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The major goal of the Summit was to foster discussion among the participants in an effort to reach consensus on important topics in the prevention, diagnosis, and treatment of osteoarthritis (OA) and to highlight future directions for research. To that end, long breakout sessions were held at the end of both days of the summit. Here, we provide a summary of the sessions. To focus the discussion, participants were challenged to develop answers to questions posed by the co-chairs (addressed below). Much of the discussion was also focused around a proposal from John Hardin of the Arthritis Foundation to develop a concentrated, multidisciplinary, multi-institutional effort centered on the stabilization of cartilage matrix after joint trauma. Applying candidate pharmacologic agents and detecting the resulting stabilization with new imaging and molecular biomarkers could be a way to achieve concrete progress in preventing OA (see John Hardin’s article elsewhere in this supplement).

A combination of both morphologic and quantitative MR provides objective data to assess not only cartilage morphology but also cartilage biochemistry, inclusive of proteoglycan content and collagen orientation. Challenges still exist, however, as these quantitative techniques increase scan time, are not universally available across sites, and are sometimes restricted to higher magnetic field strengths of 3 T. Standardization of post-processing algorithms and registration software are important to provide more uniform data in multicenter trials. Several ongoing longitudinal registries are being established to study populations at risk, and these preliminary studies will provide important information suitable for powering studies aimed at assessing potential pharmaceutical intervention to delay the progression of OA. In addition, these MR data provide important insight into the appropriate timing of surgical treatments aimed at delaying progression and provide noninvasive and objective assessment of cartilage repair techniques.

So, there can be little doubt that the whole joint is involved in OA, resulting in changes in function and proprioception and onset of altered nociception and pain that compound the problem. So, functional assessments of joint function should also be included in any measures of joint changes in OA. Many additional parameters might help in detecting and measuring disease onset and progression instead of relying on traditional measures of loss of and/or damage to articular cartilage. Most, if not all, joint tissues potentially offer important new opportunities as targets for therapeutic intervention.

In the past, pain mechanisms in osteoarthritis (OA) have received surprisingly little attention, although this is now changing. Attempts to discriminate between OA and other rheumatologic disorders, such as rheumatoid arthritis, through verbal descriptions of pain have generally proved unsuccessful as the patterns of pain often overlap. Use-related pain in OA is common but rest pain and night pain sometimes occur, and a variety of patterns of pain are described by different patients, varying from a dull ache to sharp, stabbing pains [1]. It seems probable that a variety of different mechanisms contribute to symptoms in this disorder and that the relative importance varies among individuals. The presence and severity of joint pain correlate poorly with structural evidence of joint damage. Current evidence suggests that OA joint damage predisposes to pain, but that little correlation between pain severity and the extent of joint damage exists. The probable explanation of these observations lies in that fact that pain perception arises in response to a complex series of underlying neurophysiologic events involving transduction of stimuli, transmission of encoded information, and subsequent modulation of this activity at both peripheral and more central levels. In all but acute situations, the relation between tissue injury and resultant symptoms becomes less well defined and more susceptible to extraneous influences originating both within and external to the individual. Minor injuries or damage within the joint produce short lived excitation of specialized high threshold nociceptors with brief, spatially localized pain. More severe tissue damage associated with the release of inflammatory mediators produces not only direct nociceptor excitation, but also modified response properties to subsequent stimuli (peripheral sensitization) [2]. Under these circumstances, the response to a noxious stimulus becomes exaggerated. Alternatively, normally innocuous stimuli such as standing or walking may produce pain.

Osteoarthritis (OA) affects 27 million Americans. This leading cause of disability results in 632,000 joint replacements each year, accounts for approximately 5% of overall health care costs, and is expanding rapidly as the population ages and deals with the obesity epidemic [7, 9]. This is a bad situation now and unless remedial action is taken it will get a lot worse soon. Despite its personal and societal impact, relatively little attention has been directed at OA. Moreover, our pharmaceutical companies are discouraged from developing new interventions because present outcome measures are very insensitive. To change this picture, we need vigorous efforts in public health to increase awareness of OA and encourage life styles that do not promote OA. We need public policies that effectively combat obesity and encourage healthy behavior. And, we need research that will lead to an understanding of how to detect and reverse OA at its earliest stages.

textabstractOsteoarthritis (OA) can be considered an organ failure with pathological aspects in cartilage, bone, ligaments, and synovium. Altogether, these tissue changes can result in pain and immobilization—a failure of the joint. It is well regarded that OA is a complex multifactorial disease with many risk factors and different etiological pathways that all lead to an apparently similar end stage. Bony changes are clearly observed in advanced OA. However, little understanding exists on the role of these changes, whether they are a consequence of cartilage damage or precede this damage and maybe play an important role in the etiological process. Even more important is the issue of pain. Radiological scores of OA do not match well with pain and mobility scores, which questions the value of these scoring systems. It seems that we do not assess the most relevant parameters. Evaluation of conventional and new radiographic parameters is still an extensive part of the OA research field. We may have overlooked certain (subtle) parameters that can be extracted from x-rays, but other imaging modalities such as MRI, CT, or SPECT might better represent OA in a clinically relevant manner.

Osteoarthritis (OA) is the most common form of arthritis and represents the leading cause of disability in the USA. Importantly, with an aging population, the prevalence, impact, and economic consequences of OA will rise dramatically within the next decades. Although much has been learned concerning the factors that play a role in the initiation and progression of OA, this information has not been effectively translated into individual or public health strategies that have significantly altered the natural history of this disabling form of arthritis. While total joint arthroplasty is an effective treatment for the late stages of OA, no validated pharmacologic interventions exist for effectively eliminating pain and restoring function during disease progression. Although initially regarded as a disease of articular cartilage, numerous lines of investigation have established that OA represents an example of total “organ failure,” in which every component of the joint tissues, including the cartilage, synovium, periarticular bone, and connective tissues, is affected by the disease process. Given OA’s pleiotropic effects on joint tissues, the development of effective diagnostic, preventative, and treatment strategies requires a broad interdisciplinary approach that embraces multiple scientific and public health disciplines. This need formed the basis for the sponsorship of the “Osteoarthritis Summit: Frontiers in OA Research, Prevention, and Care” that was held at the Hospital for Special Surgery in New York in June, 2011, the results of which are published in this issue of the HSS Journal. The Osteoarthritis Summit brought together research scientists; clinicians caring for patients with OA; governmental officials responsible for aiding and directing research; representatives from major OA research societies and foundations; and members of the pharmaceutical, device, and insurance industries in a workshop setting (Fig. ​(Fig.1).1). The meeting was organized into a series of six sessions that included concise presentations from the meeting attendees. Each session focused on a specific aspect of OA, progressing from an overview of the clinician’s perspective and the classification and epidemiology of OA to a session on pathological and pathogenic processes in OA, including structural alterations and the onset and characterization of symptoms. The third session focused on the diagnosis and assessment of OA, while the fourth centered on strategies for OA prevention. The fifth and sixth sessions covered current treatments for OA and identified opportunities and priorities for development of future therapies and public health strategies. The formal presentations were followed by extended breakout sessions that provided an open forum for discussion of perspectives that addressed critical questions related to OA with the goal of reaching consensus on the current state of knowledge of OA research and the strategies for OA diagnosis, prevention, and treatment. Fig. 1 Participants of the Osteoarthritis Summit: Frontiers in OA Research, Prevention, and Care. Courtesy of Hospital for Special Surgery. Bottom row (left to right): Virginia Kraus, MD, PhD; Steven Goldring, MD; Timothy Wright, PhD; Linda Sandell, MD; Constance ...

Articular cartilage has significant limitations for repair or regeneration. It does not respond to an injury or disease with the normal inflammatory sequence of events that results in repair of most other tissues. The issues that preclude a functional repair in articular cartilage include its avascularity, the presence of cells (chondrocytes) that have a limited capacity to respond, and a complex structure that is difficult to reproduce. A plethora of approaches has been applied in an attempt to repair articular cartilage. Although short-term functional repair has been reported, a long-term biological regeneration has yet to be accomplished.

Common mediators determine initiation and progression of cartilage damage across various models of osteoarthritis that can also be observed in the human form of the disease. Work during the past years has uncovered interactions among these mediators that impact the disease process and may inform us about new directions for targeted therapies [16].

In summary, low- to moderate-intensity exercise effects are known: they reduce pain and improve function, but have no effect on disease progression. Primary and secondary prevention studies using nonpharmacologic interventions such as exercise and weight loss are needed to clarify how exercise protocols can retard or even prevent the onset of osteoarthritis. These studies should include clinical, mechanistic, and structural outcomes, such as assessments of pain and ambulatory function, measures of actual joint loads applied by the patients, and assessment of disease progression. The interventions should be long term (≥18 months), and retention and compliance are of the utmost importance [2].

By changing pathological joint mechanics, gait modification may have disease modifying potential for medial compartment knee OA. The most effective gait modification methods may well be a combination of an assisted modification and a learned modification taught via a real-time feedback system—for example, variable stiffness shoes with medial thrust gait. Addition of other holistic elements such as strength or flexibility training may be valuable as well. Determination of the best target quantity will be critical for gait modification to make a positive clinical impact.

Data are released on a regular basis to OAI online. As of April 2011, 1,911 users had registered for OAI Online from 83 countries, with over 7,975 datasets downloaded and 321 image sets distributed. Data are currently being released in a single bolus for the entire visit. Recent releases have included the 36-month questionnaire and exam data and images for the full cohort, as well as the 30-month questionnaire and exam data and images for a subset of the progression cohort. Clinical data and images from the 48-month visits should also have been released by the time this article is published. An increasing number of abstracts and papers are being produced based on the use of the OAI data and images (see www.oai.ucsf.edu/datarelease/Publications.asp). This groundbreaking study is expected to advance our understanding of how modifiable and non-modifiable risk factors are linked to the development and progression of knee osteoarthritis. These findings may in turn lead to improved strategies for disease prevention, identification of novel treatment targets, and ways to prevent disability in later life.

The Cartilage Restoration Center at the University of Pittsburgh conducts research using novel imaging technologies to detect early microstructural changes to articular joint tissues in degenerative and traumatic injury-induced articular cartilage and meniscus disease. Identification of early changes to joint tissues permits the identification of patients who could potentially benefit from therapeutic interventions. Quantitative strategies for the diagnosis and staging of joint tissue degeneration prior to the breakdown of the articular cartilage or meniscal surfaces remain a challenge. Our research has shown that the current clinical standard, arthroscopic visualization, and palpation of cartilage and menisci, may be insensitive to early subsurface alterations in these tissues, particularly in the deepest layers of articular cartilage [1–3]. Our work with quantitative Magnetic Resonance Imaging (MRI) and Optical Coherence Tomography (OCT) reveals a strong potential for these methods to provide information regarding early diagnosis and staging of subsurface tissue injury that are not readily available with current technologies [3–5].

Our studies in this murine model of PTA suggest that the response of the joint to injury is an organ level, or possibly even systemic response, and not simply a response of the cartilage in isolation [11]. This knowledge may be helpful in understanding how to translate findings from in vivo investigations into future therapies. There is a great need to understand the human response to injury. At this time it is not clear whether the response to an articular fracture is similar in character to a response seen in other forms of osteoarthritis. The primary advantage of the intra-articular fracture model is a defined time point of disease onset. Focus on the articular fracture response may give clues to mechanisms that may be in play in other types of arthritis.

As the group uniquely representing the field of osteoarthritis, the Osteoarthritis Research Society International (OARSI) has taken up a mandate to promote and advance research for the prevention and treatment of OA, a task that includes evaluating therapies and developing consensus statements and guidelines in respect of the medical treatment of OA. Research into OA therapeutics is currently highly active, so OARSI has also recognized the need to keep its guidelines current though repeated iterations of its update and consensus-building activities.

Our current understanding of the role of synovitis in osteoarthritis has evolved substantially over the past decade. We understand that inflammation is present even early in the course of the disease and is associated with symptoms, function, and progression of cartilage damage (Fig. 1). Whether synovitis is a predictive marker in posttraumatic osteoarthritis remains to be established. Data from a recently published rodent model suggested that synovitis may be a good therapeutic target in posttraumatic osteoarthritis [1]. Elucidating how synovial inflammation is triggered and sustained in the joint is likely to guide the design of future treatment regimens targeting synovitis in osteoarthritis. Fig. 1 Relationship between synovitis and outcomes in osteoarthritis and important remaining questions. Synovitis has been associated with pain, joint dysfunction, and rate of structural progression in osteoarthritis. Important questions remaining are how variable ... Acknowledgement Carla R. Scanzello is supported by 1K08AR057859 award from the National Institute of Arthritis, Musculoskeletal and Skin Diseases. Rush University Medical Center and the Hospital for Special Surgery have filed a patent application on behalf of the author on inflammatory biomarkers in osteoarthritis.

Racial/ethnic disparities in the use of joint replacement surgery for knee and hip osteoarthritis (OA) have long been described [4, 9, 23]. Whether these represent differences in the frequency and severity of OA at various joint sites [11, 12] or differences in patient preference, access to medical care, or other factors has been the source of considerable study in the last 10 to 15 years [6]. This article emphasizes racial/ethnic differences in, and factors associated with, the use or lack of use of various therapeutic interventions for OA, and new insights into potential mechanisms underlying these disparities, with an eye toward understanding how effective modalities might be applied in various populations likely to benefit.

Developing therapies for chondroprotection offers the potential to prevent debilitating osteoarthritis and associated joint replacement following acute joint trauma. Although many significant challenges must be overcome, in comparison to expensive and time-consuming conventional osteoarthritis clinical trials, therapeutic chondroprotection may provide an easier path to evaluate treatments that have potential as disease-modifying therapies for osteoarthritis.

Osteoarthritis is now appropriately recognized as a joint disease (see the article by Robin Poole in this Supplement), and as such, the biomechanical factors that affect its etiology and progression can best be understood by considering the mechanical function of the whole joint.

Health care costs for members with osteoarthritis have been estimated as twice the cost of a random population, controlling for comorbid conditions. This population generates approximately 5% of the medical cost of a health plan. As such, patients with osteoarthritis provide opportunity to improve outcomes and are candidates for medical management. The goals of medical management are improvement in the quality of health care and a reduction in its cost—preferably both simultaneously. Opportunities in osteoarthritis include assurance of a reasonable and appropriate medical plan, support, and education of the patient to promote adherence, reduction of adverse events and drug reactions, and concurrent management of comorbidities and psychosocial barriers. Several domains of effort are available.

The future of OA biomarkers is great. The number of studies currently underway has increased greatly, including longitudinal studies. More research on new biomarkers is underway, and we hope to increase awareness and use of biochemical biomarkers over the next few years. The goal is clear—to move the diagnosis of OA from a radiologic viewpoint back to a pre-radiologic viewpoint and on to the molecular events that initiate cartilage breakdown and joint failure.

Our understanding of the role that meniscal degeneration plays in the natural history of OA of the knee would benefit from observational studies that address the natural history of intrasubstance signal change with compositional imaging, the clinical significance of different meniscal pathologies, and the relation of meniscal alteration to altered contact area and joint loading. In addition, the weak evidence base for many of the current treatments suggests a great need for well-designed, randomized, controlled clinical trials to assess the true effects of arthroscopic meniscal resection, meniscal repair or transplantation, or nonsurgical treatments.

Research to date supports a comprehensive approach to the evaluation of the OA illness experience, incorporating the quality, intensity, and predictability of the pain as well as its impact on fatigue, mood, sleep, and disability. A greater understanding of the relative efficacy and effectiveness of OA treatment options on each of these symptoms has potential to improve selection of the best therapies for an individual patient. Recognition of, and attention to, the influence of contextual factors on the OA illness experience, in particular coping skills and social support, may further reduce the impact of the disease. Finally, disordered sleep and mood and the presence of pain sensitization should be considered as alternative treatment targets, particularly among patients for whom first-line OA pain medications, e.g., NSAIDs, cannot be safely used.

Total hip and knee replacement are among the most successful surgical procedures in medicine. The long-term survival of total hip replacements for which both the femoral and acetabular components were fixed to the surrounding bones with cement demonstrates durable results [1, 3], even in young patients [11]. For example, 35-year follow-up of cemented total hip replacements revealed a survival rate of 78% with the need for revision surgery for any reason as the end point [3]. In younger patients, the 25-year survival is 93% for the femoral component, though only 77% for the cemented acetabular component [11]. The introduction of newer designs that relies on biologic fixation through bone ingrowth into porous coatings on the metallic components has also proven durable. Twenty-year survival of porous-coated acetabular components has been reported at 86% [6] with revision for any reason associated with the acetabular component as the end point. In a direct comparison of cemented and cementless acetabular components performed by the same surgeon [8], survival at 18 years improved from 81% to 94%. Long-term results for porous-coated femoral components are just as impressive [2, 7, 9]. Joint replacement patients enjoy function which is comparable to their peers without osteoarthritis. Patient-reported outcomes such as the short-form health outcomes survey (the SF-36), together with objective functional measures, such as the 6-min walk, show no meaningful differences between total hip patients and normative values (Fig. 1). Fig. 1 SF-36 scores for total hip replacement patients (“Study”), those patients with two or more comorbidities, and normative values (“Norm”) demonstrate that total hip patients reach levels found in the normal age-matched population ... The major problem remaining in total hip replacement is the bearing surface. Osteolysis caused by the biological reaction to wear debris remains a common mode of failure. Considerable improvement has been made in the wear resistance of bearing surfaces, most recently by the widespread adoption of highly cross-linked polyethylene for acetabular components. Randomized clinical trials comparing cross-linked to conventional polyethylene show reductions in wear and osteolysis [13], though follow-up is not long enough at this time to determine the impact of these improvements on the need for revision surgery. Like total hip replacement, total knee replacement has similar durable results up to 10 to 20 years [4, 8–20]. Unicondylar knee replacement, in which only one compartment is replaced, has similar outstanding results, at least in older patients, though younger patients have not fared as well at long-term follow-up [17]. As with hip replacement, wear and osteolysis are major issues, particularly with modular designs for which backside wear between the polyethylene insert and the metallic tray provides an added source of debris [14]. This appears to apply especially in young, active osteoarthritis patients [16]. Similarly, mobile-bearing designs which incorporate a second bearing surface between the tibial insert and the tibial tray have an excellent long-term survival, but osteolysis secondary to an increased burden of wear debris appears to increase with time [4]. Cementless fixation has not gained acceptance in total knee replacement as it has in total hip replacement, despite promising long-term results [10]. Osteotomies are another surgical treatment for osteoarthritis, aimed at realigning joint surfaces and thus delaying disease progression. Newer procedures for osteotomies around the hip are encouraging at mid-term follow-up, with acceptable complications when performed by well-trained surgeons [5]. Knee procedures include closing and opening wedge osteotomies performed in the proximal tibia. Closing wedge osteotomies have produced unpredictable results that are not always durable [15]. Newer opening wedge osteotomies may provide more durable and more predictable results, but no long-term follow-up is available.

Taken together, these recent advances in understanding of how mechanical forces cause loss of articular cartilage including identification of mechanically induced mediators of cartilage loss and of how changing joint loading can promote joint remodeling provide the basis for new biologic and mechanical approaches to the prevention and treatment of OA.

Keywords tissueengineering.bone.cartilage.scaffolds.bioreactorsIntroductionThere is a strong medical need for biological tissue graftsthat could reestablish the structure and function of skeletaltissues lost to congenital abnormalities, trauma, and disease.Both the prosthetic devices and autologous tissue grafts aremost helpful in providing the necessary tissue structure, butthey each have serious limitations [1]. Tissue engineeringoffers potential to grow fully biological substitutes of nativetissues, through the individual and combined use of cells,biomaterial scaffolds, and culture systems [2–5].The Potential of Bioengineered Human TissuesIn its most complex incarnation, tissue engineering involvesthe in vitro generation of living, functional tissue grafts bycultivation of cells on biomaterial scaffolds (designed toserve as a template for tissue formation) in bioreactors(providing environmental control and physical signaling).The design of tissue engineering systems has been guidedby biological principles and the need to provide native-like(biomimetic) environments in order to unlock the fullbiological potential of the cells (Fig. 1). Variations of thisapproach resulted in engineered cartilage, bone, andosteochondral grafts [2–4] for implantation studies inanimal models and eventual translation into clinical use.One recently developed approach enables the in vitrocultivation of living human bone grafts customized to matchthe exact anatomical features of the specific defect, usingthe patient’s own cells (Fig. 2). Importantly, engineeredtissues also find application for in vitro screening of cellsand regulatory factors and construction of disease models[6]. Furthermore, engineering a tissue under controllableconditions brings new insights into the progression of tissuedevelopment and identification of the underlying factorsand mechanisms. This knowledge can then also be used todevelop therapeutic modalities that involve mobilizationand regulation of the host’s cells by bioactive acellularimplants.SummaryBioengineered culture platforms can provide tight environ-mental control and the physiological transport and signal-ing, enabling study of cartilage/bone development,regeneration, and disease under conditions that predict thehuman in vivo context [2–4, 6]. The field of bone andcartilage tissue engineering holds significant potential forproviding clinically relevant tissue grafts for restoring jointfunction. These grafts can be personalized using imaging-guided techniques and the patient’s own cells. As our abilityto grow mechanically functional bone and cartilage graftshas progressed, efforts are focusing at tissue interfaces,vascularization of bone, stratification of cartilage, and“conditioning” of grafts to better tolerate the inflammatoryenvironment of an osteoarthritic joint.

Osteoarthritis (OA) is the most common form of arthritis and is a major cause of morbidity, limitation of physical activity, and health care utilization, especially in people aged 45 and above [1]. OA has been defined as “… a progressive disease of synovial joints that represents failed repair of joint damage. This ultimately results in the breakdown of cartilage and bone, leading to symptoms of pain, stiffness, and functional disability” [2]. The term “degenerative joint disease (DJD)” should not be used by health care practitioners to describe this entity; it is a misnomer and suggests to patients that nothing can be done for their condition. Thus, OA can be considered as a disease characterized by structural abnormalities at the joint level and an illness defined by a person’s symptoms [2]. The symptoms that characterize knee OA include frequent pain, aching or discomfort, stiffness, fatigue, and sleep disturbance. These symptoms result in functional limitations leading to reduced participation in activities and decreased health-related quality of life.

Clinical trials represent the most rigorous approach to evaluating the efficacy of interventions. The clinical trial is a relatively young methodology, used rarely until the middle of the twentieth century. Most clinical trials evaluate medications. In fact a review of clinicaltrials.gov in 2011 indicated that of more than 100,000 registered trials, over 70% were drug trials [1]. The remainder was divided among devices, surgery, and behavioral and educational interventions. While drug trials are important for development of therapeutics in osteoarthritis, trials of surgery, devices, and educational and behavioral interventions are critical as well.

We are making progress in understanding the connection between aging and OA, but clearly more work is needed. Suggestions for future studies are provided in Table 1. Table 1 Where should we go from here to better understand aging and OA? Disclosures The author certifies that he or she has no commercial associations (e.g., consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article.

Qualification is defined as the “graded, ‘fit-for-purpose’ evidentiary process linking a biomarker with biology and clinical endpoints” [5]. As recently defined by the Federal Drug Administration (FDA), “qualification is a conclusion that within the stated context (manner and purpose) of use, the results of assessment with a drug development tool (DDT) can be relied upon to have a specific interpretation and application in drug development and regulatory decision making” [3].