Introducing the next-generation of arthritis treatments

Contrary to what many doctors were once taught, osteoarthritis and cartilage defects can now in fact be treated and repaired! Evidence has shown new capabilities in restoring cartilage structure and function, reducing pain, and replacing or delaying the need for major surgical interventions, and several clinical trials are now in process for these therapies. The underlying mechanisms of osteoarthritis are multifactorial and still under active investigation, and while affected joints often include the main weight-bearing joints of knees, hips, or facet joints of the spine, as well as joints with a history of traumatic injury, osteoarthritis can also affect any joint regardless of activity or mechanical injury. We have begun early clinical implementation of novel cartilage preserving and cartilage restoring therapeutic agents with both intra-articular and extra-articular delivery applications. These regenerative therapeutic interventions involve using minimally-invasive image-guided injections to deliver novel orthobiologic agents and glycosaminoglycans, particularly bioactive peptides, platelet-rich fibrin, alpha-2-macroglobulin, pentosan polysulfate, and stem cells derived from bone marrow or adipose tissue, which in early phase results have demonstrated improved function with reduced pain and inflammation. We are now entering the new and long-awaited era of true regenerative medicine! The science of these novel therapies, including the underlying molecular signalling pathways and laboratory evidence of these regenerative approaches is also described in further detail below.

"Orthopedic surgeons are at an exciting crossroads in medicine, where biologic therapies are evolving and increasingly available. Time-tested interventions such as arthroplasty have shown good results and still have a major role to play, but newer regenerative approaches have the potential to effectively delay or reduce the requirement for such invasive procedures." --Aaron Krych and Mario Hevesi, Orthopedic Surgeons at the Mayo Clinic, International Orthopaedics, Feb 2021.

Evidence has shown that cartilage, tendon, and ligament are not static structures, but are constantly synthesizing new protein structure at a high rate (0). Unfortunately some practitioners continue to use high-dose steroid injections and local anesthetics as a shotgun approach for many arthritic ailments even though these medications cause atrophy of tendon, ligament, cartilage, bone, and skin due to downregulation of collagen synthesis, thus causing worsening or recurrence of the problem and deleterious feedback cycles. Local anesthetics can cause chondrolysis (cartilage breakdown) when injected in joints, and there are actually only a few instances where corticosteroids should be used (for specific inflammatory processes and seldom for chronic or repetitive degradative injuries, etc.) (1) (2) (3) (4) (5) (6) (7) (8) (9). Rather than use injections of degradative medications, we prefer to use regenerative injections that actually help stimulate tissue repair, including stem cells, PRF, pentosan, peptides, biologics, shockwave therapy, hyaluronic acid and chondroitin (viscosupplementation), which all help promote connective tissue rebuilding rather than inhibit it as corticosteroids do. We suppress inflammatory processes as necessary and focus on providing therapeutic interventions for many different forms of arthritis and chondromalacia, and we also keep up to date with innovative regenerative therapies that can kickstart healing phases to optimize tissue repair using image-guided injections with a cocktail of factors that are carefully chosen for your specific injury or pathology. Also read about natural anti-inflammatory agents and good nutrition for arthritis at our nutrition page.

Conditions Treated with Regenerative Therapies Include:

New Regenerative Therapies Include:

Pentosan Polysulfate: a unique agent that both stimulates cartilage matrix synthesis and inhibits cartilage breakdown, thus showing new promise as a powerful therapeutic agent for osteoarthritis and cartilage repair. Originally designed as an intra-articular injection, it has also shown potent effects as an injection around the joint or under the skin, and it is one of the only agents that has been shown to strengthen cartilage tissue by increasing cross-linking and polymerisation of the large molecules found in cartilage. In particular, pentosan is a unique glycoasminoglycan that also has powerful anti-inflammatory properties, regenerative matrix remodeling and repair effects, promotion of chondroprogenitor cell lineages, along with significant pain reduction in clinical studies, and it typically only needs to be used for just a few weeks for long-term therapeutic effects (10) (11) (12) (13) (14) (15) (16) (17). Pentosan may be used for any osteoarthritic joint pathology, including knees, hips, ankles, shoulders, and degenerative discs and facets joints in the spine. It appears to be particularly effective for alpha-virus induced arthritis and cartilage damage (18). Furthermore, it can be combined with HA+Chondroitin treatments and/or PRF treatments and/or peptide treatments for enhanced synergistic effects.

PRF: delivers fibrin-activated release of growth factors from platelets and circulating BMSCs, including BMP-2, BMP-7, FGF, VEGF, PDGF, TGF-Beta, IL-1R Blockers, Thrombospondin, and α2-macroglobulin ("alpha-2M" or "A2M" protein), which has been shown to slow the loss of cartilage in osteoarthritis and inhibit inflammation (without all the downsides of cortisone steroid injections). Several enzymes have been shown to be involved in the degradation of cartilage, including cytokines, matrix metallaproteinases, ADAMTS (a disintergrin and metallaproteinase with thrombospondin motifs), and proteases like cathepsin, which all destroy cartilage and increase inflammation. However, alpha-2-macroglobulin (A2M) is a powerful protease inhibitor and cytokine transporter that can be purified from your own blood proteins, and it acts as a master inhibitor of these inflammatory cartilage-destroying signals, making it a powerful new therapeutic agent for treating cartilage diseases such as osteoarthritis, post-traumatic arthritis, degenerative disc disease, and many other arthropathies! This approach is currently being studied for several types of arthritis using intra-discal, epidural, intra-spinal, and intra-articular joint injections. PRF also acts as a lubricant of joints and contains regenerative growth factors listed above. PRF injections of arthritic joints, tendon sheaths, and osseoligamentous structures can be done alone or as a part of pentosan therapy and stem cell therapy to maximize recovery of the joints. These can also be combined with peptides or other orthobiologic agents (like plasma or autologous conditioned serum) that accelerate and optimize joint repair (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) (30) (31) (32) (33) (34) (35) (36).

Stem Cells: We can harvest stem cells from your own bone marrow or from stromal vascular fractions of adipose tissue, and these stem cells work in synergy with PRF to further help enhance tissue repair and clinical improvements. Of note, PRF can also capture small amounts of your own circulating stem cells and uses your own cells and platelets to focally release growth factors such as BMP, FGF, VEGF, PDGF, eNOS, and others which are released locally to accelerate and strengthen tissue repair, and these factors further activate recruitment and differentiation of MSCs as well as expression of several tissue remodeling genes. When injected into joints, studies have shown evidence that MSCs combined with platelet-rich fibrin (PRF) can help regenerate new hyaline cartilaginous matrix (as opposed to just fibrocartilage type scar tissue) even in full-thickness articular cartilage defects, and further clinical studies are being conducted to further optimize the protocols and techniques that achieve the best results (37) (38) (39) (40) (41) (42) (43) (44) (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) (55) (56) (57) (58) (59) (60) (61) (62) (63) (64) (65) (66). In addition to regenerative and protective effects of stem cells, studies have shown that MSCs also have many other good anti-inflammatory and immunomodulatory effects on injured or degenerative parts of the body.

Viscosupplementation: injections with hyaluronic acid and chondroitin is another good option for osteoarthritis that can easily be done in our clinic. These gel-like agents can help restore joint function and mechanical properties of shock absorption, lubrication, and cartilage protection, and this procedure has good evidence for alleviating pain for a few months at a time, so it is a useful adjunct to other therapies when pain is significant. Studies have shown a 77% reduction in pain, 78% improvement in mobility and 74% reduced consumption of analgesics with use of hyaluronic acid and chondroitin sulfate in osteoarthritis (67). However, viscosupplementation typically needs repeat injections every few months and does not regenerate cartilage or joint function, but fortunately additional regenerative substances like PRP, PRF, & stem cells can be injected either in conjunction with hyaluronic acid or alone to provide the same lubrication and pain relief while also adding regenerative factors that promotes cartilage repair. (68) (69) (70) (71) (72) (73) (74) (75) (76) (77) (78) Lastly, although a local numbing agent like lidocaine can also be injected into the joint at the same time for temporary pain relief, there is some evidence that this actually degrades cartilage (chondrolysis) and worsens arthritis in the long run. Thus, regenerative therapies are a much better choice for long-term tissue function.

Adalimumab (Humira), Etanercept (Enbrel), Infliximab (Remicade), & Biosimilars: interestingly, some types of arthritis involve aberrant immunological signaling, including spondyloarthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis. Biologic monoclonal antibodies can used in the treatment of these autoimmune arthritides. These agents work by binding and sequestering TNF-alpha, which is known to cause severe degradation of joints, cartilage, and entheses. These diagnoses tend to be associated with the HLA-B27 marker but diagnosis can be complicated by the fact that many symptoms may or may not be present and no single imaging study or lab test can make the diagnosis. There are several subtle yet important differences between these medications that should be taken into consideration. Because of the immunosuppressive effects of this class of biologic agents, latent infections like tuberculosis should be ruled out before starting therapy (79) (80) (81) (82) (83) (84) (85). We are also studying new small molecule inhibitors of TNF-alpha like TIM1c (86).

Reactive Arthritis and Other Arthropathies: The forms of joint damage can also be induced by over-active interleukin and cytokine signaling, often in the context of latent infectious agents, immune complexes, or in the aging process. Some patients have taken the approach of stem cells and "young blood transfusions" to temporarily treat these arthritic aging symptoms, which we can offer, but we now understand that there are also ways of blocking these specific niche inflammatory pathways at their source, shutting off inflammatory signaling cascades that induce several types of arthritis and that accelerate aging dysfunctions of stem cells. For example, interleukin-1β (IL-1β) signaling has been implicated as a major factor in arthritis and stem cell aging, and these types of targeted therapeutic agents have also been shown to renew bone marrow stem cell health and regenerative functions, thus decreasing markers of biologic age and potentially increasing healthspan. Macrophages were also once thought to help reduce knee inflammation but have now been shown to drive joint inflammation and attract immune cell infiltration with chemokines and interleukins, leading to synovial membrane inflammation (87). These effusions can weaken and stretch joint capsule and ligaments over time, leading to further joint degeneration, cartilage damage, and osteophyte formations. Fortunately, we are studying many different types of agents to shut down these inflammatory pathways and reduce drivers of arthritis along with rejuvenating the regenerative capacity of your own stem cells, including peptides, proteins, exosomes, mRNA, biologic agents like anakinra, anti-aging medications like sirolimus, and natural medicines as ancient as aspirin (88) (89) (90) (91) (92) (93) (94) (95) (96).

LNA043: a new medication in early research phase, LNA043 acts as an ANGPTL3-agonist that modulates certain pathways that may help cartilage regeneration. Early research showed that treatment with intra-articular injections of LNA043 could induce regeneration of damaged cartilage in some patients with articular cartilage lesions of the knee (97) (98).

Bisphosphonate Therapies: several studies have suggested that bisphosphonate therapy (zoledronate, aledronate, risedronate, pamedronate, etc.) not only strengthen bones by increasing bone density and preventing spread of metastatic cancer through bones, but may also provide significant chondroprotective effects on articular cartilage, including reduced cartilage degradation, decreased collagen II breakdown in cartilage, increased glycosaminoglycans (GAG) content in cartilage, increased subchondral bone density, reduced chondrocyte apoptosis, and improved cartilage microstructure with reduced degeneration of the articular cartilage (99) (100) (101) (102) (103) (104) (105) (106) (107) (108) (109). We can provide IV infusions of these bisphosphonate agents directly in our clinic along with proper preparation to accelerate the beneficial effects while also preventing any possible complications from these medications.

Other Future Therapies: recent research has also shown that injecting programmed stem cells that have been modified with CRISPR gene editing to produce certain biologic agents that inhibit specific inflammatory cytokines (similar to the drug anakinra that suppresses IL-1) can protect against bony erosions and joint damage in inflammatory arthritis (110). This type of bioengineered approach holds great promise for future therapies for many diseases and conditions.

Nutritional Approaches: There may also be simple nutritional approaches like eating many antioxidants, polyphenols, vitamins, and minerals found in vegetables, as well as good hydration, omega-3 oils, collagen, and/or other agents (111). N-Acetyl Cysteine (NAC) is an antioxidant that scavenges free radicals and helps sustain the production of another essential antioxidant called glutathione, and animal studies suggested that NAC might help prevent osteoarthritis degeneration because oxidative stress has been shown to be an important mediator of osteoarthritis (OA) (112) (113) (114), but unfortunately in human trials this did not work and may even be detrimental (115) (116) possibly due to NAC's ability to reduce disulphide bonds in procollagen and proteoglycans or a variety of other mechanisms.

Also see additional information for the newest treatments of connective tissue injuries (tendon, ligament, labrum, cartilage, etc.), joint injuries, spine injuries, and other injuries and pathologies at the PRF, peptides, spine, shockwave, and treatment pages.


AAMI © 2021 All Rights Reserved

*Disclaimer: The information presented here is for informational use and cites the ongoing cutting-edge research and medical advancements on these relevant topics. There are many treatments, interventions, and protocols routinely practiced in medicine and surgery which the FDA has not studied nor formally approved yet which have demonstrated overwhelming evidence of efficacy and clinical benefit. The FDA does not regulate the practice of medicine but rather regulates medical marketing of devices and drugs. The FDA does not conduct clinical trials or attempt to discover new treatments, but rather requires companies or other entities to fund marketing approvals. Breakthrough technologies typically require years to decades of research work to optimize the technology and collect enough data to prove efficacy and superiority, which in some cases can optionally be submitted to the FDA if there is sufficient financial backing to market a specific product or drug. Thus the FDA has not yet studied, evaluated, or formally approved many regenerative therapies currently practiced by many of the top physicians and surgeons in the United States and around the world. Some therapies, products, or interventions may still be considered investigational or "off-label" even with substantial evidence of efficacy, and many different applications of regenerative therapies continue to be researched by our institute and other top institutions around the world. We seek to always provide the highest-quality evidence-based care to our patients, which may include FDA-approved therapies as well as additional investigational or alternative therapies. We always discuss potential risks and benefits of all these options. The rapid evolution and advancement of medicine demands that physicians continually update their knowledge and practice techniques to adapt to future improvements and advancing technologies. These statements have not been evaluated by the FDA, and the treatments and products presented here are for informational purposes and not intended or guaranteed to diagnose, treat, cure, or prevent any specific disease or condition. All injuries and conditions should be formally evaluated by a knowledgeable medical professional whereby standard treatments and/or additional therapeutic interventions may be considered with the diagnosis and treatment plan.