How to Manage the Active Patient with Osteoarthritis:: Biological Approaches

Introduction

Osteoarthritis (OA) is a debilitating condition that can lead to chronic pain, disability, decreased quality of life and inability to perform activities of daily living. Authors have reported that OA and diabetes are responsible for the largest increase in years lived with disability at the global population level, in part because of the obesity epidemic and aging populations. It has been reported that patients with symptomatic knee or hip OA have a 55% greater all-cause mortality compared with the general population. There are more than 30 million Americans affected by OA. Others have stated that at least one in four people may develop symptomatic OA in his or her lifetime. ^, The most commonly affected joints include the knee, hand and hip. ^, Annually the treatment of OA puts significant strain on the healthcare system and has wider socioeconomic as our populaces age. Published numbers attribute medical costs in excess of US$140 billion to arthritis-related care and more than US$450 billion in costs when account for costs to the economy and lost wages. The mainstay first-line treatments for symptomatic OA are nonsurgical, such as activity modification, nonsteroidal antiinflammatory medications, weight optimisation and low-impact exercise and strengthening programs. Alternative medications such as tramadol have historically been used for palliation in OA patients but 2019 Cochrane evidence suggests that tramadol alone or in conjunction with Tylenol has ‘no important benefit on mean pain or function in people with osteoarthritis’. When patients fail to improve with other conservative measures, providers may turn to injection therapies or surgical intervention. Surgical options differ depending on the stage of OA and the joint involved but may involve arthroscopy with debridement for palliation or arthroplasty. Although total joint arthroplasty has been shown to be highly effective definitive management for OA especially of the hip and knee, that is not always a viable option depending on patient age, surgical risk and medical comorbidities. As such, nonsurgical injection therapies have been developed in an attempt to achieve durable symptomatic relief and ideally offer disease-modifying benefits.

For more than 100 years now, intraarticular injections have been used as potentially therapeutic substances of OA, specifically of the knee. ^, Many of the early injection strategies were abandoned because of risks to the patient with minimal benefits seen. Corticosteroids became more commonplace in the 1950s and continue to be used via intraarticular injection therapy for OA. ^, Despite frequent use of corticosteroid agents for OA, the American Academy of Orthopedic Surgeons (AAOS) Clinical Practice Guidelines approved in 2013 gave an ‘inconclusive’ evidence and state ‘we are unable to recommend for or against the use of intraarticular (IA) corticosteroids for patients with symptomatic osteoarthritis of the knee’. The highest quality, Level I to II literature regarding intraarticular corticosteroid use in OA patients reports underwhelming results. After the advent of widespread corticosteroid use, hyaluronic acid (HA) was approved by the US Food and Drug Administration (FDA), but it too has not delivered the disease-altering affects that are desired. Given the lack of consistent, positive benefits of HA compared with placebo or corticosteroids in clinical trials, the AAOS guidelines offer a ‘strong’ recommendation that they cannot recommend using HA for symptomatic OA. As the AAOS guideline authors note, although meta-analyses have demonstrated improved Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function and stiffness subscales, none of the improvements met minimal clinically important improvement thresholds.

The limitations seen with both and corticosteroids have spawned research into novel biological intraarticular injection therapies – specifically, platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC) and adipose-derived mesenchymal stem cells (AD-MSCs), among others. These biological agents, known to many as orthobiologics , represent a shifting paradigm in treatment as the pathophysiology of OA continues to be better understood to target complex cellular signalling pathways that play a role in disease progression. To date, the existing human literature is most robust regarding PRP and BMAC, with few studies being published regarding AD-MSCs. Legislation that has lessened restriction through the US Public Health Section Act Section 361 Pathway has expedited the pathway from development to the marketplace for orthobiologics. Although interest and demand from both patients and providers is high for improved nonsurgical treatment options for OA, patients have been exposed to direct-to-consumer marketing campaigns that may inaccurately frame products in testimonials instead of touting peer-reviewed research. As authors have reported, the number of US clinics offering unproved stem cell therapies has at least doubled each year from 2009–14. As clinics have seen a boom in patients looking for biological treatments and subsequently clinics offering those treatments, there remain significant concerns regarding costs of these products. ^, Most major insurance companies do not cover orthobiologic treatments, citing a lack of high-quality evidence demonstrating their efficacy and cost-effectiveness. Orthobiologics have gain widespread public awareness through marketing campaigns and treatment of professional athletes. The use of buzzwords in the media such as ‘stem cells’ to represent minimally manipulated, multipotent mesenchymal cells can be misleading and confusing to patients. To be clear, the adult MSCs found in cell therapies such as BMAC and AD-MSC preparations originate from the mesoderm and have a limited array of cells they may become. These cells include chondrocytes, osteoblasts, myoblasts and adipocytes, all of which have been shown to be impactful paracrine signal cells to mediate cellular recruitment, immune system modulation and regeneration. ^, These orthobiologic agents are the focus of this review. In this chapter we detail the indications for these injection modalities; discuss each injection, including different preparations and current clinical outcomes evidence; and review published statements by AAOS and orthopaedic subspecialty groups regarding biologics use for OA.

Indications

Although adults or elderly populations have the highest prevalence of OA, young, active people may be affected, leading to decreased functionality and quality of life. Many demographic, activity and medical history factors have been found to be associated with OA, including genetics, obesity, previous joint injury, recreational activities, occupation, gender and race. The indications for orthobiologics have not been uniformly described, but generally these modalities are for patients who lead an active lifestyle and do not have radiographic evidence of Kellgren-Lawrence (KL) grade 4 OA or advanced imaging evidence of diffuse, full-thickness articular cartilage loss. How age affects treatment efficacy of orthobiologics is an active area of research to better define indications because PRP, BMAC and AD-MSCs are all autologous products. The metabolic activity and paracrine effects of MSCs present specifically in BMAC and AD-MSCs may be affected by the age of the patient. For example, several authors have reported a reduction in the absolute number of MSCs within BMAC and decreased proliferative capacity with age. ^, Further considerations when discussing treatment options should include a thorough evaluation for concomitant meniscal, ligamentous and malalignment pathological conditions. Many of these concomitant pathological conditions may be driving factors in OA disease progression, and without correction orthobiologics may be limited in their efficacy.

Platelet-Rich Plasma

PRP, or autologous conditioned plasma, is autologous plasma that has undergone centrifugation to concentrate platelets, growth factors and cytokines postulated to aid in tissue healing and anabolism. ^, Although the exact concentration of what platelet concentration constitutes PRP has not been universally agreed on, PRP typically contains at least 3 to 5 times physiological platelet levels but can reach as high as 9.3 times. ^, Specific growth factors such as platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) have been shown to collectively have a chemotactic effect on MSCs. The attraction of MSCs is thought to be important in helping conduct increased proteoglycan and cartilage production. Further effects of these proteins and growth factors include antiinflammatory properties through modifying gene expression and limiting production of matrix metalloproteinases and nuclear factor–κB. ^,