Objective: Multimorbidity related to menopause and/or increased age will put healthcare systems in western nations under ever-greater strain. Effective strategies to prevent diseases are thus of high priority and should be started earlier in life. The purpose of the study was to evaluate the long-term effect of exercise on different important health parameters in initially early postmenopausal women over a 16-year period. Methods: In 1998, 137 early postmenopausal women with osteopenia living in Erlangen-Nurnberg were included in the study. Eighty-six women joined the exercise group (EG) and conducted two supervised group and two home training sessions per week, whereas the control group (CG: n = 51) maintained their physical activity level. Primary outcome parameters were clinical overall fractures incidence; secondary study endpoint was Framingham study-based 10-year risk of coronary death/myocardial infarction and low back pain. Results: In 2014, 59 women of the EG and 46 women of the CG were included in the 16-year follow-up analysis. Framingham study-based 10-year risk of myocardial infarction/coronary death increased significantly (P < 0.001) in both groups; however, changes were significantly more favorable in the EG (5.00% +/- 2.94% vs CG: 6.90% +/- 3.98%; P = 0.02). The ratio for clinical "overall" fractures was 0.47 (95% CI: 0.24-0.92; P = 0.03), and thus significantly lower in the EG. Although we focused on a high-intensity exercise strategy, low back pain was favorably affected in the EG. Conclusions: Multipurpose exercise programs demonstrated beneficial effects on various relevant risk factors and diseases of menopause or/and increased age, and should thus be preferentially applied for primary or secondary prevention in postmenopausal women.