Series
Osteoporosis treatment: recent developments and ongoing challenges

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Summary

Osteoporosis is an enormous and growing public health problem. Once considered an inevitable consequence of ageing, it is now eminently preventable and treatable. Ironically, despite tremendous therapeutic advances, there is an increasing treatment gap for patients at high fracture risk. In this Series paper, we trace the evolution of drug therapy for osteoporosis, which began in the 1940s with the demonstration by Fuller Albright that treatment with oestrogen could reverse the negative calcium balance that developed in women after menopause or oophorectomy. We note a watershed in osteoporosis drug discovery around the year 2000, when the approach to developing novel therapeutics shifted from one driven by discoveries in animal studies and clinical observations (eg, oestrogen, calcitonin, and teriparatide) or opportunistic repurposing of existing compounds (eg, bisphosphonates) to one driven by advances in fundamental bone biology (eg, denosumab) coupled with clues from patients with rare bone diseases (eg, romosozumab, odanacatib). Despite these remarkable advances, concerns about rare side-effects of anti-resorptive drugs, particularly bisphosphonates, and the absence of clear evidence in support of their long-term efficacy is leading many patients who could benefit from drug therapy to not take these drugs. As such, there remains an important clinical need to develop ways to enhance patient acceptance and compliance with these effective drugs, and to continue to develop new drugs that do not cause these side-effects and have prolonged anabolic effects on bone. Such changes could lead to a true reversal of this potentially devastating disease of ageing.

Introduction

The past 30 years have witnessed remarkable developments in our understanding of the pathogenesis of osteoporosis and the availability of new drugs to treat the disease. In the late 1980s, a doctor could offer a postmenopausal woman little else but oestrogen replacement and perhaps calcitonin, along with calcium and vitamin D supplementation, as a treatment for osteoporosis. In 2017, the options include not only oestrogen and calcitonin, but also a selective oestrogen-receptor modulator (SERM; raloxifene),1 four bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid),2 a human monoclonal antibody to the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL; denosumab),3 and the parathyroid hormone analogue teriparatide.4 On the horizon are two new drugs: a parathyroid hormone-related peptide analogue (abaloparatide)5 and a humanised monoclonal antibody to sclerostin (romosozumab).6 A third candidate drug, the cathepsin K inhibitor odanacatib, had significant anti-fracture efficacy, but the pivotal phase 3 clinical trial was terminated because of an unforeseen increased risk of stroke.7 Despite this remarkable progress in drug development for the prevention and treatment of fractures, major challenges to implementing appropriate treatment remain, even for patients who unequivocally need therapy. For example, among 22 598 patients in an American commercial health plan who had a hip fracture, use of bisphosphonates decreased from only 15% in 2004 to 3% in 2013.8

In this Series paper, we briefly review the history of drug development for osteoporosis, noting an important shift in discovery approaches around the year 2000. We then focus on drugs that are on the horizon and present ongoing challenges to ensuring that patients who are at increased fracture risk receive appropriate treatment. Finally, we review the case that despite the tremendous progress to date, compelling reasons exist for continued drug discovery and development for the prevention of fractures.

Section snippets

Overview of existing therapies

An overview of existing drugs for the prevention or treatment of osteoporosis and their development pathways are shown in table 1.

Shift in drug discovery approaches

Since the development of denosumab, new drugs for osteoporosis treatment have been discovered by careful analysis of rare bone diseases and bone cell biology, particularly subcellular assessment of the osteoclast—underlining the importance of translational research.39 Thus, the two human bone phenotypes of sclerosteosis40 and van Buchem's disease,41 both characterised by increased bone mass and intrinsic resistance to fractures as a result of functional loss of the Wnt inhibitor sclerostin,

The growing gap in treatment options

Despite the increasing number of effective drugs to treat osteoporosis, discouraging evidence suggests that many patients who should receive pharmacological treatment are either not being offered these drugs or, when prescribed, are not taking them.62 This is true even in patients recovering from hip fracture, for whom there is universal agreement of the importance of pharmacological therapy.63 Although many reasons exist for this gap in osteoporosis treatment, perhaps the two most important

The case for new drug development

Classic anti-resorptive drugs such as bisphosphonates and denosumab are associated with the risk of osteonecrosis of the jaw and atypical femur fractures. Although the anti-fracture benefit by far outweighs their risk, public perception of these complications has contributed to reduced treatment rates. The cathepsin K inhibitor odanacatib was unique because it left osteoclasts viable, allowing intercellular communication and perhaps reducing the risk of osteonecrosis of the jaw, but its

Conclusion

The evolution of drug development for osteoporosis, from clinical observations or opportunistic discoveries to the more recent framework of fundamental bone biology driving novel therapeutics, is truly remarkable. It represents perhaps one of the best examples of private and public investments in discovery science facilitating the development of drugs that have the potential to benefit patients. With the available anti-resorptive drugs and the expanding list of anabolic options for the

Search strategy and selection criteria

We searched PubMed for articles published between Jan 1, 1990, to April 30, 2017, with the terms “osteoporosis”, “bone loss”, and “fractures” in combination with the terms “randomised-controlled trials”, “bisphosphonates”, “denosumab”, “raloxifene”, “parathyroid hormone”, “strontium ranelate”, “sclerostin”, “abaloparatide”, or “cathepsin K”. Peer-reviewed full articles resulting from this search strategy and key references cited in those articles were reviewed. Only articles published in

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