Improving the outcome of established therapies for osteoporosis by adding the active D-hormone analog alfacalcidol

While in other chronic diseases combined treatment regimens are the rule there is a lack of reported experience or study data on combining different specific drugs to treat osteoporosis. Significant differences in the mode of action (MOA) of the substances to be combined may be important for achieving optimal therapeutic results. Recognising that today bisphosphonates are the leading therapy for osteoporosis we suggest that the active D-hormone analog alfacalcidol with its completely different mechanisms of action could be an interesting combination to improve the therapeutic outcome of the pure antiresoptive action of bisphosphonates. Alfacalcidol is activated by the enzyme 25-hydroxylase in the liver for systemic and in osteoblasts for local D-hormone actions. It possesses a unique pattern of pleiotropic effects on, e.g. gut, bone, pararthyroids, muscle and brain. Alfacalcidol is superior to plain vitamin D (cholecalciferol) because the final kidney activation of the latter is regulated by a negative feedback mechanism. In vitamin D replete patients or patients with impaired kidney function no increased D-hormone action at the target tissues can be achieved. Animal studies and several trials in humans with alendronate plus calcitriol or alfacalcidol proved that the combination induced significantly higher increases of bone mineral density (BMD) than the respective mono-therapies. The results of the 2-year AAC-trial from our group indicate that the combination alendronate and alfacalcidol is also superior in terms of falls, fractures and back pain. From the review of the literature and the own new results we conclude that this combined therapeutic regimen is a very promising option for treating established osteoporosis and propose a differentiated use of alfacalcidol alone or the combination with alendronate in different stages and clinical situations of osteoporosis.