The aim of any intervention for osteoporosis is the prevention of fractures at all skeletal sites in patients who have not yet fractured or of the progression of the disease in patients who have already sustained a fragility fracture. Correction of deficiencies/insufficiencies in vitamin D (and calcium) should be the first step in management. The effects of pharmacological interventions are above those obtained with calcium and vitamin D, as in clinical trials these are usually given to placebo-treated patients. The evidence of the antifracture efficacy of pharmacological interventions varies among approved agents and for treatment decisions the highest level of available evidence should be selected. Consistent with the pathophysiology of osteoporosis, pharmacological interventions are distinguished into inhibitors of bone resorption, stimulators of bone formation and compounds whose action on bone remodeling has not yet been fully elucidated, such as strontium ralenate. Of those, only the bisphosphonates alendronate, risedronate and zoledronate and the RANKL-inhibitor denosumab have been shown to reduce the risk of all osteoporotic fractures with variable efficacy up to 5 years of treatment. Despite the fact that the primary action of all four agents is the reduction of bone resorption and turnover, there are also considerable differences between bisphosphonates and denosumab that can be considered in clinical practice. In the absence of head-to-head studies with fracture endpoints these data together with the safety profile should be considered in therapeutic choices for individuals at risk. Cathepsin K inhibitors that decrease bone resorption while maintaining bone formation are not yet available for clinical use. Reduction of bone resorption, though essential for the maintenance or improvement of bone strength, cannot replace already lost bone. For this, specific stimulation of bone formation is required. The teriparatide paradigm illustrated the possibility of stimulating bone formation in osteoporotic patients and opened the way for the development of novel forms of PTH or PTHrP are at different stages of clinical development but a synthetic analog of PTHrP (abaloparatide) given for 18 months was recently shown to decrease the incidence of vertebral and nonvertebral fractures in women with osteoporosis. However, optimal pharmacological management of osteoporosis should aim at concurrently decreasing bone resorption and stimulating bone formation at all skeletal envelopes. Such approach will not only prevent the structural decay of bone tissue but will also substantially increase bone mass leading to enhanced reduction of the risk of fractures particularly at sites with predominantly cortical bone. The combination of teriparatide with denosumab that allows continuous stimulation of bone formation by teriparatide by blocking its concurrent stimulating effect on bone resorption by denosumab may be an interesting option in severely affected patients. The recognition of the central role of the Wnt signaling pathway in bone formation provided attractive targets, such as sclerostin, for the development of bone building pharmaceuticals that reduce also bone resorption. Neutrlizing antibodies to sclerostin (romosozumab, blosozumab) represents a very promising novel anabolic therapy for patients with osteoporosis, in whom 2-year data of phase II studies are available. These new developments may allow tailoring pharmacotherapy to the specific needs and pathophysiological profile of the individual patient. Because osteoporosis is a chronic disease, knowledge of the long-term efficacy and risk profile of every individual agent prescribed is essential for proper patient care.
Disclosure of Interest S. Papapoulos Consultant for: Amgen, Axsome, Merck, Mereo, Novartis, UCB
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