The objective was to quantify the outcome of osteoporosis (OP) in terms of health-related quality of life (HR-QOL) and cost of ambulatory care and to look at the association between these two outcomes variables. A cross-sectional health survey of 4800 Belgian individuals over the age of 45 years was used. Individuals having reported OP were retrieved and for each of them, at least two matched individuals for age, sex, residency location, and health insurance status were identified. All individuals were assessed with the SF-36. The two major health insurance providers furnished cost value for ambulatory care. HR-QOL and cost data were compared between the OP group and control group. Beta-coefficients from linear regression were calculated to give information on the relative importance of the association between each SF-36 dimensions and cost of ambulatory care. Of 4796 individuals appropriately surveyed, 221 (4.8%) reported OP. The control group included 651 individuals. The OP group experienced impaired HR-QOL compared to their matched counterparts, all the difference in mean or median SF-36 scores being significant at the level of P < 0.001. Osteoporotic respondents averaged 816 in cost of ambulatory care whereas controls averaged 579 (P < 0.001). When looking at detailed comparisons between categories of cost, costs in the OP group far exceeded those in the control group, all the differences being significant at the level of P < 0.001 except for home health nurse (P = 0.012). In the OP group, vitality dimensions played the most important role in the determination of cost (beta = -0.28, P < 0.001), followed by physical functioning (beta = -0.26, P < 0.01), general health, and social functioning (beta = -0.23, P < 0.01). This study evidences the burden of OP in terms of HR-QOL and cost of ambulatory care. Exploring the association between HR-QOL and cost show that mental dimension such as vitality can play an important role in the determination of cost. Conclusively, they should not be neglected in future management of OP.