In scientific nomenclature, “hyaluronan” is the accepted term for hyaluronic acid (HA) and the physiological salts of hyaluronate, the conjugate base of hyaluronic acid.
HA is classified as a glycosaminoglycan (GAG). GAGs are long, unbranched polysaccharides made of repeating disaccharide units of glucuronic acid and glucosamine. The polymer chain of HA ranges in molecular weight from hundreds of units (or daltons) up to several million.
HA is ubiquitous throughout the body. It is either directly or indirectly involved in every physiological function. HA is found in dense concentrations in the cartilage, synovial fluid, skin, vertebral discs, bones, urinary tract, cardiac valves, eyes, and various other soft tissues. HA is most abundant during embryogenesis and declines in overall quantity and quality throughout life.
In diarthrodial joints, HA is the principal macromolecular component of synovial fluid and one of the chief constituents of articular cartilage. The concentration, molecular weight, and amount of HA strand entanglement determine its ability to function as a lubricant and shock absorber. The greater the amount of strand entanglement, the more viscous HA becomes in solution.
HA’s ability to resist shear and tensile stress is best demonstrated in synovial fluid, where it cushions the joints against downward forces and provides for fluid movement. Within a healthy joint, HA enhances joint mobility through both shock absorption and lubrication with articulation.
In addition to its role in synovial fluid, the compression of HA and its elastic rebound are required for the nutrition of articular cartilage. This explains why moderate exercise is needed for the maintenance of joint health, because without this compression-rebound cycle, no nutrients are carried to the avascular articular cartilage.
Exercise that effectively elicits mechanical load to strengthen bones involves impact, such as walking, running, or jumping. Growing bones are most responsive to this strengthening effect. And this type of exercise is efficient because the cellular mechanosensors within bone direct osteogenesis to where it is most needed to improve the strength and mass of bone.
Within the bone itself, the presence of HA is primarily linked to bone modeling and remodeling processes. The formation and resorption of bone is coordinated within remodeling, and HA has been shown to regulate bone remodeling by stimulating osteoblasts and osteocytes as well as inhibiting osteoclasts. Thus an imbalance in bone formation and resorption underpins many diseases.
Oral hyaluronan supplementation
Intriguingly, HA taken orally has been shown to reduce urinary markers of bone resorption and estrogen-related bone loss, indicating HA suppresses bone resorption. This led to the hypothesis that orally supplemented HA may be useful in the treatment of osteolytic conditions and patients with chronic joint symptoms (CJS).
Current research has shown pro- inflammatory mediators are down- regulated via TLR-4 by oral administration of HA. One study showed oral supplementation of HA in subjects with osteochondrosis led to lower scores for synovial effusion as well as higher HA, NO, and PGE2 concentrations in synovial fluid.
Studies with technetium-labeled (99mTc), high-molecular-weight HA administered orally show distribution to the joints in as little as four hours post-administration.
Chronic joint symptoms
One quarter of the American adult population reports CJS. Over 50 percent of those reporting CJS have symptoms with multiple joints. For this evaluation, CJS is defined as joint pain, aching, and stiffness during the past 30 days with symptom onset of more than
three months.
Treatment of CJS is usually limited to short-term symptom control with palliative over-the-counter and prescription drugs. In my practice we also frequently inject HA directly into affected joints. The notion of orally replenishing native HA for systemic arthrotherapy has strong appeal so it warranted a closer look.
Studying HA first hand
HA directly affects the composition of synovial fluid and provides scaffolding for cartilage matrices. Apart from its structural role, HA influences cell proliferation, differentiation, and migration; angiogenesis, as well as inflammation and immune cell function.
HA provides a surface to which activated lymphocytes can attach, attenuating the inflammatory response and interrupting chronic substance-P-mediated pain signaling. We assessed the therapeutic effects of a high-molecular-weight oral HA biopolymer among active adults with CJS.
We evaluated the effects of daily oral supplementation with HA on 50 adult subjects (average age 59 years).
Subjects self-administered one-half to one teaspoon of HA in the form of viscous syrup twice daily for 30 consecutive days.
Direct-feedback surveys completed daily by participants facilitated compliance. Subjects identified the affected joints, their pain levels, and daily activity levels.
Forty two subjects (84 percent) reported good-to- excellent results in relief of pain and stiffness. To be included in the good-to-excellent group, the subject had to report a noticeable improvement in joint symptoms with continued relief once the effect was noticed.
Four subjects (8 percent) noticed only minimal benefit during the trial, but within four to five days of trial termination reported an increase in pain and stiffness, concluding that improvements were gradual and unremarkable during the trial. This group is not included with the positive results reported above.
Another four subjects (8 percent) reported no benefits during the trial. Time to improvement ranged from five to 30 days with an average of 21 days. There were no reports of side effects or drug interactions, and no one discontinued the trial. Several subjects voluntarily reduced their non- steroidal anti-inflammatory drug (NSAID) use based on improvements during the trial.
Conclusions
In a clinical setting, daily oral supplementation of high- molecular-weight HA alleviated symptoms of CJS. HA supplementation relieved joint pain and inflammation, contributing to improved range of motion and an increase in daily activity among the majority of subjects.
HA supplementation as an adjunct therapy helps stabilize cartilage and bone matrices and increases friction-free movement. Therefore, HA supplementation can be incorporated into an overall treatment plan as a means of ameliorating disease manifestation and promoting systemic bone and joint health.
Douglas W. Kiburz, MD, FAAOS, is a board-certified orthopedic surgeon who specializes in joint replacement, trauma, and sports medicine. He sees patients at Bothwell Orthopedics & Sports Medicine in Sedalia, Missouri; is a fellow of the American Academy of Orthopaedic Surgeons; has served as the president of the Missouri State Orthopaedic Association; and is the acting medical advisor for Cogent Solutions Group, LLC. He can be contacted through cogentsolutionsgroup.com.
