Introduction to Chondroprotection

Not a day goes by when I am not asked about what patients can do to alter the arthritis changes that affect their joints resulting in pain and impairment in their daily lives.  Below is an article from an online reference that explores the issue of protecting what cartilage remains in the arthritis joint. Introduction Osteoarthritis is a common, chronic, and debilitating disease. There are few effective treatments, with joint replacement a primary exception. A joint replacement, however, is costly to the healthcare system, and the procedure carries risk. The remaining therapies are moderately effective at best, and none have been clearly demonstrated to alter the natural history of the disease. For this reason a large focus of drug development in osteoarthritis is identification of a disease modifying osteoarthritis drug (DMOAD) that is safe and provides some structural modification. Several therapeutic targets have been identified, with the most frequent target involving cartilage. The term chondroprotection is now used to categorize these agents. We will review briefly the potential molecular targets, the agents thus far developed, and the evidence for their use. Potential Targets There are a number of molecular targets for DMOAD development. These include inhibiting molecules that break down cartilage, such as Interleukin-1(IL-1), aggrecanases, and matrix metalloproteinases (MMPs); components of healthy cartilage and synovial fluid, such as glucosamine, chondroitin sulfate, and hyaluronan; and promoters of cartilage growth and repair (TGFβ, such as bone morphogenic protein.) Doxycycline and Diacerein Tetracyclines appear to be inhibitors of several MMPs, including collagenase and gelatinase, which are known to be upregulated in arthritic cartilage. In animal models and in some human trials, doxycycline appeared to have a modest benefit. In one human study, the rate of joint space narrowing in the group receiving doxycycline was 33% less, although there was no effect on pain. Diacerein, available only in Europe, has an active metabolite that inhibits IL-1β, a known component of immune response in osteoarthritis. A recent systematic review showed a modest pain benefit in osteoarthritis.  The data on structural benefits, however, are weak. Hyaluronan Hyaluronan is an integral component of healthy cartilage and synovial fluid in joints. It serves numerous functions within the joint and has been identified as an important molecule in the pathogenesis of osteoarthritis. Synthetic hyaluronan (what I often refer to as "joint lubricants" or viscosupplements) has been available as a therapeutic agent with the potential to improve pain, joint function, and joint structure. A recent meta-analysis comparing hyaluronan in intra-articular corticosteroids showed a relative pain benefit with hyaluronan; another comparing hyaluronan to placebo confirmed a modest but statistically significant benefit for hyaluronan. Early data suggest that there may be some disease-modifying effects as well, but larger studies are needed. Vitamins Nutritional micronutrients are known to be important for cartilage health. Numerous micronutrients have been proffered as therapies, including selenium, beta carotene, and vitamins C, D, E, and K.  The data supporting their use are limited, and toxicity at high doses is a concern for several, including vitamin D. Herbals  Several herbal remedies for knee osteoarthritis have been advocated, including avocado/soybean unsaponifiables (ASU) and rose hip extracts. ASU has a variety of potential effects, including promotion of immunomodulation and cartilage synthesis. It has been shown to have modest pain benefit compared with placebo in knee osteoarthritis. Rose hip is thought to have antioxidant properties due to high vitamin C and lycopene content, and it has been shown to improve pain in knee osteoarthritis in a meta-analysis of several small studies.  Data on structural modification are lacking for both of these agents. Glucosamine and Chondroitin Glucosamine and chondroitin are important components of cartilage. Increasing the level of these substrates could, theoretically, aid in cartilage repair or slow cartilage destruction. Their use as osteoarthritis treatment has received a great deal of attention and controversy. Although several studies have shown a symptomatic benefit, a large nonindustry-sponsored study demonstrated no benefit for knee osteoarthritis.  Meta-analyses support a modest pain benefit, but the results are heterogeneous. Evidence that these agents modify structure shows a modest, but statistically significant benefit, but the results were heterogeneous, making interpretation difficult. Clinical Guidelines Clinical guidelines vary for each of the agents currently available. Several support the use of hyaluronan, glucosamine, and chondroitin, while the American Academy of Orthopaedic Surgeons does not recommend use of either.  The remaining agents have not been mentioned in clinical guidelines due to insufficient data. The clinician must balance the relative safety of these agents, the desires of the patient, and the emerging evidence when recommending them. Summary Development of a DMOAD that demonstrates halting or slowing of structural damage in osteoarthritis is a major focus of research efforts. Some have been found to improve pain in osteoarthritis, but the data for structural modification are relatively weak. More evidence will be required. Additionally, we must consider whether to accept structural benefit without a pain benefit when designing new studies. Lastly, identification of DMARDs likely requires a more sensitive biomarker than the X-rays used in most of these studies. Reference

A very nice summary.


Thanks,


JTM, MD

What causes tendon wear and tear called tendinopathy?

I am frequently asked about the cause of those wear and tear changes we see in the tendons of the rotator cuff and elsewhere in the body.  In general, I explain it is a result of those age related changes that we all experience in life.  A study below explores that topic further and may shed some light on why some patients who may not be active develop tendon problems.  It is translated from orthopedics to English below.


Conventional thinking says that tendinopathy—defined as chronic tendon degeneration—is due to tendon overload, leading to microscopic collagen fiber failure and a failed healing response.  It also says that inflammation is not part of the pathologic process, because inflammatory cells are not seen in biopsies obtained at the time of surgery in patients with tendinosis.

Fig. 1 Histologic appearance of tendinosis tissue shows a characteristic pattern of fibroblasts and vascular, atypical, granulation-like tissue. Courtesy of Scott A. Rodeo, MD

But according to recent studies tendinopathy may be due to mechanical understimulation of tendon cells, rather than tendon overload, and that abnormal differentiation of tendon stem cells may play a role in the development of the condition.

In addition, he noted, there may be an important interaction among load, inflammatory mediator expression, and matrix metalloproteinase (MMP) expression at the microscopic level.

Tendon overload vs. “underload”

According recent studies have demonstrated that stress deprivation leads to increases of collagenase (which breaks down collagen in tendons) expression and a loss of tendon cells.

In addition, he noted, there may be an important interaction among stress on the tendon  inflammation, and matrix metalloproteinase (MMP) expression at the microscopic level. MMP breaks down tendon tissue.

This collagenase production may weaken the tendon and put more of the extracellular matrix at risk for further damage during subsequent loading.

More than a decade of research has shown that microscopic collagen fiber failure may play an important role in the development of tendinopathy.

When microscopic collagen fiber failure occurs, cells in the injured area are exposed to less load; they are deprived of stress. This leads to upregulation of interleukin-1 beta (IL-1β), which is an inflammatory mediator, as well as upregulation of MMPs. The end result is decreased structural and mechanical properties.

Stem cells

Stem cells may also play a role in the development of tendinopathy.  Tendon stem cells can differentiate into tenocytes, which lead to tendon repair, or into osteocytes or adipocytes.

Researchers have found that treating tendon stem cell cultures with prostaglandin E2 (PGE2) induces both adipogenesis and osteogenesis.  As a result, the number of tenocytes is reduced and fatty and calcified tissues are produced, as seen in tendinopathy.

An analysis of the effect of mechanical load on tendon stem cells found that when tendon stem cells were stretched, they could continue to differentiate into tenocytes with 4 percent strain. At an 8 percent strain, however, some of the cells differentiated into adipogenic, chondrogenic, and osteogenic lineages. “So, mechanical load clearly plays a role in these pathways,” he concluded.

Inflammatory mediators

The expression of inflammatory mediators may occur in the early stages of tissue injury. MMPs play an important role in tissue degradation and matrix remodeling and that inflammatory mediator expression can increase MMP activity.

Imbalances between MMPs and their inhibitors have been implicated in the underlying origin of tendinopathy.

Researchers conducted a study in which they biopsied rotator cuff synovium and bursa at the time of rotator cuff repair.  They found increased expression of MMPs and inflammatory mediators.  Increased synovial inflammation and tissue degradation correlated with cuff tear size.

Implications for treatment

Eccentric exercise may work via mechanical stimulation, leading to modulation of inflammatory mediators and a shift in the balance of MMPs and catabolic and anabolic gene expression.

MMP inhibitors have the potential to prevent ongoing tendon degeneration.

Some studies have shown that MMP inhibitors can prevent the matrix degeneration that occurs with stress deprivation in rat tail tendon.  In addition, MMP inhibitors prevented loss of material properties associated with stress deprivation.

Therefore, new agents that block either inflammatory mediators or MMPs may be effective in treatment of tendinosis.

Bottom line

• Recent studies have found that mechanical understimulation of tendon cells, rather than tendon overload, may cause tendinopathy and that abnormal differentiation of tendon stem cells may play a role in its development.
• Research also indicates important interactions occur among load, inflammatory mediator expression, and MMP expression at the microscopic level.
• Future studies involving the role of mechanical load may suggest ways to modulate the loading environment to stimulate tissue repair.
• MMP inhibitors may have the potential to prevent ongoing tendon degeneration.

Additional resources

Treating tendinopathy with PRP
Tendinopathy treatment tips

AAOS Now
May 2011 Issue
Reference




Thanks,


JTM, MD

Knuckle Cracking and Hand Osteoarthritis

I am frequently asked by patients if knuckle cracking will lead to arthritis of the hand.  It is a question asked by mothers whose sons (usually) have the annoying habit of cracking their knuckles. I have always indicated that there is no connection between the cracking of knuckles and hand arthritis but now there is a study that has  proven that.  Sorry Mom.

From Journal of the American Board of Family Medicine

Background: Previous studies have not shown a correlation between knuckle cracking (KC) and hand osteoarthritis (OA). However, one study showed an inverse correlation between KC and metacarpophalangeal joint OA.


The authors conducted a retrospective case-control study among persons aged 50 to 89 years who received a radiograph of the right hand during the last 5 years. Patients had radiographically proven hand osteoarthritis (wear and tear arthritis) OA, and controls did not. Participants indicated frequency, duration, and details of their knuckle cracking behavior and known risk factors for hand OA.

Results: The prevalence of knuckle cracking among 215 respondents (135 patients, 80 controls) was 20%. When examined in aggregate, the prevalence of OA in any joint was similar among those who crack knuckles (18.1%) and those who do not (21.5%; P = .548). When examined by joint type, knuckle cracking was not a risk for osteoarthritis in that joint. Total past duration (in years) and volume (daily frequency × years) of knuckle cracking of each joint type also was not significantly correlated with OA at the respective joint.

Conclusions: A history of habitual KC—including the total duration and total cumulative exposure—does not seem to be a risk factor for hand OA.

Introduction

Knuckle cracking (KC) is a behavior that involves manipulation of the finger joints that results in an audible crack, and it is often done habitually. Prevalence estimates vary between 25% and 54%, depending on the population studied.
The behavior can become habitual because of immediate joint tension release and increased joint range of motion.


During an attempt to crack a knuckle, the joint is manipulated by axial distraction, hyperflexion, hyperextension, or lateral deviation. This lengthens part or all of the joint space and greatly decreases intra-articular pressure, causing gases that have dissolved in the synovial fluid to form microscopic bubbles, which coalesce. When the joint space reaches its maximum distraction (up to 3 times its resting joint space distance), joint fluid rushes into the areas of negative pressure. The larger bubbles suddenly collapse into numerous microscopic bubbles, leading to the characteristic cracking sound. The maneuver leaves the joint space wider than it had been and synovial fluid more widely distributed. The stretching of joint ligaments required to produce the widened joint space also leaves the joint with greater range of motion. It typically takes at least 15 minutes for the joint to be able to be cracked again because of the time required for the microscopic bubbles to fully dissolve into solution and for the joint space to retract back to its resting position.
 
Common urban legend suggests that knuckle cracking will lead to arthritis of the hand joints. Adverse effects of knuckle cracking have been cited but are not well supported in the medical literature. Case reports of acute joint damage from unusually vigorous and deviant knuckle cracking attempts are rare. 

 
The amount of force required to crack a knuckle has been shown in vitro studies to exceed the energy threshold that can lead to articular cartilage damage.

Based on these facts, it is logical to theorize that habitual knuckle cracking may lead to gradual thinning of articular cartilage and eventual clinical osteoarthritis (OA). However, this claim remains unsubstantiated in the medical literature. The cavitation effect of intra-articular bubble formation and collapse is also mechanically similar to cavitation of ship propellers, a process that has been shown to produce wear on the propeller surfaces.

A MEDLINE search using keywords "joint cracking" and "knuckle cracking" revealed 2 studies that addressed the incidence of OA in knuckle crackers. The first looked at 300 randomly selected persons older than age 45 (mean age, 63 years). Participants were assessed by a questionnaire and a physical examination of the hands. Those who cracked knuckles were more likely to have hand swelling and reduced grip strength, but the prevalence of hand OA was 16% among those who cracked knuckles and those who did not.  The investigators did not specify which joints were cracked nor which joints were affected with OA.

Another study involved examination of the hand radiographs of 28 nursing home residents (average age, 78 years). Participants were asked to recall if they currently or previously cracked knuckles, but investigators did not specify which joints. In this study, knuckle cracking of the MCP (first knuckle of the fingers) joint was found to be negatively correlated with OA. The prevalence of KC in the 6 persons with OA of the MCP joint was 17%, whereas the prevalence of KC in the group without OA of the MCP joint was 64%. This suggests that KC may be associated with a lower prevalence of OA at the MCP joint.
 
Though somewhat useful, neither of these studies specified which joints participants cracked. Neither quantified the duration or frequency of KC, both of which could have correlations with the presence or absence of OA. Duration and frequency may be relevant because, based on the mechanical logic above, the more times that the maneuver is performed, the more the risk of mechanical wear on affected surfaces would, theoretically, increase.

OA of the hand increases in prevalence and severity with age.The prevalence of symptomatic hand OA has been reported to be 22% in persons age 71 to 100 years among the general population. Other risk factors include prior joint trauma, family history of hand OA, and history of heavy labor involving the hands. Those with hand OA have reduced maximal grip strength, more difficulty writing and handling small objects, and more difficulty carrying objects. Given this burden of suffering from hand OA and the lack of curative or disease-modifying treatments, factors that potentially protect against OA warrant further investigation. One such factor is knuckle cracking.

This study represents the most comprehensive evaluation to date of habitual KC and any association with hand OA. Our findings support the conclusions of 2 previous studies. It confirms that the presence of knuckle cracking is not associated with hand osteoarthritis. This is the first study to correlate the duration and the total volume of previous knuckle cracking with OA, in addition to the presence or absence of knuckle cracking. Participants described how frequently each day they crack each type of knuckle and for how many years they have been doing it. First, our results indicated that the duration of KC has no correlation to the presence of OA in the DIP, PIP, and MCP joints. 

They also calculated "crack-years," which roughly quantified the total amount of exposure to this behavior. This allowed investigation of a possible "dose–response" relationship between the mechanical effects of knuckle cracking and OA. Again, when looking at knuckle cracking of each joint type, the authors found no significant correlation of "crack-years" with OA in the respective joint.

What we do not know yet are all the reasons why people crack their knuckles and the effect this has on their joints in the long term. Though some people may start knuckle cracking because of joint symptoms, patients with OA in our study started knuckle cracking long before the onset of OA symptoms. Some people may crack knuckles because of the sense of relief it can bring, some because of habit, and some from both. People may stop knuckle cracking when hand symptoms appear either because of fear of what knuckle cracking might do to their joints or because knuckle cracking becomes too uncomfortable. 


What we can conclude, however, is that, in these cohorts of persons aged 50 to 89 years, a history of habitual KC—including the total duration and total cumulative exposure to KC—does not seem to be a risk factor for hand OA. 


Reference: Translated from Orthopedics to English for better patient understanding by JTM

Thanks,

JTM, MD