ReviewFuture therapeutics for osteoarthritis
Introduction
The most common form of joint disease, osteoarthritis (OA) represents a major cause of morbidity and disability, particularly in the second half of life. The burden of this disease has been steadily gaining importance in the last few decades with the aging of the world's population and has become by far the most common musculoskeletal disease, imposing enormous costs and challenges on the healthcare system. The increasing number of patients seeking treatment for this disease could very well cause a global financial “tsunami” in the near future.
Although important advances have been made in understanding the pathophysiological processes of OA, today's treatments still focus mainly on improving the symptoms. As the relationship between the pathology and pain of OA has become better defined, new concepts have emerged allowing the development of new therapeutic approaches that are likely to improve symptomatic treatment. The newer agents of this category will be reviewed.
Even though in the last few decades, finding a disease modifying OA drug (DMOAD) has remained elusive, research into the development of such new and innovative agents continues. The progress made in the understanding of the pathophysiology of OA and the identification of risk factors has guided DMOAD development programs toward promising therapeutic targets. These, as well as new drugs and agents aiming at stopping the disease progression, will be reviewed.
Of note, this review may not be fully comprehensive of all development programs as this field is advancing rapidly.
Osteoarthritis, which mainly affects the diarthrodial joints, is a chronic disease that develops progressively over decades, making it very difficult to precisely identify the different etiological and risk factors that influence the onset of the disease. In the majority of patients, the disease is considered to be idiopathic.
It is now well recognized that OA is not a single disease entity, but rather the common final stage of joint failure. Osteoarthritis of the knee is a heterogeneous chronic disease involving all the joint tissues and the initial stages can be triggered by numerous causes and/or factors. Hence, it would seem logical that the disease be divided into subgroups, some of which may have a more biomechanical, biochemical, inflammatory or genetic signature. All these subgroups may eventually converge into a common phenotype.
It is well known that OA structural changes are mediated by a multitude of complex autocrine and paracrine anabolic and catabolic factors that act upon diverse cells from articular tissues. Studies have revealed that there is some continuity between the subchondral bone and cartilage as well as between the synovial membrane and cartilage, suggesting cross-talk between these tissues. However, the exact sequence of pathological events in OA remains unclear, as the temporal relationship between cartilage erosion, chronic synovial inflammation and subchondral bone remodeling has yet to be determined.
Section snippets
Symptomatic drugs for osteoarthritis (Table 1)
The most common treatment prescribed for OA is for symptomatic relief, to control the pain and improve joint function. Pain in OA is difficult to classify, as the factors contributing to its genesis such as inflammation and neuropathic and/or nociceptive pain components have yet to be fully identified. The specific sources of OA pain within the joint have also remained elusive and are likely to be multiple, including tissues of the joint such as the subchondral bone, the synovium, and the soft
Disease modifying osteoarthritis drugs (DMOADs)
The ultimate vision for the treatment of OA has been to find agents that can reduce or stop the progression of the disease. Thus far no such treatment has been approved by regulatory authorities as meeting the appropriate guidelines and criteria. However, a number of agents present several interesting properties including an extremely low incidence of side effects, a carryover effect of several weeks, and some have an additive effect with NSAIDs. These include chondroitin sulfate [30], [31],
Targeting synovial membrane inflammation
In OA, the role of synovial inflammation in the pathophysiology of OA is now widely accepted. Synovitis has been considered secondary to the cartilage changes yet findings indicate that synovial inflammation could be a component of the early events leading to the clinical stage of OA. Synovial inflammation leads to the production and release of pro-inflammatory cytokines and several other inflammatory mediators. Some of these factors, including the pro-inflammatory cytokines, diffuse through
Targeting subchondral bone remodeling
Emerging evidence suggests that changes in subchondral bone are closely involved in the disease progression. Data even indicate that the subchondral bone alterations may precede cartilage changes, and this tissue is suggested to be the site of the causally most significant pathophysiological events occurring in the cartilage. It is now believed that very early in the OA process, biological and morphological disturbances occur at the subchondral bone level that play a role in modulating
DMOAD clinical research
Based on experience from the conduct of DMOAD trials in the last decades, there is no doubt that such studies present major challenges. Firstly, protocols for these trials were highly variable from one study to another. For example, inclusion/exclusion criteria including disease severity, demographics, risk factors, and structural changes differed quite significantly among the studies, having an obvious impact on the results and making it very difficult to analyze and compare the results of a
Conclusion
A number of major hurdles are responsible for the almost idle effort to develop new DMOADs and these can be explained quite simply by three major factors that are intertwined: the slowly progressive loss of cartilage, the multifactorial nature of the disease, and the cyclical course with periods of active disease followed by remission. The unsatisfactory efficacy of currently available treatment options has led the current development efforts to focus mainly on pain drugs. This effort is
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