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Editorial Commentary: More Clinical Trials Should Focus on Primary Prevention of Osteoarthritis: Disruptive Thinkers Are Required

      Abstract

      With increasing life expectancy and an increased prevalence of osteoarthritis, the total number of individuals with symptomatic degenerative arthritis will most likely increase considerably. The current focus of nonoperative treatment is on weight loss, exercise, muscle strengthening, physical therapy, nonsteroidal anti-inflammatory drugs, intra-articular injection therapies with corticosteroids, hyaluronic acid, or platelet-rich plasma, and lately, disease-modifying drugs. Obviously, prevention is better than cure, but only 5% of all studies registered on ClinicalTrials.gov in the United States are intending to develop strategies for prevention. The overall majority of included studies (89%) will target symptom resolution, and 6% will investigate disease-modifying drugs.
      Life expectancy is steadily increasing and has exceeded the age of 80 years in most countries.
      • Burger O.
      • Baudisch A.
      • Vaupel J.W.
      Human mortality in evolutionary context.
      In fact, a 72-year-old in Japan has the same odds of dying as a 30-year-old in the preindustrial world.
      • Burger O.
      • Baudisch A.
      • Vaupel J.W.
      Human mortality in evolutionary context.
      Life expectancy is linked to higher income per capita, availability of public health services, and poverty reduction.
      • Bohk C.
      • Rau R.
      Impact of economic conditions and crises on mortality and its predictability.
      With increasing age, it is inevitable that health will eventually deteriorate. Certainly, musculoskeletal conditions and, in particular, degenerative osteoarthritis will also affect aging individuals. Currently, the estimated prevalence based on a 2015 National Health Survey estimated that 14 million persons in the United States have symptomatic knee osteoarthritis.
      • Deshpande B.R.
      • Katz J.N.
      • Solomon D.H.
      • et al.
      Number of persons with symptomatic knee osteoarthritis in the US: Impact of race and ethnicity, age, sex and obesity.
      More than half of these patients are older than 65 years.
      • Deshpande B.R.
      • Katz J.N.
      • Solomon D.H.
      • et al.
      Number of persons with symptomatic knee osteoarthritis in the US: Impact of race and ethnicity, age, sex and obesity.
      Globally, the annual incidence rate increased from 162 per 100,000 in 1990 to 202 per 100,000 in 2017 and the age-standardized prevalence increased from 2,090 to 6,128 cases per 100,000 population.
      • Safiri S.
      • Kolahi A.A.
      • Smith E.
      • et al.
      Global, regional and national burden of osteoarthritis 1990-2017: A systematic analysis of the Global Burden of Disease Study 2017.
      The general increase in patients with osteoarthritis also has direct health economic consequences. In the United States, the annual average direct cost (adjusted to 2015 US dollar equivalent) was shown to range from $1,442 to $21,335.
      • Xie F.
      • Kovic B.
      • Jin X.
      • He X.
      • Wang M.
      • Silvestre C.
      Economic and humanistic burden of osteoarthritis: A systematic review of large sample studies.
      These costs increase even further when taking into consideration the sick-leave days and days off owing to informal care by relatives.
      • Rabenda V.
      • Manette C.
      • Lemmens R.
      • Mariani A.M.
      • Struvay N.
      • Reginster J.Y.
      Direct and indirect costs attributable to osteoarthritis in active subjects.
      This leads to the inevitable question, What can we do about it, and how can we treat this growing problem in the future? Currently, the focus of nonoperative treatment is on weight loss, exercise, muscle strengthening, physical therapy, nonsteroidal anti-inflammatory drugs, intra-articular injection therapies with corticosteroids, hyaluronic acid, or platelet-rich plasma,

      Sofat N, Watt FE, Lyn Tan A. Development of medical therapies in osteoarthritis: Time to improve patient care [published online March 14, 2021]. Rheumatology (Oxford). https://doi.org/10.1093/rheumatology/keab263.

      • Zhang W.
      • Moskowitz R.W.
      • Nuki G.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines.
      • Filardo G.
      • Kon E.
      • Longo U.G.
      • et al.
      Non-surgical treatments for the management of early osteoarthritis.
      and lately, disease-modifying drugs.

      Sofat N, Watt FE, Lyn Tan A. Development of medical therapies in osteoarthritis: Time to improve patient care [published online March 14, 2021]. Rheumatology (Oxford). https://doi.org/10.1093/rheumatology/keab263.

      ,
      • Oo W.M.
      • Yu S.P.C.
      • Daniel M.S.
      • Hunter D.J.
      Disease-modifying drugs in osteoarthritis: Current understanding and future therapeutics.
      Primary prevention is another important factor and most likely the most neglected point.
      • Runhaar J.
      • Zhang Y.
      Can we prevent OA? Epidemiology and public health insights and implications.
      ,
      • Neogi T.
      • Zhang Y.
      Osteoarthritis prevention.
      Identified risk factors are individuals who have a heavy physical work load or perform heavy lifting, individuals who are physically active, individuals with previous injuries, and finally, overweight or obese individuals.
      • Runhaar J.
      • Zhang Y.
      Can we prevent OA? Epidemiology and public health insights and implications.
      Obviously, some of these factors are not correctable, and the only factor that may prevent osteoarthritis is the avoidance of joint injuries.
      • Runhaar J.
      • Zhang Y.
      Can we prevent OA? Epidemiology and public health insights and implications.
      ,
      • Neogi T.
      • Zhang Y.
      Osteoarthritis prevention.
      It is somehow surprising and sad that 60 years after hip replacement
      • Charnley J.
      Arthroplasty of the hip. A new operation.
      and 50 years after the first knee replacement,
      • Ranawat C.S.
      History of total knee replacement.
      we are still chasing the perfect solution for this disease.
      Where are we at this moment in time? We clearly need to obtain a current inventory of whether we have made any progress and then establish what is missing and, finally, in which direction we should go. This is what DePhillipo, Aman, Dekker, Moatshe, Chahla, and LaPrade have accomplished.
      • DePhillipo N.N.
      • Aman Z.S.
      • Dekker T.J.
      • Moatshe G.
      • Chahla J.
      • LaPrade R.F.
      Preventative and disease-modifying investigations for osteoarthritis management are significantly underrepresented in the clinical trial pipeline: A 2020 review.
      In their study titled “Preventative and Disease-Modifying Investigations for Osteoarthritis Management Are Significantly Underrepresented in the Clinical Trial Pipeline: A 2020 Review,” DePhillipo et al. have reviewed the ClinicalTrials.gov website for all US studies registered that involved the prevention, symptomatic resolution, or disease modification of osteoarthritis. And the results are rather disheartening. Of the 311 included studies, the vast majority (89%) will target symptom resolution, 6% will target disease modification, and only 5% will investigate prevention. Could the study design and search criteria be partially responsible, or can we simply not perform any better? One could certainly argue that the authors, by using only the search term “United States,” may have missed other studies in the pipeline from the rest of the world. But these criteria were well within the authors’ purpose; they intended to evaluate US work only.
      The question remains, Where do we go from here? Prevention is better than cure, and the fact that only 5% of the future studies will investigate prevention tells us that we know it all already or are simply not that interested. We are surgeons, correct? Why should we care about prevention? However, even for nonsurgical specialties, the percentage is low. For me, it is not really surprising that nearly 90% of studies will investigate symptom resolution. Commercial interests, mainstream research (this is what we have always done), and lack of innovation and ideas may contribute. Or, has this part of medicine simply matured and there is no more need for any research in this field? Possibly not. Although only 6% of studies are investigating disease modification, one would hope that this percentage will increase over time. This seems important and could help to avoid surgery completely. But we may also have to look at osteoarthritis and degenerative diseases from a different perspective. It may be time for disruptive minds to come to the front with new ideas. We definitely need outside-the-box thinkers to help us out here. DePhillipo et al.
      • DePhillipo N.N.
      • Aman Z.S.
      • Dekker T.J.
      • Moatshe G.
      • Chahla J.
      • LaPrade R.F.
      Preventative and disease-modifying investigations for osteoarthritis management are significantly underrepresented in the clinical trial pipeline: A 2020 review.
      have set the stage and provided us with an inventory, and now it is time to get to work.

      Supplementary Data

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