Biocomputational modeling as developed under the European Virtual Physiological Human (VPH) and the US NIH program on “Predictive Multiscale Models of the Physiome in Health and Disease” is the area of ICT to most likely revolutionize the practice of medicine. The VPH is a framework of methods and technologies that, once fully established, will make possible the investigation of the human body as a whole. There is considerable demand for measurable evidences that such complex technology is actually worth the cost. How is it possible to quantitatively assess ex ante such technologies in terms of safety, efficacy, and socio-economic impact on our health systems? With the example of osteoporosis management, a socioeconomic assessment framework is presented that captures how the transformation of clinical guidelines can be evaluated. Applied to the clinical decision support system under development in the European Osteoporotic Virtual Physiological Human Project, a consequent cost-benefit analysis delivers promising results, both methodologically and substantially.