Hyaluronic Acid or Glucocorticoids?

By December 2, 2022 No Comments

Osteoarthritis is the most common form of arthritis in the United States. OA is estimated to affect 54.4 million or 23% of the adult population

Osteoarthritis commonly affects the

  • Knee-41% involvement
  • Hands- 30%
  • Hips-19%
  • Other-10% (Spine, Shoulder, Elbow, Wrists, Ankle, Feet)


The etiology of osteoarthritis is a complex usually multi- causative

  • Genetic
  • Mechanical Stress to the Joint
  • Ethnicity
  • Nutritional
  • Sex
  • Prior Trauma or Surgery

Treatment Modalities

  • Weight Control
  • Exercise
  • Drug Therapy such as NSAID
  • Steroids
  • Opioids
  • Platelet Rich Plasma
  • Intra-articular steroids
  • Viscosupplementation
  • Surgery

Pain is the common major symptom of osteoarthritis. The pain is caused by the cartilage degradation and is mediated by cytokines, growth factors, and macrophages. The pain in advanced OA is caused by macrophages infiltrating the synovium of the joint. These activated macrophages then release pro-inflammatory cytokines causing inflammation and more pain. There are three important mediators in this process,

  • Interleukin-1beta
  • Interleukin-6
  • Nerve Growth Factor

Interleukin-1beta (IL-1b) induces bone erosion in inflammatory sites by activating osteoclastic activity. It is a key cytokine involved in the activation and survival of osteoclasts.

Interleukin-6 (IL-6) is a proinflammatory cytokine that interacts with the cells involved in bone remodeling. IL-6 may indirectly promote or diminish osteoblastic activity.

The Nerve Growth Factor (NGF) belongs to a group of proteins called neurotrophins. NGF regulates many physiologic mechanisms that have neurotrophic, metabotropic or immunologic effects.

These three markers are currently considered promising clinical markers for monitoring the progression of OA.

First Line Therapy for OA

After weight control and exercise programs including physical therapy, drug therapy is usually indicated and initiated.

The pharmacological approach in symptomatic OA mainly focuses on the control or improvement of symptoms, pain and reduction in the underlying inflammation. The goal is to provide analgesia, increase the quality of life and avoid surgery. Drugs in this class do little to rejuvenate the damaged tissues.

Recently in Rheumatoid Arthritis, the pharmacologic therapy has been broadened by the inclusion of DMARDS. These disease modifying compounds target different pathways in the overall disease process. However, OA has multiple pathways that interconnect and the target or blockage of one pathway does not seem to be a totally effective treatment.

NSAID are the primary drugs used for OA but the reported side effects are of major concern especially with other disease process. Before starting therapy, each patient should be assessed for other medical conditions that can be adversely affected by the use of these drugs.

  • Hypertension
  • Cardiovascular Disease
  • Heart Failure
  • GI Bleeding or Ulceration
  • Kidney Disease
  • History of Bleeding or Blood Dyscrasias
  • Liver Disease

Due to the drug interaction with many other diseases, analgesics have been instituted in many cases but the use of this class of drugs is addicting and should be used only when all other pharmacological options have been considered and failed.


Glucocorticoids have been used since the 1950s for treating pain and inflammation in both OA and rheumatoid diseases associated with joint inflammation and cartilage degeneration. In the twentieth century, new treatment for rheumatoid arthritis developed using extracts of animal adrenal tissue. This led to a need for increasing quantities and subsequent research and  chemical synthesis developed the first synthetic cortisone and many more followed.

  • Hydrocortisone
  • Fludrocortisone
  • Prednisone
  • Prednisolone
  • Triamcinolone
  • Methylprednisolone
  • Dexamethasone (the most potent member of the family)

Although the beneficial effects of GCs are well known, there is much controversy about their use. Harmful side effects from systemic delivery were found early on leading to the limited use of these drugs orally and injection therapy was developed in the 1950s. Even today, the mechanism of action of these drugs is not well understood. The GCs can affect a variety of cellular pathways suppressing inflammation but causing many off target side effects such as increasing glucose.

The greatest concern in the use of GCs for treatment in arthritis is the catabolic effects on cartilage. Several studies have also shown that GCs, have an analgesic effect due to the anti-inflammatory properties but with repeated injections, the GCs can lose this pain reduction especially with repeated use.

Several studies using healthy human chondrocytes have reported even low doses of Decadron cause cell death and reduce cell proliferation suggesting potential cytotoxic and catabolic side effects.

Another study demonstrated after 2 weeks of decadron treatment, the collagen internal network of the cartilage was markedly changed, with thinner and more disperse fibers demonstrating a greater change than the effect of arthritis induction alone.

Another study injected decadron into pony weanlings for 11 months. This caused massive degeneration of the joints, with articular lesions, fibrous scars and large necrotic areas in both the cartilage and bone. These changes were attributed to a severe depression of overall cartilage metabolism.

Many studies have reported significant loss of cell viability after Decadron exposure. One mechanism is the dysregulation of metabolism triggered by DEX, leading to upregulation of reactive oxygen species within the chondrocytes. This process can trigger an autophagic response. Autophagy is the degradation of the cell components. This process removes unnecessary or dysfunctional components of the cell.

Autophagy causes chondrocyte apoptosis after DEX exposure and ROS induced apoptosis. Reactive oxygen species has been linked to catabolic effects in OA.

Due to the potential for catabolic effects on cartilage and bone along with systemic side effects, chronic repeated administrations of steroids may do mare harm to the joint.


Viscosupplementation consists of injection of hyaluronic acid supplements into affected joints with the goal of restoring the physiologic viscoelasticity in the synovial fluid. Synovial fluid is a solution found in joints with the primary role of reducing friction on the articular cartilage during movement.

Hyaluronic acid (HA) is naturally occurring and an important component of synovial fluid. Studies have showed the molecular composition and composition of HA are fundamental to the proper lubrication of joints. HA not only provides lubrication to the joint but has many chondroprotective biologic functions.

Wang et al. showed that HA down regulated pro-inflammatory cytokines through the interaction with fibroblasts and synoviocytes in the joint space.

Yasuda et al. showed HA suppresses production of macrophage related prostaglandin.

Sasaki et al. showed the production of matrix metalloproteinases involved in the degradation of matrix proteins were decreased in the presence of HA.

Several societies have noted the absence of benefits from viscosupplementation while others have noted significant benefits.

In 2015, Richette concluded through an updated meta-analysis of trials with low- risk bias that HA supplementation provided a moderate but real benefit for patients with osteoarthritis.

The following year, Xiao et al. led a systematic review of 12 meta-analysis and concluded that HA is both effective and safe intervention in treating knee OA.

There have been several high-grade studies investigating the effectiveness of HA in the past 5 years. From a large cohort that included 1,863 patients with grade IV OA of the knee (the most severe classification) 75% of the patients delayed the need for total knee replacement for 7 years or more. The study concluded that HA led to clinically significant improvements in pain and function with the results most pronounced at the 3- and 6-month period.

Other studies have demonstrated that a single injection of HA provided superior symptomatic relief of OA over cortisone at the 6-month interval. The single injection of corticosteroid resulted in improved pain control initially, but HA was more effective in the long rum with little to no side effects compared to steroids.

Integrative Practice Solutions has been involved in the viscosupplement field for years. IPS has trained hundreds of health care professionals in the use of these products and through our experience, developed the AARP protocol. This patented program, employs guided injections of hyaluronic acid, unloading bracing and home or office physical therapy. Through the institution of the AARP protocol, many patients had their functional life restored and have avoided the side effects and risks of steroid injections and ultimately total joint replacement.

Discussion with your health care professional is paramount to good medical care and options are available for the treatment of Osteoarthritis.

Regenerative Regards,

Dr. Robert McGrath


Overview of First-Line and Second-Line Pharmacotherapies for Osteoarthritis with Special Focus on Intra-Articular Treatment

Int J Mol Sci 2022 Jan 29;23(3):1566  PMID 35163488

A Comprehensive Review of Viscosupplementation in Osteoarthritis of the Knee

Orthop Rev 2021;13(2):255-49  PMID 34745480

Dexamethasone: Chondroprotective Corticosteroid or Catabolic Killer?

Eur Cell Mater 2019 Nov 22;38:246-263  PMID 31755076