Biologic Treatments for OA: A Sports Medicine Perspective

Sideline Consult

Bert R. Mandelbaum, MD, DHL (Hon)


July 15, 2015

A Comprehensive Approach to Knee Osteoarthritis

To be a good surgeon these days, you can't just focus on what you do with your knife.

I thought of that when reading the recent editorial in the British Journal of Medicine against performing knee arthroscopy for degenerative joint disease in middle-aged and older patients.[1] Based on a meta-analysis of nine studies,[2] the editorial combines statistics on patients in different stages and circumstances of knee degeneration and concludes that surgery for knee pain provides hardly any benefit.

The study makes an important point. For those older adults who never plan to return to vigorous activity, knee arthroscopy as an isolated intervention may not have significant benefit.

But many of the studies on which its findings are based are dated, and the study oversimplifies complex questions. In the real world, knee problems come in all shapes and sizes. Patients range from young to old, from within their proper weight range to obese, and from out of shape to well-trained, and they have different levels of arthritis.

In addition, the study disregards a wide variety of interventions, including exercise and weight loss, and a spectrum of biologic treatments.

As part of a comprehensive approach to degenerative diseases of the knee, sports medicine specialists must play an active role before injuries take place. Randomized controlled trials have shown that systematic neuromuscular training programs, such as the FIFA 11+,[3] can reduce the risk for knee injury by 50% or more.

But no regimen can completely eliminate knee injuries. And we know that meniscus and anterior cruciate ligament (ACL) injuries substantially increase the risk for long-term osteoarthritis.[4,5]

We are beginning to understand that these injuries cause a catabolic cascade of matrix metalloproteinases and cytokines that contribute to the development of osteoarthritis.[6]

Biologic Treatments Offer New Hope

That's why I'm excited about new findings that have the potential to substantially slow this degeneration, decrease pain, and improve joint function and performance.

Hyaluronic acid. Twenty years of research suggests that viscosupplementation with hyaluronic acid can enhance the function of the joint by improving lubrication, inhibiting inflammation, promoting cartilage matrix regeneration, and stimulating endogenous hyaluronic acid synthesis. This leads to regeneration of the physiologic joint environment.

A randomized trial showed a small clinical improvement with hyaluronic acid, though less than that seen with corticosteroids.[7]

On the other hand, a systematic review concluded that viscosupplementation has comparable efficacy to nonsteroidal anti-inflammatory drugs, with long-term benefits comparable with those achieved with intra-articular corticosteroid injection.[8]

Platelet-rich plasma. Platelets bring to the injury sites 1500 proteins that are responsible for stimulating proliferation of new cells and collagen and suppressing inflammation and cell death. Recent studies suggest that platelet-rich plasma injections may aid in healing after joint surgery and show benefit as treatment for osteoarthritis.[9,10]

Stem cells. Stem cell therapy may also prove useful in reducing the risk for osteoarthritis after knee injuries. But it's hard to get the right kind of stem cells to the right place and make them do the right thing. It remains to be seen whether any kind of stem cell treatment offers any additional benefits over platelet-rich plasma injections, which recruit stem cells to the healing joint.[9]

Interleukin receptor antagonists. Interleukin is a catabolic cytokine that breaks down cartilage. Early trials of interleukin receptor antagonists have not been conclusive, but researchers remain keenly interested in this area.[11]

Glucosamine and chondroitin. Glucosamine and chondroitin are found in the healthy cartilage matrix and affect proteoglycan synthesis. They act synergistically to reverse damage and promote repair at plasma concentrations found after oral ingestion,[12] and they may be particularly effective in osteoarthritis patients with moderate-to-severe knee pain.[13]

In a randomized controlled trial in 200 patients, 1500 mg glucosamine sulfate was as effective as 1200 mg ibuprofen in knee osteoarthritis patients but with fewer adverse effects.[14] A meta-analysis of seven trials involving 372 patients found that chondroitin significantly reduced pain and improved joint function vs placebo control.[15]

Hormone replacement. Estrogen and testosterone both protect cartilage. Because sex hormone production declines at different ages in men and women, men start to get osteoarthritis at about age 70 years and women at about age 50 years. One of the things that affect the number of sex hormone receptors in the cartilage is ACL injury.

Estradiol reduces levels of matrix metalloproteinases and increases production of type-2 collagen and aggrecan. Estrogen deficiency is also associated with increased reactive oxygen species and activates nuclear factor-κB and proinflammatory cytokine production.[16]

A 10-year study in 2621 women showed that higher concentrations of estradiol were associated with a lower incidence of total knee replacement, while higher levels of androstenedione were linked to a lower risk for total hip replacement.[17] In one study, cartilage volume increased 7.7% in 5 years with estrogen replacement therapy.[18]

But androgenic hormones also play a role. The balance of hormones is very critical, depending on age and the state of premenopause and perimenopause. The ideal balance is still being worked out.[16]

It's important to note the risks of hormone therapy as well. Estrogen replacement therapy has been linked to breast cancer.[19] And some research suggests that testosterone supplementation can increase the risk for pulmonary embolism and osteonecrosis.[20]

In the next decade, I expect we will start using sex hormones inside the joint to avoid some of the risks of systemic supplementation. For now, we are a long way from knowing the exact cocktail of adjuvants that will most benefit each patient with a knee injury.


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