Current therapy for knee osteoarthritis (OA) most often focuses on pain relief, often with nonsteroidal anti-inflammatory medications that have only modest functional benefit, do not slow disease progression, and have potentially serious cardiovascular and gastrointestinal side effects [1
]. Recent evidence also casts doubt on the effectiveness of arthroscopic surgery for adults with mild-to-moderate knee OA [3
]. Modern approaches to OA management should recommend targeting modifiable risk factors, including obesity, malalignment, and muscle weakness.
Obesity (BMI ≥ 30.0 kg/m2
) is associated with increased risk of functional impairment and is considered the most modifiable risk factor for knee OA [4
]. Although caloric restriction has produced dramatic changes in many biological systems and proven beneficial to obese adults suffering from knee OA, no study has directly addressed whether intensive dietary induced weight loss also slows the progression of structural damage in people with OA or determined mechanistically how it happens.
Dietary weight loss is considered the best potential non-pharmacologic intervention to prevent or to slow disease progression [6
]. Christensen et al. [7
] recently found that an 11% weight loss in older adults with knee OA over an 8-week period resulted in a 3-fold improvement in self-reported function relative to a control group. Radiographic evidence of progression was not studied in this trial and would not be expected to change in an 8-week period. The mechanisms responsible for improvements in function and pain in patients with knee OA consequent to long-term intensive dietary weight loss and exercise interventions in obese adults remain unknown. Reductions in joint loads and inflammatory cytokines, each thought to exacerbate joint destruction, are potential pathways. Our current Intensive Diet and Exercise for Arthritis (IDEA) randomized clinical trial will examine the effects intensive weight loss has on the biomechanical and inflammatory osteoarthritis disease pathways. We suggests that a long-term weight loss of at least 10% of baseline body weight, with or without exercise, will reduce knee joint loads and decrease inflammation resulting in a slowing of disease progression and improved clinical outcomes (Figure ).
Figure 1 Theoretical model by which intensive dietary restriction plus exercise decreases knee joint loads, improves strength and power, and decreases inflammation leading to a slowing of disease progression, reduced pain, improved function, and less disability (more ...)
Recent studies demonstrate that low-grade inflammation plays a pathophysiological role in OA. The inflammatory cytokine interleukin-1 beta (IL-1β) is present in the joint fluids of OA patients [8
]. An inflammatory component associated with OA can be detected in the circulation since serum concentrations of inflammatory markers, such as cytokines (interleukin-6, IL-6; tumor necrosis factor alpha, TNFα) and the acute-phase reactant C-reactive protein (CRP), are higher in persons with knee or hip OA compared to those without [9
]. In addition, longitudinal studies demonstrate that high systemic CRP and TNFα concentrations predict increased radiographic progression of knee OA as much as 5 years later [10
]. Moreover, OA severity and impaired physical function are associated with higher inflammatory markers in the blood [12
]. Thus, severity, mobility, pain, stiffness, and radiographic progression may be partly mediated by the level of chronic inflammation in OA patients.
Obese individuals have higher concentrations of inflammatory markers and may be at greater risk of functional limitation and OA disease progression. Besides direct effects on the joint, inflammatory mediators can affect muscle function and sensitize nerves leading to increased pain [13
]. Studies are beginning to show that both exercise training and weight loss decrease overall inflammation [14
]. Our Arthritis, Diet, and Activity Promotion Trial (ADAPT) showed that a dietary intervention producing a 5% weight loss significantly reduced CRP, IL-6, and TNFα soluble receptor 1 concentrations compared to a control group [16
]. We still do not know whether there is a "threshold" – a relative or absolute weight loss that maximally reduces inflammatory markers – or if improvements in physical function, pain, and OA progression are related to declines in chronic inflammation with weight loss and exercise.
Previous studies indicate that knee OA has an adverse effect on gait mechanics, but little is known about the influence of obesity. Epidemiological and biomechanical data suggest that the additional mechanical stress obesity places on weight-bearing joints increases the propensity for knee OA. We found that as BMI increased, older adults with knee OA changed their gait, walking slower and exerting greater impact forces [17
]. There are no definitive data on whether weight loss is beneficial for reducing OA progression; however, these data support our proposed model in which intensive dietary induced weight loss and exercise interventions slow disease progression. This study could make intensive dietary weight loss combined with exercise the standard-of-care for overweight and obese adults with knee OA and enhance our understanding of the OA disease process and weight-loss and exercise recommendations for older people generally.
This paper describes the design of IDEA, a large scale long-term intensive weight loss and exercise randomized clinical trial, and provides new reliability data on knee joint loads calculated using musculoskeletal modeling, and measures of osteoarthritis disease progression using magnetic resonance imaging (MRI).