Objectives. Although cartilage loss occurs with advancing age and is a hallmark of OA, the factors that affect cartilage change are not well established. The aim of this study was to explore the determinants of change in patella cartilage volume over 2 yrs among healthy middle-aged women with no clinical knee OA. Methods. One hundred and forty-eight women with no clinical knee OA were recruited from a previous population-based cross-sectional study of healthy women aged 40-67 yrs. MRI was performed at baseline and at 2 yrs, to assess patella cartilage and bone volume. Self-reported exercise was assessed by questionnaire. Results. Annual loss of patella cartilage volume was 1.6% (95% CI 1.2, 1.9). Age was positively associated with patella cartilage volume loss after adjustment for confounders (P = 0.05). For every 1 mm3 increase in patella bone volume at baseline, annual cartilage loss was reduced by 8.05 mm3 (95% CI 12.91, 3.19; P = 0.001). Fortnightly participation in exercise promoting an increased heart and respiratory rate for at least 20 min also tended to be associated with a reduced rate of patella cartilage volume loss (P = 0.09). Conclusion. Among middle-aged women with no clinical knee OA, advancing age expedites the rate of patella cartilage volume loss, while increased patella bone volume and exercise participation tends to be associated with a reduction in the rate of patella cartilage volume loss. Interventions targeting modifiable factors, such as physical activity, warrant further investigation as they may help to prevent patellofemoral OA.