Challenges for the Development of Bone-Forming Agents in Europe

Abstract

In recent years, significant advances have been made in the management of osteoporosis, particularly with respect to the development of pharmacological interventions to reduce fracture risk. Approved pharmacological interventions in Europe include bisphosphonates, strontium ranelate, raloxifene, bazedoxifene, denosumab, and parathyroid hormone peptides [1–4] (Table 1). Treatments are approved for osteoporosis in postmenopausal women, but alendronate, etidronate, risedronate zoledronic acid, and teriparatide are also approved for the prevention and treatment of glucocorticoid-induced osteoporosis in Europe [3], and alendronate, risedronate, zoledronic acid, strontium ranelate, and teriparatide are approved for the treatment of osteoporosis in men. Most of these agents are primarily inhibitors of bone turnover, sometimes referred to as anticatabolic agents [5], whereas teriparatide, parathyroid hormone (PTH), and, arguably, strontium ranelate act in part or predominately by the stimulation of bone formation (anabolic agents). There is now a number of bone-forming agents in clinical development, including agents targeting the endogenous inhibitors of bone formation sclerostin and dickkopf-1, cathepsin K inhibitors, new formulations of PTH and PTH related protein (PTHrp) analogs, and calcilytics. The clinical use of these agents in the management of osteoporosis is dependent on marketing authorization from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency. Guidelines for product development are available and are regularly updated. The last revision came into effect in 2007 [6]. In phase 3 (the demonstration of efficacy), authorization is dependent on the demonstration of significant efficacy on fracture risk reduction and acceptable safety in postmenopausal women at high or imminent risk of experiencing osteoporotic fractures on the basis of an increased 10-year probability of fractures. Because treatment to prevent fractures may be regarded as a long-term treatment, the CHMP recommends that a duration of randomized JAK has received consulting fees, advisory board fees, lecture fees, and/or grant support from the majority of companies concerned with skeletal metabolism. C C has received consulting fees and paid advisory boards for Alliance for Better Bone Health, GlaxoSmithKline, Roche, Merck Sharp and Dohme, Lilly, Amgen, Wyeth, Novartis, Servier, and Nycomed. RR: Paid advisory boards and lecture fee for Merck Sharp and Dohme, Eli Lilly, Amgen, Servier, Takeda, and Danone. J-Y R on behalf of the Department of Public Health, Epidemiology and Health Economics of the University of Liege, Liege, Belgium. Consulting fees or paid advisory boards: Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, Theramex, UCB. Lecture fees when speaking at the invitation of a commercial sponsor: Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Theramex, Nycomed, Novo-Nordisk.