Treatment needs and current options for postmenopausal osteoporosis

ABSTRACT Introduction: Osteoporosis is a chronic, skeletal disorder characterized by compromised bone strength and increased risk of fractures, affecting up to 50% of postmenopausal women worldwide. Over the past 2 decades there have been consistent developments in the pharmacotherapy of osteoporosis with the availability of potent inhibitors of bone resorption (bisphosphonates, and denosumab) or stimulators of bone formation (PTH analogs) with substantial improvements over calcitonin or estrogen replacement. Areas covered: In this review we summarize the effects of existing treatment options for postmenopausal osteoporosis along with the unmet clinical needs and we discuss about the potential benefits of new compounds under development. Expert opinion: Despite the recent progresses, there are still limitations and unmeet needs with all the available drugs, mainly concerning treatment adherence, efficacy on the prevention of nonvertebral fractures and the long-term adverse events of antiresorptive regimens. Moreover, PTH analogs are the only available compounds able to stimulate bone formation, but with a restricted anabolic window of no more than 2 years. Of interest, the more recent advances in bone biology identified new targets for the development of drugs with a more potent and selective activity on either osteoclasts or osteoblasts, thus making possible to uncouple bone formation from bone resorption.

[1]  D. Bauer,et al.  Managing Osteoporosis in Patients on Long‐Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research , 2016, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[2]  Hang Lee,et al.  Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial , 2015, The Lancet.

[3]  R. Nuti,et al.  Appropriate models for novel osteoporosis drug discovery and future perspectives , 2015, Expert opinion on drug discovery.

[4]  S. Cummings,et al.  Osteoporosis: the evolution of a diagnosis , 2015, Journal of internal medicine.

[5]  F. Cosman Abaloparatide: a new anabolic therapy on the horizon. , 2015, BoneKEy reports.

[6]  E. Lewiecki,et al.  Denosumab for the treatment of osteoporosis , 2015, Expert opinion on drug metabolism & toxicology.

[7]  J. Zanchetta,et al.  Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. , 2015, The Journal of clinical endocrinology and metabolism.

[8]  R. Recker,et al.  A Randomized, Double‐Blind Phase 2 Clinical Trial of Blosozumab, a Sclerostin Antibody, in Postmenopausal Women with Low Bone Mineral Density , 2015, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[9]  E. Roehm A Reappraisal of Women's Health Initiative Estrogen-Alone Trial: Long-Term Outcomes in Women 50–59 Years of Age , 2015, Obstetrics and gynecology international.

[10]  S. Ferrari Future directions for new medical entities in osteoporosis. , 2014, Best practice & research. Clinical endocrinology & metabolism.

[11]  J. Eisman,et al.  Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial , 2014, Osteoporosis International.

[12]  B. Komm,et al.  An overview of current and emerging SERMs , 2014, The Journal of Steroid Biochemistry and Molecular Biology.

[13]  R. Chapurlat,et al.  Emerging drugs for osteoporosis , 2014, Expert opinion on emerging drugs.

[14]  S. Manolagas Wnt signaling and osteoporosis. , 2014, Maturitas.

[15]  F. Naftolin,et al.  The Women's Health Initiative trial and related studies: 10 years later: A clinician's view , 2014, The Journal of Steroid Biochemistry and Molecular Biology.

[16]  M. Manolson,et al.  Novel techniques in the development of osteoporosis drug therapy: the osteoclast ruffled-border vacuolar H+-ATPase as an emerging target , 2014, Expert opinion on drug discovery.

[17]  S. Silverman,et al.  The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group , 2014, Osteoporosis International.

[18]  J. Małyszko New renal anemia drugs: is there really anything new on the horizon? , 2014, Expert opinion on emerging drugs.

[19]  T. Spector,et al.  Effect of ONO‐5334 on Bone Mineral Density and Biochemical Markers of Bone Turnover in Postmenopausal Osteoporosis: 2‐Year Results From the OCEAN Study , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[20]  Cesar Libanati,et al.  Romosozumab in postmenopausal women with low bone mineral density , 2014, The New England journal of medicine.

[21]  B. Komm,et al.  Current and evolving approaches to individualizing estrogen receptor-based therapy for menopausal women. , 2014, The Journal of clinical endocrinology and metabolism.

[22]  Srijit Das,et al.  Bone metabolism and histomorphometric changes in murine models treated with sclerostin antibody: a systematic review. , 2013, Current drug targets.

[23]  B. Komm,et al.  Tissue-selective estrogen complexes for postmenopausal women. , 2013, Maturitas.

[24]  T. Bellido Osteocyte-Driven Bone Remodeling , 2013, Calcified Tissue International.

[25]  Jacques P. Brown,et al.  The Effect of Three or Six Years of Denosumab Exposure in Women With Postmenopausal Osteoporosis: Results From the FREEDOM Extension , 2013, The Journal of clinical endocrinology and metabolism.

[26]  Hang Lee,et al.  Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial , 2013, The Lancet.

[27]  R. Chapurlat,et al.  Effects of odanacatib on BMD and safety in the treatment of osteoporosis in postmenopausal women previously treated with alendronate: a randomized placebo-controlled trial. , 2013, The Journal of clinical endocrinology and metabolism.

[28]  R. Lobo,et al.  Global Consensus Statement on menopausal hormone therapy. , 2013, Maturitas.

[29]  S. Khosla,et al.  Estrogen and the skeleton , 2012, Trends in Endocrinology & Metabolism.

[30]  N. Binkley,et al.  Odanacatib in the treatment of postmenopausal women with low bone mineral density: Five years of continued therapy in a phase 2 study , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[31]  S. Cummings,et al.  Continuing bisphosphonate treatment for osteoporosis--for whom and for how long? , 2012, The New England journal of medicine.

[32]  T. D. de Villiers,et al.  The WHI: the effect of hormone replacement therapy on fracture prevention , 2012, Climacteric : the journal of the International Menopause Society.

[33]  R. Recker,et al.  Benefits and risks of bisphosphonate therapy for osteoporosis. , 2012, The Journal of clinical endocrinology and metabolism.

[34]  L. Duong,et al.  Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[35]  L. Duong,et al.  Odanacatib treatment increases hip bone mass and cortical thickness by preserving endocortical bone formation and stimulating periosteal bone formation in the ovariectomized adult rhesus monkey , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[36]  S. Boonen,et al.  Inhibition of Cathepsin K for Treatment of Osteoporosis , 2012, Current Osteoporosis Reports.

[37]  N. Loveridge,et al.  Patients with sclerosteosis and disease carriers: Human models of the effect of sclerostin on bone turnover , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[38]  S. Cremers,et al.  Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis , 2011, Nature Reviews Rheumatology.

[39]  J. Mönkkönen,et al.  Biochemical and molecular mechanisms of action of bisphosphonates. , 2011, Bone.

[40]  T. Spector,et al.  Safety and efficacy of the cathepsin K inhibitor ONO‐5334 in postmenopausal osteoporosis: The OCEAN study , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[41]  T. Rachner,et al.  Osteoporosis: now and the future , 2011, The Lancet.

[42]  S. Boonen,et al.  Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[43]  S. Papapoulos Targeting sclerostin as potential treatment of osteoporosis , 2011, Annals of the rheumatic diseases.

[44]  R. Goswami,et al.  Investigational anabolic therapies for osteoporosis , 2010, Expert opinion on investigational drugs.

[45]  C. Löwik,et al.  Sclerostin: Current Knowledge and Future Perspectives , 2010, Calcified Tissue International.

[46]  R. Rizzoli,et al.  Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three‐year continued therapy and resolution of effect , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[47]  J. Eisman,et al.  Odanacatib, a cathepsin‐K inhibitor for osteoporosis: A two‐year study in postmenopausal women with low bone density , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[48]  Claus Christiansen,et al.  Denosumab for prevention of fractures in postmenopausal women with osteoporosis. , 2009, The New England journal of medicine.

[49]  Mathieu Charlebois,et al.  Improvements in Vertebral Body Strength Under Teriparatide Treatment Assessed In Vivo by Finite Element Analysis: Results From the EUROFORS Study , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[50]  A. Pioszak,et al.  Structural Basis for Parathyroid Hormone-related Protein Binding to the Parathyroid Hormone Receptor and Design of Conformation-selective Peptides* , 2009, The Journal of Biological Chemistry.

[51]  L. Gennari Perspectives in the treatment and prevention of osteoporosis. , 2009, Drugs of today.

[52]  P. Roschger,et al.  Treatment of Osteoporosis with Parathyroid Hormone and Teriparatide , 2009, Calcified Tissue International.

[53]  J. Bilezikian Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. , 2009, The American journal of medicine.

[54]  J. Reginster,et al.  Bone-forming agents in the management of osteoporosis. , 2008, Best practice & research. Clinical endocrinology & metabolism.

[55]  Ego Seeman,et al.  Bone remodelling: its local regulation and the emergence of bone fragility. , 2008, Best practice & research. Clinical endocrinology & metabolism.

[56]  J. Bilezikian Combination anabolic and antiresorptive therapy for osteoporosis: Opening the anabolic window , 2008, Current osteoporosis reports.

[57]  J. Falgueyret,et al.  The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. , 2008, Bioorganic & medicinal chemistry letters.

[58]  R. Jackson,et al.  The role of hormone therapy and calcium plus vitamin D for reduction of bone loss and risk for fractures: Lessons learned from the women’s health initiative , 2007, Current osteoporosis reports.

[59]  E. Seeman Is a change in bone mineral density a sensitive and specific surrogate of anti-fracture efficacy? , 2007, Bone.

[60]  Andrea Giustina,et al.  Mechanisms of anabolic therapies for osteoporosis. , 2007, The New England journal of medicine.

[61]  R. Baron,et al.  Wnt signaling and the regulation of bone mass , 2007, Current osteoporosis reports.

[62]  S. Cummings,et al.  Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. , 2007, The New England journal of medicine.

[63]  B. Komm,et al.  Wnt signaling and osteoblastogenesis , 2007, Reviews in Endocrine and Metabolic Disorders.

[64]  P. Delmas,et al.  Change in Lumbar Spine BMD and Vertebral Fracture Risk Reduction in Teriparatide‐Treated Postmenopausal Women With Osteoporosis , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[65]  T. Keaveny,et al.  Effects of Teriparatide and Alendronate on Vertebral Strength as Assessed by Finite Element Modeling of QCT Scans in Women With Osteoporosis , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[66]  M. Kleerekoper Osteoporosis prevention and therapy: preserving and building strength through bone quality , 2006, Osteoporosis International.

[67]  J. Reginster,et al.  Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover. , 2006, Bone.

[68]  Y. Yazici,et al.  Denosumab in postmenopausal women with low bone mineral density. , 2006, The New England journal of medicine.

[69]  P. Delmas,et al.  Bone quality--the material and structural basis of bone strength and fragility. , 2006, The New England journal of medicine.

[70]  O. MacDougald,et al.  Regulation of bone mass by Wnt signaling. , 2006, The Journal of clinical investigation.

[71]  R. Russell,et al.  Bisphosphonates: from bench to bedside. , 2006, Annals of the New York Academy of Sciences.

[72]  L. Raisz Pathogenesis of osteoporosis: concepts, conflicts, and prospects. , 2005, The Journal of clinical investigation.

[73]  E. Schwartz,et al.  Combination Teriparatide and Raloxifene Therapy for Postmenopausal Osteoporosis: Results From a 6‐Month Double‐Blind Placebo‐Controlled Trial , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[74]  D. Black,et al.  Clinical Practice. Postmenopausal Osteoporosis. , 2005, The New England journal of medicine.

[75]  G. Dalsky,et al.  Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. , 2005, Archives of internal medicine.

[76]  S. Boonen,et al.  Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies , 2005, Osteoporosis International.

[77]  Colin R Dunstan,et al.  A Single‐Dose Placebo‐Controlled Study of AMG 162, a Fully Human Monoclonal Antibody to RANKL, in Postmenopausal Women , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[78]  A. LaCroix,et al.  Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. , 2003, JAMA.

[79]  M. Kulldorff,et al.  Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial. , 2003, JAMA.

[80]  Mary Cushman,et al.  Estrogen plus progestin and the risk of coronary heart disease. , 2003, The New England journal of medicine.

[81]  R. Marcus,et al.  The Skeletal Response to Teriparatide Is Largely Independent of Age, Initial Bone Mineral Density, and Prevalent Vertebral Fractures in Postmenopausal Women With Osteoporosis , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[82]  Sundeep Khosla,et al.  Sex steroids and the construction and conservation of the adult skeleton. , 2002, Endocrine reviews.

[83]  J. Compston,et al.  Mechanisms by which high-dose estrogen therapy produces anabolic skeletal effects in postmenopausal women: role of locally produced growth factors. , 2001, Bone.

[84]  J. Reginster,et al.  Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. , 2001, The New England journal of medicine.

[85]  G Shimamoto,et al.  Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density , 1997, Cell.

[86]  R. Lindsay,et al.  Anabolic actions of parathyroid hormone on bone. , 1993, Endocrine reviews.

[87]  S. Cummings,et al.  Bone density at various sites for prediction of hip fractures , 1993, The Lancet.

[88]  C. Christiansen,et al.  Estrogens, bone loss and preservation , 1990, Osteoporosis International.

[89]  J Reeve,et al.  Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. , 1980, British medical journal.

[90]  L. Klenerman,et al.  ANABOLIC EFFECT OF LOW DOSES OF A FRAGMENT OF HUMAN PARATHYROID HORMONE ON THE SKELETON IN POSTMENOPAUSAL OSTEOPOROSIS , 1976, The Lancet.

[91]  T. Gardella,et al.  Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling. , 2016, Endocrinology.

[92]  D. Bauer,et al.  Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. , 2013, The American journal of medicine.

[93]  A. Meikle Odanacatib in the Treatment of Postmenopausal Women With Low Bone Mineral Density: Three-Year Continued Therapy and Resolution of Effect , 2011 .

[94]  B. Clarke,et al.  Effects of Teriparatide Treatment and Discontinuation in Postmenopausal Women and Eugonadal Men with Osteoporosis , 2010 .

[95]  Sundeep Khosla,et al.  Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. , 2008, Endocrine reviews.

[96]  T. Gardella,et al.  Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor. , 2008, Molecular endocrinology.

[97]  B. Clarke,et al.  Effect of Recombinant Human Parathyroid Hormone (1-84) on Vertebral Fracture and Bone Mineral Density in Postmenopausal Women with Osteoporosis: A Randomized Trial , 2008 .

[98]  B. Clarke,et al.  One Year of Alendronate After One Year of Parathyroid Hormone (1–84) for Osteoporosis , 2006 .

[99]  L. Boothby Bisphosphonates for the Prevention and Treatment of Osteoporosis , 2003 .

[100]  R. Eliakim,et al.  [Postmenopausal osteoporosis]. , 1983, Harefuah.