvest or therapy, and most studies report some clinical benefit.105,106 Nevertheless, the effectiveness of stem cell therapy for OA has not been conclusively established. While the effects of mesenchymal stem cell therapies are encouraging, larger studies with longer follow-up periods are required to assess the safety and efficacy of this OA treatment.

Cellular Senescence in Osteoarthritis and the Potential of Senolytics

Senescent cells are cells that no longer divide properly and exhibit metabolic dysfunction described as the senescence-associated secretory phenotype. These cells release harmful chemical signals into their local environment that may contribute to tissue inflammation, disease, and aging.107 Note that cell senescence does not cause aging itself, but rather is a normal pathway intended to remove damaged cells from the body through apoptosis (cell death) and removal by the immune system. As we age, however, the immune system may not be able to clear these cells effectively.107

Cellular senescence is thought to play a role in the development of OA.108 Senescent cells may accumulate in a damaged joint, contributing to the pain and inflammation associated with OA.109 Research in mouse models suggests senolytic agents, which are compounds that eliminate senescent cells, may help reduce inflammation and repair damaged tissue.109

In an open-label pilot study, 14 patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF) received two senolytic agents, dasatinib (100 mg/d) and quercetin (1,250 mg/d), for three days each week for three weeks. Researchers evaluated quality of life, side effects, physical function, and biological parameters. Physical function, as measured by the six-minute walk distance, four-minute gait speed, and chair-stand time, improved significantly. Further research, particularly with trials involving larger sample sizes, are required to validate these findings, and also determine whether senolytics can help improve physical function in people with other conditions that limit mobility, including OA.110

Cellular and animal research suggests fenofibrate, a medication used to reduce cholesterol and triglyceride levels in the blood, may also reduce inflammation and the number of senescent cells, as well as protect cartilage against degredation.111,112 In a recent clinical trial, 14 people with erosive hand OA, a rare form of OA characterized by rapid onset, joint swelling, and loss of bone at the center of the interphalangeal joints of the hands, received 145 mg/d fenofibrate for 12 weeks.113 Subjects reported decreased pain and joint tenderness, as well as a decrease in the duration of joint stiffness in the morning.114 Fenofibrate may be clinically useful in combating age-related cartilage degeneration and in treating OA.111 Controlled trials with larger sample sizes are needed to help clarify these results.

Tanezumab

Tanezumab is a drug that targets nerve growth factor to relieve pain. Thus far, results from trials have been mixed. In a randomized, double-blind, controlled study, 3,021 people with hip or knee OA received either 2.5 mg tanezumab subcutaneously every eight weeks; 5 mg tanezumab every eight weeks; or 500 mg naproxen, 100 mg celecoxib, or 75 mg diclofenac twice daily for 56 weeks. Patients were observed for 24 weeks after treatment. Tanezumab at 5 mg showed significant improvements in pain relief and physical function compared with NSAIDs.115 However, the participants’ overall assessment of their OA did not differ from the assessments by those who took NSAIDs. Of concern was the safety profile, as more than 7% of the high-dose tanezumab treatment arm developed rapidly progressive OA compared with the control group (1.5%).116

Another study of 2,700 people with knee or hip OA involved intravenous tanezumab at 5 or 10 mg every eight weeks with or without oral naproxen at 500 mg twice daily or celecoxib at 100 mg twice daily. Safety and efficacy endpoints were measured at week 16. Tanezumab improved pain and physical function parameters compared with NSAID use alone, while the combination of tanezumab and NSAIDs performed better than either alone. However, adverse events were more frequently reported with tanezumab and were highest in combination therapy. Researchers concluded that tanezumab may be effective in relieving pain associated with OA, but the safety outcomes required further study.117

Hyaluronic Acid Injections

Hyaluronic acid, a naturally occurring lubricant in the joint, may break down in people with OA. A doctor can directly inject hyaluronic acid into the affected joint to provide some extra cushioning.3 Research is mixed, as one review indicated a benefit118 while other research indicates that there is no clinically significant improvement in OA pain or function with hyaluronic acid injections.119 Hyaluronic acid injections tend to be fairly expensive and are not supported by consistent and robust evidence of benefit versus placebo and other therapies, so they are not generally recommended.91

MicroRNA Blockers

Researchers have discovered a molecule called microRNA-181a-5p that may contribute to inflammation and break down cartilage.120 This results in joint destruction, which is associated with OA. A recent study involving human and animal cell lines found that a microRNA blocker called LNA-miR-181a-5p ASO blocks this destructive molecule, protecting cartilage.121 Further research is required on this novel new mediator, which may play a role in modifying OA disease progression.

9 Dietary and Lifestyle Considerations

Diet

Dietary factors can modulate inflammatory tendency throughout the body. For example, a diet rich in pro-inflammatory omega-6 fatty acids and deficient in anti-inflammatory omega-3 fatty acids creates an environment conducive to systemic inflammation and oxidative stress, and has been linked to numerous age-related diseases, including osteoarthritis (OA).122-125 Research suggests the ideal ratio of omega-6 to omega-3 fatty acids is about 4:1; however, the typical Western diet has a ratio of closer to 20:1.124,126

Arachidonic acid is an omega-6 fatty acid that is a building block of several inflammatory mediators, which contribute to pain, swelling, and joint destruction.127,128 In an observational cohort study of 472 people who had or were at high risk for developing knee OA, those with higher blood levels of omega-6 fatty acids, particularly arachidonic acid, exhibited increased synovial inflammation. Also, those with higher blood levels of omega-3 polyunsaturated fatty acids had less cartilage loss in some parts of their knee joints.129

Studies also suggest the Mediterranean diet, which emphasizes anti-inflammatory foods such as fruits, vegetables, olive oil, nuts, whole grains, fish, moderate dairy, and red wine, may have a positive influence on symptoms of OA as well as diabetes, obesity, heart disease, and dementia.130 The Mediterranean diet includes foods high in omega-3 fatty acids, fiber, and essential vitamins and minerals.130 The diet also limits pro-inflammatory foods, such as red meat, saturated fat, and sugar.

In a six-week, prospective, open-label trial, 37 people with OA either consumed a plant-based diet of whole-foods or continued their customary diet. The intervention group showed significant improvements compared with the control group in self-reported energy levels, vitality, and physical functioning.131 In another randomized trial, 99 people with OA followed either the Mediterranean diet or their normal diet for 16 weeks. Analysis found that a biomarker of cartilage degradation (ie, sCOMP or serum cartilage oligomeric matrix protein) decreased in those who had followed the Mediterranean diet and there was improvement in knee and hip flexibility and movement.132

A 2016 longitudinal cross-sectional study including over 4,400 people at high risk for OA found that adherence to the Mediterranean diet was associated with lower BMI, reduced incidence of diabetes and fractures, and less arthritis pain and disability. Subjects also reported less depression and overall enhanced quality of life.133

Physical Activity

Physical activity offers many significant health benefits for OA patients, including promoting healthy weight and physical function.62 A regular physical activity program can help reduce stress, relieve pain, improve mood, and support movement.1

Research suggests exercise provides benefits comparable to analgesics and NSAIDs, but with fewer side effects.61 Exercise programs consisting of muscle strengthening and range-of-motion movements are associated with significant improvements in OA symptoms.60 Research also suggests aerobic activity can reduce pain and disability in people with OA of the knee.61,134 A literature review found that the benefits of exercise may be sustained for two to six months after treatment ended in some people.135 Another review of 10 randomized controlled trials found that land-based exercise programs reduced pain and improved function in people with hip OA.136 Adults, including those with OA, should aim for 150 minutes of moderate exercise or 75 minutes of vigorous exercise per week for optimal health.

Other Approaches

Several integrative therapies may help alleviate OA symptoms. therapies, such as tai chi or yoga, involve gentle exercise and deep breathing to reduce stress, relieve pain, and improve movement.3

Hot and cold therapy involves using heat and cold to relieve pain and reduce swelling in the joint by relaxing muscles and decreasing muscle spasms.3

Shoe inserts and assistive devices (eg, a cane) may help reduce pain when standing or walking by relieving pressure in the joint.3

A grabbing tool may make daily activities easier for those with OA in their fingers.3

For some with OA in their knee or hip, transcutaneous nerve stimulation may help relieve pain.3 This involves the use of a low-voltage electrical current to deliver electricity along nerve fibers.137

Acupuncture may also relieve pain symptoms in some people, although the benefits have not been validated in robust clinical trials.119

10 Integrative Interventions

Glucosamine and Chondroitin

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 needed to function properly.138 In laboratory models, glucosamine has been shown to possess anti-inflammatory effects, and research suggests at doses up to 1,500 mg, it may reduce the severity of osteoarthritis (OA) symptoms.139,140 In addition, preclinical research suggests that glucosamine may support cartilage integrity by modulating synthesis of cartilage structural components by chondrocytes.141 Glucosamine also plays a crucial role in maintaining joint lubrication.138

Chondroitin sulfate is a complex sugar molecule found in bone, cartilage, tendons, ligaments, and skin.142 Chondroitin sulfate helps cartilage retain water and add lubrication and resiliency. One study found that cartilage samples from arthritic joints had lower concentrations of chondroitin sulfate than samples from healthy joints.143 In laboratory studies, chondroitin sulfate reduced inflammation and promoted a healthy balance between breakdown and new formation of bone and cartilage.142 Laboratory studies of cartilage-producing cells suggest glucosamine and chondroitin sulfates may work in complementary fashion to protect cartilage.144

In a double-blind randomized study of 350 people with knee OA, 1,200 mg per day of chondroitin sulfate reduced pain.145 In another randomized, placebo-controlled, double-blind study of 162 people with hand OA, chondroitin sulfate decreased pain and improved function compared with placebo.146 A double-blind, randomized, controlled trial involving over 600 people with knee OA treated participants with either 200 mg celecoxib or 400 mg chondroitin plus 500 mg glucosamine three times daily for six months. The glucosamine and chondroitin group showed improvements in pain, stiffness, and joint swelling similar to those in the celecoxib group.147

A randomized controlled trial compared 1,200 mg per day chondroitin sulfate to 200 mg per day celecoxib 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. MRI measurements, however, showed that those taking chondroitin sulfate had significantly less cartilage volume loss.148,149 In a randomized clinical trial with 605 participants with OA of the knee, a group receiving a combination of 800 mg chondroitin sulfate plus 1,500 mg glucosamine sulfate daily had less joint space narrowing after two years than groups receiving placebo or either supplement alone.150

Omega-3 Fatty Acids

Omega-3 fatty acids (in particular docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) reduce inflammation and may help alleviate symptoms associated with OA. Research suggests omega-3 polyunsaturated fatty acids may also reduce markers of degradation in chondrocytes, and supplementation has been associated with reduced OA symptoms in studies.151 Animal research suggests omega-3 fatty acid supplementation improves daily activity performance and symptoms of physical disability in models and cases of OA.152,153 A cohort study involving 472 people with knee OA noted an inverse relationship between total omega-3 polyunsaturated fatty acid levels and patellofemoral cartilage loss.129

Krill oil is similar to fish oil, as they are both sources of omega-3 fatty acids. However, fish oil is typically sourced from fish such as tuna, sardines, or herring, while krill oil comes from krill, which are small animals similar to shrimp.154 In a double-blind, randomized, placebo-controlled, crossover study comparing the effects of krill and fish oil on plasma and red blood cell fatty acid profiles, 24 healthy volunteers took krill or fish oil (providing 600 mg of omega-3 polyunsaturated fatty acids) or placebo for four weeks, followed by an eight-week washout period, then switched to a different treatment regimen. The authors found that krill oil was well tolerated and safe, and that it could be more effective at increasing omega-3 levels and reducing the ratio of omega-6 to omega-3 fatty acids in the body.155

Krill oil is believed to reduce the inflammation associated with OA. Research utilizing animal models indicates that krill oil supplementation may improve cartilage structure.156 In a randomized double-blind study, 50 adults with mild knee pain received either 2 grams/d of krill oil or placebo for 30 days. The krill oil group reported improved symptoms, notably pain and stiffness, compared with placebo.157 A randomized, double-blind, placebo-controlled study to determine the effect of 4 grams of deep sea krill oil on knee pain in adults with mild-moderate OA is currently underway. The study is expected to be completed in July of 2020.158

Avocado/Soybean Unsaponifiables

Avocado/soybean unsaponifiables, a natural extract made from soybean oil and avocado oil, may reduce OA progression by modulating a number of pathways implicated in OA.159 Avocado/soybean unsaponifiables also have chondroprotective effects, reduce pain and stiffness, improve joint function, and possibly decrease dependence on analgesics.160 In a randomized, double-blind, placebo-controlled trial in 14 women with OA and arthralgia, avocado/soybean unsaponifiable treatment for four months resulted in a decrease in pain and improved quality of life, as well as reduction in pain medicine use, compared with placebo.161 In a prospective, randomized, double-blind study, 399 people with hip OA received either 300 mg/d of avocado/soybean unsaponifiable extract or placebo. The treatment group showed joint structure modification, indicating avocado/soybean unsaponifiables may play a clinical role in halting the progression of hip OA.162 Further research is warranted.

Topical Olive Oil

Olive oil, which is rich in phytonutrients, may help alleviate pain and inflammation when applied topically. In 2012, a four-week clinical trial compared topical virgin olive oil to topical piroxicam, an NSAID, among 30 women aged 40‒85 who had knee OA. Those receiving olive oil reported greater improvements in pain and physical function than those using piroxicam.163 In a randomized study involving 16 women and 14 men with knee OA, subjects were assigned to either a group that received topical extra virgin olive oil and an exercise program, a topical NSAID (ketoprofen gel) and exercise program, or a group that only performed the exercises three times per day. Treatments were carried out for five days a week for a two-week period. All groups demonstrated significant improvements in OA symptoms, with the olive oil and topical NSAID groups experiencing comparable results that were superior to exercise alone in relieving pain.164

Hyaluronic Acid

Hyaluronic acid is a building block for cartilage that is found primarily in the skin.165 Highly purified forms of hyaluronic acid are used in intra-articular injections to provide temporary relief from arthritis symptoms. When administered orally, hyaluronic acid has demonstrated pain relief and increased functionality in OA patients.166

In one study, 40 subjects with joint discomfort who were otherwise healthy consumed yogurt supplemented with hyaluronic acid or plain yogurt daily for 90 days. Subjects whose yogurt contained hyaluronic acid exhibited improved muscle strength at the knee joint.167 In another study, 20 subjects aged 40 or older with knee OA took 80 mg per day of a chicken comb extract providing 60% hyaluronic acid or a placebo for eight weeks. Participants who took the hyaluronic acid supplement experienced greater improvements in some measures of pain and function than those who took the placebo.168

Collagen

Collagen, which is the most abundant protein in mammals, is the main structural protein of connective tissues throughout the body (including bones and cartilage).169 Supplementation with collagen peptides, typically derived from hydrolyzed collagen, has been shown in clinical trials to ease symptoms of OA. In a randomized controlled trial that examined whether supplemental collagen peptides helped manage knee OA, participants were given supplemental collagen peptides or placebo for 13 weeks. People who took the collagen supplements reported improved quality of life and pain compared with those who took a placebo.170

Undenatured type II collagen is a natural form of collagen that can be derived from chicken cartilage.171 Some researchers have suggested that, upon ingestion, undenatured type II collagen interacts with parts of the immune system that reside in the gut, known as the gut-associated lymphoid tissue. Through this interaction, undenatured type II collagen may help train immune cells not to attack collagen peptides similar to those that may be exposed as cartilage breaks down in joints affected by arthritis.172,173 However, more research needs to be done to clarify the mechanism(s) by which type II collagen supplementation supports joint health.

A clinical trial involving 52 people with knee OA found that 5 mg of undenatured type II collagen, taken twice daily, improved pain, physical function, and stiffness after 90 days of treatment compared with 750 mg of glucosamine and 600 mg of chondroitin twice daily.174 In another randomized placebo-controlled trial, 39 people with knee OA received either 1,500 mg acetaminophen or 1,500 mg acetaminophen plus 10 mg undenatured type II collagen daily for three months. The acetaminophen and collagen group experienced greater improvements in joint pain with walking, function, and quality of life compared with acetaminophen alone group.175

In another multi-center, randomized, double-blind, placebo-controlled trial, 190 subjects with knee OA received either 40 mg of a preparation containing undenatured type II collagen, 1,500 mg of glucosamine and 1,200 mg of chondroitin, or placebo for 180 days. The group taking the collagen showed greater improvements in pain, stiffness, and function compared with the other groups.176

S-adenosyl-methionine (SAMe)

S-adenosyl-methionine (SAMe), a naturally occurring compound in the body that helps facilitate many metabolic reactions by serving as a methyl donor, has been studied in the context of OA, liver disease, and depression. Some evidence suggests it can provide pain relief and improve joint function by reducing inflammatory mediators and promoting cartilage synthesis.177 In a long-term multi-center trial involving approximately 100 patients with hip, knee, and spine OA receiving 600 mg SAMe for two weeks and then 400 mg daily for 24 months, SAMe improved clinical symptoms, such as morning stiffness and pain, as well as depressive symptoms.178

In a randomized, double-blind, crossover study, 61 people with knee OA received either 1,200 mg SAMe or 200 mg celecoxib daily for 16 weeks. At the end of the first month, celecoxib showed a greater reduction in pain scores. By the end of the second month, there was no difference between the treatment groups. Both groups also showed functional improvements in joint health. Researchers concluded that SAMe was as effective as celecoxib in managing symptoms of knee OA.179

Curcumin

Curcumin is an active component of turmeric root, a plant related to ginger that is grown throughout Asia, India, and Central America. Turmeric has traditionally been used to treat a variety of medical conditions and is commonly used today as a major ingredient in curry powder.180 Curcumin has potent anti-inflammatory properties,181 and curcumin extracts may help to relieve the pain and symptoms associated with OA.182

A randomized, double-blind, placebo-controlled trial involving 40 people with mild-to-moderate knee OA demonstrated that 1,500 mg/d of curcuminoids reduced pain and improved physical function scores compared with placebo.183 In another randomized, placebo-controlled, double-blind study, 50 people over age 40 with knee OA received either 180 mg/d curcumin or placebo. After eight weeks, the treatment group reported significantly less knee pain than the placebo group.184 Animal model studies also support the anti-inflammatory and chondroprotective effect of curcuminoids. In one study, the authors concluded that the extract may even modify the progression of OA.185

Boswellia

Boswellia serrata, a tree that grows in the mountains of India, Northern Africa, and the Middle East, has traditionally been used for religious and cultural purposes. Gum resin extracts of this tree have been shown to have potent anti-inflammatory properties.186 Boswellia may play a role in alleviating asthma, arthritis, and Crohn’s disease. Its biological activity is believed to be at least partly attributable to boswellic acids.181

Older randomized clinical studies have suggested a role for this extract in treating OA (at 333 mg of extract three times daily or 100 or 250 mg of a 30% boswellic acid extract).187,188 More recently, in a randomized, double-blind, placebo-controlled study involving 60 people with OA, a composition of boswellia (100 mg) or placebo was given for 30 days. The treatment group experienced significant improvements in pain and physical function, which was demonstrated as early as five days into the trial.189 Animal studies also indicate that both oral and topical boswellic acid treatment can be therapeutic for those with OA.190

Research suggests boswellia may be useful in combination with other herbal extracts. In a recent randomized double-blind study, 201 patients with OA received either placebo, 333 mg curcumin, or a 500 mg capsule containing 250 mg curcumin and 150 mg boswellic acid three times daily for 12 weeks. Physical function and pain were assessed, and those patients taking the combination therapy had the most pain relief.191 Another randomized study of 28 people with moderate OA compared a Curcuma longa and Boswellia serrata combination at 500 mg twice daily and 100 mg celecoxib twice daily for 12 weeks. There were greater improvements in reported pain, walking distance, and joint line tenderness in the boswellia-curcumin group compared with those that took celecoxib. The treatment was also found to be safe and well-tolerated.181

Ginger

Ginger is a tropical plant traditionally used both as a spice and to treat gastrointestinal issues. Some evidence suggests its anti-inflammatory properties may help combat OA.192 An older randomized, double-blind, placebo-controlled trial evaluated 261 people with OA of the knee who were experiencing moderate-to-severe pain. Subjects received either ginger extract or placebo twice daily, with acetaminophen allowed as rescue medication. The treatment group experienced greater reductions in knee pain after standing or walking 50 feet and required acetaminophen less frequently than the placebo group.193

In a randomized, double-blind, placebo-controlled trial, 120 people in moderate-to-severe pain from OA were divided into three groups: one group received 30 mg ginger extract (in two 500 mg capsules), another received placebo, and a third took three 400 mg tablets of ibuprofen daily. Ginger extract and ibuprofen were equally effective at improving symptoms, including pain and joint motion.194 In another randomized clinical trial, 204 people with knee OA took either 250 mg powdered ginger or placebo twice daily for six weeks. Those in the treatment group showed more significant improvements in pain and stiffness than the placebo group.195

White Mulberry (Morus alba) and Cutch Tree (Acacia catechu)

White mulberry (Morus alba) is a fast-growing type of mulberry tree, and extracts of the leaves, fruit, and bark of this tree have been used traditionally to treat sore throats, high blood pressure, and diabetes, among other conditions.196 Animal research suggests white mulberry in combination with cutch tree (Acacia catechu) extract may minimize bone damage, improve joint pain and inflammation, and support the integrity of joint cartilage by slowing the progression of cartilage degeneration during OA.197 Cutch tree is a thorny tree found in Thailand and India. The wood and bark of this tree are rich in catechin, a flavonoid with anti-inflammatory and tissue-protecting properties.197 Extracts have traditionally been used to treat sore throats and diarrhea.

In a recent randomized, double-blind, placebo-controlled trial, 135 people with knee OA received either a proprietary blend of cutch tree and white mulberry (400 mg/d), glucosamine (1,500 mg/d) and chondroitin (1,200 mg/d), or placebo for 12 weeks. All three study arms reported pain relief at 12 weeks, but those taking the herbal combination reported a greater reduction in pain compared with placebo and the other treatment group at day 56. Researchers also examined C-terminal cross-linking peptide (CTX-II) levels, which measures the breakdown of collagen, and therefore is a marker of joint damage. Those taking the herbal extract showed a decrease in urinary levels of CTX-II, which indicates a reduction in OA progression over time. The placebo group, by contrast, showed higher CTX-II levels, while there was no change in the glucosamine-chondroitin group.198

An animal model study found that the combination of these two herbs (at doses of 100‒300 mg/kg) in mice with pain and inflammation of the paw was as effective as ibuprofen at reducing pain and swelling when taken at the highest dose.199

Chinese Skullcap (Scutellaria baicalensis)

Chinese skullcap (Scutellaria baicalensis), a flowering plant native to China, Russia, Korea, and Mongolia, has traditionally been used to treat arthritis, hepatitis, and cancer, and may promote cardiovascular health.200 Preclinical studies indicate that when used in combination with cutch tree extracts, Chinese skullcap promotes joint health and reduces inflammation.201

In one randomized, placebo-controlled, double-blind pilot study, 52 people with knee or hip OA received either a placebo, 200 mg/d celecoxib, or 250 or 500 mg of a combination of Chinese skullcap and cutch tree extracts. Subjects were followed in 30-day increments for up to 90 days to assess their pain, stiffness, and function. At 30 and 90 days, both doses of the herbal combination were more effective at pain reduction than celecoxib, while the higher dosage of the herbal combination was superior to placebo by day 90. Celecoxib was not more effective at reducing pain than placebo by days 30 or 90.202 Physical function was improved in the herbal supplement and celecoxib groups at all time points, but the supplement was superior to the drug by day 90. Those taking the higher dose (500 mg) of the herbal combination showed less physical impairment compared with the other treatment arms.202

In another randomized double-blind study involving 79 men and women with mild-to-moderate OA, participants received either 500 mg of an herbal combination of Chinese skullcap and cutch tree extracts (UP446) or 440 mg/d of naproxen for one week. Researchers wanted to determine if the herbal mixture could improve pain and physical activity. The group taking UP446 demonstrated less pain and increased range of motion, while both treatments reduced stiffness.203

Vitamin E

Vitamin E, a fat-soluble vitamin and potent antioxidant, also plays a vital role in immune health. It is found naturally in nuts, seeds, and leafy green vegetables.204 Vitamin E may help prevent OA due to its anti-inflammatory effects. A recent literature review of clinical and preclinical studies demonstrated that vitamin E reduced oxidative stress in cartilage cells, while animal studies showed vitamin E prevented cartilage degradation. Some human observational studies have linked low vitamin E levels with OA.205 Another review of preclinical studies suggested vitamin E may slow the progression of OA by maintaining skeletal muscle and modulating the expression of genes involved in OA pathogenesis.206

In a randomized double-blind study, 15 dogs with OA received either 400 IU vitamin E or placebo daily for 55 days. Improvements in lameness, pain, cartilage lesions, and inflammatory markers in the synovial fluid were noted in the treatment group.207

A study involving 23 people with knee OA found that the concentration of vitamin E in the synovial fluid was inversely related to severity of OA.208 In another study, 40 healthy subjects and 40 people with knee OA received either 200 mg vitamin E or placebo for three months. The group taking vitamin E had lower levels of inflammatory markers, which may protect against deterioration of the joints caused by oxidative stress.209

Vitamin D

Vitamin D is a fat-soluble vitamin that plays a role in bone health, cell growth, immune function, and fighting inflammation. Sources of vitamin D include sun exposure and foods such as fatty fish, beef liver, cheese, and egg yolks.210

In a randomized controlled trial, 103 people with knee OA who were deficient in vitamin D received 60,000 IU vitamin D or placebo once daily for 10 days and then 60,000 IU once a month for 12 months. Those in the treatment group reported decreased pain and improved funciton.211 A case-control study that examined the relationship between dietary nutrients and knee OA found that lower intakes of vitamin C and D were significantly associated with OA. While more research is needed to clarify the role diet plays in OA onset and progression, low intakes of vitamins C and D may be a risk factor.212

A recent meta-analysis of four randomized clinical trials involving 1,136 people with knee OA found that supplementation with over 2,000 IU vitamin D decreased pain and increased function, but did not prevent cartilage loss.213 In another study, 340 subjects with knee OA had their vitamin D status measured at baseline, three months, six months, 12 months, and 24 months. The group with consistently sufficient vitamin D status had less tibial cartilage loss and improved physical function compared to those with insufficient levels of vitamin D.214

Pycnogenol (Maritime Pine Bark Extract)

Pycnogenol, derived from the bark of French maritime pine trees, is believed to have anti-inflammatory and antioxidant properties.215 Preclinical studies indicate pycnogenol may inhibit proteases (enzymes that degrade cartilage), and three clinical studies demonstrated that it reduced pain and stiffness.216

A randomized pilot study involved 33 people with severe OA receiving either 100 mg pycnogenol twice daily or no treatment three weeks before knee arthroplasty. Researchers then examined cartilage homeostasis markers and mediators of inflammation in the blood serum and synovial fluid. Pycnogenol downregulated genes related to cartilage degradation and decreased inflammatory markers.217

Bromelain

Bromelain is a mixture of enzymes found in the stem and fruit of pineapples that has anti-inflammatory properties. It has been used to combat nasal swelling and inflammation and muscle soreness.218 Recent evidence suggests it may help relieve symptoms of OA. In a randomized, single-blind, controlled trial, 40 people with knee OA were given 500 mg bromelain or 100 mg diclofenac for four weeks. Researchers found that both treatment arms experienced improved pain, stiffness, and function compared with baseline values.219

In an observational, prospective, open-label study, a combination of devil’s claw, turmeric, and bromelain was given to one group of people with chronic OA pain and another group with acute OA pain (a total of 42 subjects). Treatment involved two 650 mg capsules three times daily for 60 days for those in chronic pain and 650 mg capsules twice daily for 15 days for those in acute pain. Both groups experienced improvements in joint pain.220

Sulfur-containing Compounds

Sulfur-containing compounds, including methylsulfonylmethane (MSM), may reduce inflammation and pain and inhibit the degeneration associated with OA. An animal model study found that MSM reduced cartilage degeneration.221 In a prospective, randomized, double-blind, placebo-controlled trial with 49 subjects with knee OA, 1.125 grams of MSM three times daily for 12 weeks improved OA pain and physical function.222 In a randomized, double-blind, placebo-controlled trial, 50 people with knee OA pain were given either 3 grams MSM or placebo twice daily for 12 weeks. MSM supplementation decreased pain and reduced physical impairment compared with placebo.223

Another randomized, double-blind, placebo-controlled study involving 100 subjects with hip and/or knee OA found that 6 grams MSM daily for 26 weeks decreased pain and improved functional performance compared with placebo.224 In another trial, 37 people with knee OA received two tablets containing 500 mg glucosamine, 400 mg chondroitin sulfate, and 250 mg MSM three times daily. Patients who completed the study reported improvements in pain and function and gradual improvements in joint mobility.225 Further research is needed at lower dosages and with larger sample sizes to determine if sulfur-containing compounds may be useful in treating OA.

Angelica gigas Nakai

Angelica gigas Nakai is a plant found in Korea, Japan, and China whose root extracts have long been used in traditional medicine.226,227 Modern research has shown that the roots of Angelica gigas contain anti-inflammatory compounds called decursin and decursinol angelate.228,229 These Angelica compounds have been shown to modulate several inflammatory pathways.229 Of particular interest, angelica-derived compounds have been shown to modulate COX-, MMP-, and NfκB-related pathways, all of which participate in inflammation related to arthritis.230-232

Green Tea Extract

Green tea extract contains polyphenols, the most active of which is epigallocatechin gallate (EGCG). These polyphenols are believed to be potent antioxidants with many health benefits, including reduced risk of some cancers.233 Evidence suggests green tea extract may combat the inflammation associated with OA.234 In a randomized open-label clinical trial involving 50 adults with knee OA, subjects received either placebo or green tea extract and diclofenac tablets for four weeks. Those in the treatment group had improved pain and joint function parameters, but the authors called for more research of longer duration and larger sample size to determine the role green tea extract plays in joint health.235

Boron

Boron is a trace mineral that supports bone and muscle health as well as decreasing inflammation, joint stiffness, and other symptoms associated with OA.236 A controlled study involving 43 people with knee OA determined that boron levels were significantly lower in patients with OA compared with healthy controls. Lower serum boron levels were also associated with increased OA duration and severity.237 More research is required to have a greater understanding of the role boron plays in combating inflammation and OA.

Cordyceps sinensis and Cordyceps militaris

Cordycepin is an active compound isolated from a fungi that infects caterpillars (Cordyceps sinensis and Cordyceps militaris). Research has shown that cordycepin and other constituents from Cordyceps species may block inflammation via a different mechanism than most other anti-inflammatory agents; Cordycepin affects a final step in the production of mRNA, known as polyadenylation, so it may be useful in patients who have not experienced pain relief from traditional painkillers.238 A cell study involving human chondrocyte cells demonstrated that cordycepin has anti-inflammatory activity.239 In rodent models, cordycepin reduced cartilage damage and pain behaviors.238

Peony Root Extract

An extract from the root of peony, a fragrant flowering plant that can live for many years, has traditionally been used to combat inflammation and promote immune health.240 Apocynin and paeonol (APPA) are plant-based compounds from the peony that have anti-inflammatory properties. The combination of these compounds may relieve pain and improve joint function.241 A randomized controlled trial involving 55 dogs compared treatment with 40 mg/kg APPA, 0.1 mg/kg meloxicam, or placebo for four weeks. The APPA group had significantly better function compared with placebo. The authors concluded that APPA may be an alternative to NSAIDs, although further research is warranted.242

Honeybee Products

Honeybee products, including honey, bee pollen, royal jelly, beeswax, bee venom, and propolis, have long been used for their anti-inflammatory, antioxidant, anti-bacterial, and anti-fungal properties. Some believe these products may inhibit tumor growth and reduce inflammation associated with arthritis.243 In a recent controlled animal study, 50 male albino rats were divided into five groups: a control group, an arthritic group with no treatment, arthritic group treated with honey, arthritic group treated with royal jelly (a substance secreted by worker bees), and arthritic group treated with venom (a substance secreted by worker bees to defend the hive). Royal jelly, honey, and venom helped alleviate symptoms of OA and improve hematological and biochemical parameters in the treatment groups.244 Human research is needed to assess the potential of honeybee products in the clinical management of OA.

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