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
SeriesOsteoporosis treatment: recent developments and ongoing challenges
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
References (74)
- et al.
Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women
Fertil Steril
(2009) - et al.
A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the Prevent Recurrence Of Osteoporotic Fractures study
Am J Med
(2000) Bisphosphonates: the first 40 years
Bone
(2011)- et al.
Anabolic effect of low doses of a fragment of human parathyroid hormone on the skeleton in postmenopausal osteoporosis
Lancet
(1976) - et al.
Osteoprotegerin: a novel secreted protein involved in the regulation of bone density
Cell
(1997) - et al.
Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation
Cell
(1998) Osteoclasts: what do they do and how do they do it?
Am J Pathol
(2007)- et al.
Incomplete atypical femoral fractures: assessing the diagnostic utility of DXA by extending femur length
J Clin Densitom
(2013) - et al.
10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension
Lancet Diabetes Endocrinol
(2017) - et al.
Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial
Lancet
(2015)
Selective estrogen-receptor modulators—mechanisms of action and application to clinical practice
N Engl J Med
Benefits and risks of bisphosphonate therapy for osteoporosis
J Clin Endocrinol Metab
Receptor activator of nuclear factor κB ligand and osteoprotegerin regulation of bone remodeling in health and disease
Endocr Rev
Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis
N Engl J Med
Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial
JAMA
Romosozumab treatment in postmenopausal women with osteoporosis
N Engl J Med
Merck & Co. drops osteoporosis drug odanacatib
Nat Rev Drug Discov
Impact of the US Food and Drug Administration's safety-related announcements on the use of bisphosphonates after hip fracture
J Bone Miner Res
Post-menopausal osteoporosis
Trans Assoc Am Physicians
Osteoporosis in men
Endocr Rev
Long-term prevention of postmenopausal osteoporosis by oestrogen
Lancet
Treatment of postmenopausal osteoporosis with transdermal estrogen
Ann Intern Med
Effect of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial
JAMA
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial
JAMA
Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial
Obstet Gynecol
Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene results from a 3-year randomized clinical trial
JAMA
Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial
JAMA
Calcitonin: physiology and pathophysiology
N Engl J Med
Novartis. Drug regulatory affairs. FDA Joint Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committee Meeting on the benefit/risk of salmon calcitonin for the treatment of postmenopausal osteoporosis
Mechanisms of action of bisphosphonates: similarities and differences and their potential influences on clinical efficacy
Osteoporos Int
Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone Mineral Research
J Bone Miner Res
Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research
J Bone Miner Res
Bisphosphonates for osteoporosis—where do we go from here?
N Engl J Med
Hyperparathyroidism. A common and polymorphic condition as illustrated by seventeen proved cases from one clinic
JAMA
Bone neoplasms in F344 rats given teriparatide [rhPTH(1-34)] are dependent on duration of treatment and dose
Toxicol Pathol
The US postmarketing surveillance study of adult osteosarcoma and teriparatide: study design and findings from the last 7 years
J Bone Miner Res
Drugs@FDA: FDA approved drug products. Abaloparatide
Cited by (636)
A review: the mechanism of plant-derived polysaccharides on osteoblasts and osteoclasts
2024, Journal of Future FoodsPositive benefit-risk ratio of Psoraleae Fructus: Comprehensive safety assessment and osteogenic effects in rats
2024, Journal of EthnopharmacologyVSIG4 inhibits RANKL-induced osteoclastogenesis by enhancing Nrf2-dependent antioxidant response against reactive oxygen species production
2024, International Journal of Biological MacromoleculesA novel calcium phosphate-based ceramic scaffolds with unexpected high osteogenic activity by strontium doping
2024, Materials Today Chemistry