Longitudinal changes in intermuscular fat volume and quadriceps muscle volume in the thighs of women with knee osteoarthritis

Among the prominent risk factors for the onset of knee OA are increasing age, female sex, previous joint trauma, obesity, and muscle weakness; obesity and muscle weakness are also implicated in OA progression (1-3). As a strong predictor of OA (4-6), the role of obesity was originally attributed to increased mechanical loading (4, 7). This theory has been supported by the discovery of mechanoreceptors, such as integrins, on chondrocytes that, when activated, stimulate the release of inflammatory mediators including cytokines, matrix metalloproteinases (MMP) and growth factors (4, 8, 9). However, obesity is also a risk factor for OA of non-weight bearing joints such as the hand; thus adipose tissue is thought to play a metabolic role in OA (5, 10, 11). The characterization of adipose tissue as an endocrine organ has increased our understanding of the role of adipokines in OA. These adipokines are mainly proinflammatory and, accordingly, are implicated in OA pathophysiology (4, 5, 8, 12, 13). One widely studied adipokine, leptin, facilitates the release of metalloproteinases (e.g., MMP-9, MMP-13) which degrade articular cartilage (8, 14, 15). Additionally, leptin increases growth factor expression (e.g., IGF-1, TGF- β). These growth factors, which stimulate chondrocyte repair, have also demonstrated harmful effects through stimulation of osteophyte formation (8, 14, 16). Obesity may also influence knee OA through adipose infiltration into thigh skeletal muscle, which is linked to poorer lower extremity performance in older individuals (17). Like obesity, quadriceps weakness is implicated in knee OA incidence and progression (1-3, 18-22). As well as producing movement, the quadriceps muscles (QM) provide shock absorption and dynamic stability of the knee joint by dissipating loads and decreasing joint contact forces (19, 20, 23). In those with quadriceps weakness, this action would be compromised (19, 20). This weakness may result from a number of factors including poor muscle activation, and the ageing-associated loss of muscle mass and increased fatty infiltration into muscle, referred to as sarcopenia (19, 24-26). Clinical findings support the involvement of quadriceps weakness in knee OA. Ikeda and colleagues found QM cross-sectional area (CSA) to be, on average, 12% smaller in asymptomatic women with incident radiographic OA compared to age and body-mass matched controls (27). Additionally, quadriceps weakness correlated better with pain and disability than radiographic OA (18-22). Some studies have shown increased risk of disease initiation (22, 28). Quadriceps weakness has also been linked to the progression of knee OA through disuse atrophy of the quadriceps due to pain and disability: common consequences of knee OA (22). However, the amount of change in QM that occurs over time in individuals with knee OA remains unknown as previous studies have examined quadriceps CSA at a single time point (23). To the best of our knowledge, changes that occur in QM volume over time in an osteoarthritic population have not yet been reported. Given the importance of obesity and muscle weakness in knee OA, the ability to quantify muscle and intermuscular fat (IMF) volume changes longitudinally may be critical factors in understanding OA initiation and progression. To our knowledge, such longitudinal changes have not been quantified in individuals at risk for or with established knee OA. As a result, this study aimed to quantify longitudinal changes in QM and IMF volumes in postmenopausal women at risk for and with existing knee OA over two years. Secondarily, we aimed to determine if longitudinal decreases in QM and increases in IMF volumes were greater in those with progressive knee OA than in those at risk for knee OA.