Pharmacological management of osteoporosis in postmenopausal women: The current state of the art

Main Article Content

Davide Gatti
Angelo Fassio https://orcid.org/0000-0001-9187-232X

Keywords

osteoporosis, bone metabolism, bone mineral density, bisphosphonate, teriparatide, alendronate, zoledronate, risedronate, clodronate, hormonal therapy, TSEC, denosumab, romosozumab, strontium ranelate, combination therapy, sequential therapy

Abstract

Osteoporosis is a common disease that increases fracture risk. Fragility fractures bring heavy consequences in terms of mortality and disability, with burdensome health and social costs. In subjects with clinical bone fragility, the first goal is to identify the secondary forms of osteoporosis, especially in young subjects, in males and in patients who recently experienced a fragility fracture. In addition, before considering any sort of treatment, it is fundamental to check for adequate calcium and vitamin D intake, since their deficiency is the most common reason for drug failure.

In the last decade of the 20th century, several molecules have been developed and proved to be effective in achieving the true goal of any antiosteoporotic drug: fracture prevention.

 
In this article, we considered the most commonly prescribed antiresorptive drugs (hormonal therapy, bisphosphonates, and denosumab), the anabolic agents (teriparatide), the dual-action drugs (romosozumab), and the drugs characterized by an unclear mechanism of action (strontium ranelate) to provide physicians with useful insights for their clinical practice. We discussed the main criteria for the appropriate choice selection and management of each treatment. Finally, we addressed the current controversies related to treatment discontinuation, sequential, and combination therapy.

Abstract 1156 | PDF Downloads 680 HTML Downloads 26 XML Downloads 8

References

1. Consensus development conference: Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 1993;94(6):646–50.
2. Kanis JA, Cooper C, Rizzoli R, Reginster J-Y, Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis (ESCEO) and the Committees of Scientific Advisors and National Societies of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmeno-pausal women. Osteoporos Int 2019;30(1):3–44.
3. Hernlund E, Svedbom A, Ivergård M, et al. Osteoporosis in the European Union: Medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 2013;8:136.
4. Degli Esposti L, Girardi A, Saragoni S, et al. Use of antiosteoporotic drugs and calcium/vitamin D in patients with fragility fractures: Impact on re-fracture and mortality risk. Endocrine 2019;64(2):367–77.
5. Prieto-Alhambra D, Moral-Cuesta D, Palmer A, et al. The impact of hip fracture on health-related quality of life and activities of daily living: The SPARE-HIP prospective cohort study. Arch Osteoporos 2019;14(1):56.
6. Rossini M, Adami S, Bertoldo F, et al. Guidelines for the diagnosis, prevention and management of osteoporosis. Reumatismo 2016;68(1):1–39.
7. Fassio A, Rossini M, Gatti D. Vitamin D: No efficacy without deficiency. What’s new? Reumatismo 2019;71(2):57–61.
8. Adami S, Viapiana O, Gatti D, Idolazzi L, Rossini M. Relationship between serum parathyroid hormone, vitamin D sufficiency, age, and calcium intake. Bone 2008;42(2):267–70.
9. Adami S, Romagnoli E, Carnevale V, et al. Guidelines on prevention and treatment of vitamin D deficiency. Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS). Reumatismo 2011;63(3):129–47.
10. Murad MH, Drake MT, Mullan RJ, et al. Clinical review. Comparative effectiveness of drug treatments to prevent fragility fractures: A systematic review and network meta-analysis. J Clin Endocrinol Metab 2012;97(6):1871–80.
11. Freemantle N, Cooper C, Diez-Perez A, et al. Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: A meta-analysis. Osteoporos Int 2013;24(1):209–17.
12. Milhaud G, Christiansen C, Gallagher C, et al. Pathogenesis and treatment of postmenopausal osteoporosis. Calcif Tissue Int 1983;35(6):708–11.
13. Siris ES, Adler R, Bilezikian J, et al. The clinical diagnosis of osteoporosis: A position statement from the National Bone Health Alliance Working Group. Osteoporos Int 2014;25(5):1439–43.
14. Faubion SS, Kuhle CL, Shuster LT, Rocca WA. Long-term health consequences of premature or early menopause and considerations for management. Climacteric 2015;18(4):483–91.
15. Vignozzi L, Malavolta N, Villa P, Mangili G, Migliaccio S, Lello S. Consensus statement on the use of HRT in postmenopausal women in the man-agement of osteoporosis by SIE, SIOMMMS and SIGO. J Endocrinol Invest 2019;42(5):609–18.
16. Rossini M, Gatti D, Adami S. Involvement of WNT/β-catenin signaling in the treatment of osteoporosis. Calcif Tissue Int 2013;93(2):121–32.
17. Pradhan AD, Manson JE, Rossouw JE, et al. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: Prospective analysis from the Women’s Health Initiative observational study. JAMA 2002;288(8):980–7.
18. Beral V, Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362(9382):419–27.
19. Shufelt C, Bairey Merz CN, Pettinger MB, et al. Estrogen-alone therapy and invasive breast cancer incidence by dose, formulation, and route of delivery: Findings from the WHI observational study. Menopause 2018;25(9):985–91.
20. Moreno AC, Sahni SK, Smith TL, Batur P. Women’s health 2019: Osteoporosis, breast cancer, contraception, and hormone therapy. Cleve Clin J Med 2019;86(6):400–6.
21. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 2017;317(23):2402–16.
22. Torgerson DJ, Bell-Syer SE. Hormone replacement therapy and prevention of nonvertebral fractures: A meta-analysis of randomized trials. JAMA 2001;285(22):2891–7.
23. Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: Results from the wom-en’s health initiative randomized trial. J Bone Miner Res 2006;21(6):817–28.
24. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health out-comes during the intervention and extended post-stopping phases of the Women’s Health Initiative randomized trials. JAMA 2013;310(13):1353–68.
25. Reed MJ, Kloosterboer HJ. Tibolone: A selective tissue estrogenic activity regulator (STEAR). Maturitas 2004;48(Suppl 1):S4–6.
26. Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359(7):697–708.
27. Shelly W, Draper MW, Krishnan V, Wong M, Jaffe RB. Selective estrogen receptor modulators: An update on recent clinical findings. Obstet Gynecol Surv 2008;63(3):163–81.
28. Gatti D, Rossini M, Sblendorio I, Lello S. Pharmacokinetic evaluation of bazedoxifene for the treatment of osteoporosis. Expert Opin Drug Metab Toxicol 2013;9(7):883–92.
29. Silverman SL, Christiansen C, Genant HK, et al. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: Results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 2008;23(12):1923–34.
30. Silverman SL, Chines AA, Kendler DL, et al. Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: Results of a 5-year, randomized, placebo-controlled study. Osteoporos Int 2012;23(1):351–63.
31. Ellis AG, Reginster J-Y, Luo X, et al. Indirect comparison of bazedoxifene vs oral bisphospho-nates for the prevention of vertebral fractures in postmenopausal osteoporotic women. Curr Med Res Opin 2014;30(8):1617–26.
32. Ellis AG, Reginster J-Y, Luo X, et al. Bazedoxifene versus oral bisphosphonates for the prevention of nonvertebral fractures in postmenopausal women with osteoporosis at higher risk of fracture: A net-work meta-analysis. Value Health 2014;17(4):424–32.
33. Vescini F, Attanasio R, Balestrieri A, et al. Italian association of clinical endocrinologists (AME) position statement: Drug therapy of osteoporosis. J Endocrinol Invest 2016;39(7):807–34.
34. Rossini M, Lello S, Sblendorio I, et al. Profile of bazedoxifene/conjugated estrogens for the treatment of estrogen deficiency symptoms and osteoporosis in women at risk of fracture. Drug Des Devel Ther 2013;7:601–10.
35. Cianferotti L, Bertoldo F, Carini M, et al. The prevention of fragility fractures in patients with non-metastatic prostate cancer: A position statement by the international osteoporosis foundation. Oncotarget 2017;8(43):75646–63.
36. Gatti D, Adami S, Viapiana O, Rossini M. The use of bisphosphonates in women: When to use and when to stop. Expert Opin Pharmacother 2015;16(16):2409–21.
37. Axelsson KF, Wallander M, Johansson H, Lundh D, Lorentzon M. Hip fracture risk and safety with alendronate treatment in the oldest-old. J Intern Med 2017;282(6):546–59.
38. Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357(18):1799–809.
39. Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: Second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2014;29(1):1–23.
40. Nicolaou N, Agrawal Y, Padman M, Fernandes JA, Bell MJ. Changing pattern of femoral fractures in osteogenesis imperfecta with prolonged use of bisphosphonates. J Child Orthop 2012;6(1):21–7.
41. Rossini M, Adami G, Adami S, Viapiana O, Gatti D. Safety issues and adverse reactions with osteoporosis management. Expert Opin Drug Saf 2016;15(3):321–32.
42. Rizzoli R, Akesson K, Bouxsein M, et al. Subtrochanteric fractures after long-term treatment with bisphosphonates: A European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report. Osteoporos Int 2011;22(2):373–90.
43. Wang Z, Bhattacharyya T. Trends in incidence of subtrochanteric fragility fractures and bisphosphonate use among the US elderly, 1996–2007. J Bone Miner Res 2011;26(3):553–60.
44. McCloskey E, Selby P, Davies M, et al. Clodronate reduces vertebral fracture risk in women with post-menopausal or secondary osteoporosis: Results of a double-blind, placebo-controlled 3-year study. J Bone Miner Res 2004;19(5):728–36.
45. McCloskey EV, Beneton M, Charlesworth D, et al. Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: Results of a double-blind, placebo-controlled randomized study. J Bone Miner Res 2007;22(1):135–41.
46. Rossini M, Braga V, Gatti D, Gerardi D, Zamberlan N, Adami S. Intramuscular clodronate therapy in postmenopausal osteoporosis. Bone 1999;24(2):125–9.
47. Frediani B, Falsetti P, Baldi F, Acciai C, Filippou G, Marcolongo R. Effects of 4-year treatment with once-weekly clodronate on prevention of cortico-steroid-induced bone loss and fractures in patients with arthritis: Evaluation with dual-energy X-ray absorptiometry and quantitative ultrasound. Bone 2003;33(4):575–81.
48. Frediani B. Effects of two administration schemes of intramuscular clodronic acid on bone mineral density: A randomized, open-label, parallel-group study. Clin Drug Investig 2011;31(1):43–50.
49. Fassio A, Rossini M, Viapiana O, et al. New strategies for the prevention and treatment of systemic and local bone loss; from pathophysiology to clinical application. Curr Pharm Des 2017;23(41):6241–50.
50. Fassio A, Adami G, Benini C, et al. Changes in Dkk-1, sclerostin, and RANKL serum levels following discontinuation of long-term denosumab treatment in postmenopausal women. Bone 2019;123:191–5.
51. Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 1999;104(4):439–46.
52. Saag KG, Zanchetta JR, Devogelaer J-P, et al. Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: Thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis Rheum 2009;60(11):3346–55.
53. den Uyl D, Bultink IEM, Lems WF. Advances in glucocorticoid-induced osteoporosis. Curr Rheumatol Rep 2011;13(3):233–40.
54. Gatti D, Viapiana O, Idolazzi L, Fracassi E, Rossini M, Adami S. The waning of teriparatide effect on bone formation markers in postmenopausal osteoporosis is associated with increasing serum levels of DKK1. J Clin Endocrinol Metab 2011;96(5):1555–9.
55. Tamanini S, Idolazzi L, Gatti D, Viapiana O, Fassio A, Rossini M. Insight into the WNT sys-tem and its drug related response. Reumatismo 2013;65(5):219–30.
56. Padhi D, Allison M, Kivitz AJ, et al. Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: A randomized, double-blind, placebo-controlled study. J Clin Pharmacol 2014;54(2):168–78.
57. Appelman-Dijkstra NM, Papapoulos SE. Sclerostin inhibition in the management of osteoporosis. Calcif Tissue Int 2016;98(4):370–80.
58. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016;375(16):1532–43.
59. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 2017;377(15):1417–27.
60. Sing C-W, Wong AY, Kiel DP, et al. Association of alendronate and risk of cardiovascular events in patients with hip fracture. J Bone Miner Res 2018;33(8):1422–34.
61. Giollo A, Rossini M, Gatti D, et al. Amino-bisphosphonates and cardiovascular risk: A new hypothesis involving the effects on gamma-delta T cells. J Bone Miner Res 2019;34(3):570–1.
62. Bliuc D, Tran T, van Geel T, et al. Reduced bone loss is associated with reduced mortality risk in subjects exposed to nitrogen bisphosphonates: A mediation analysis. J Bone Miner Res 2019;34(11):2001–11.
63. Idolazzi L, Fassio A, Gatti D, et al. Duration of treatment for osteoporosis. Reumatismo 2013;65(1):22–35.
64. McClung MR. Romosozumab for the treatment of osteoporosis. Osteoporos Sarcopenia 2018;4(1):11–5.
65. Leder BZ. Optimizing sequential and combined anabolic and antiresorptive osteoporosis therapy. JBMR Plus 2018;2(2):62–8.
66. Cosman F, Nieves JW, Dempster DW. Treatment sequence matters: Anabolic and antiresorptive therapy for osteoporosis. J Bone Miner Res 2017;32(2):198–202.
67. Idolazzi L, Rossini M, Viapiana O, et al. Teriparatide and denosumab combination therapy and skeletal metabolism. Osteoporos Int 2016;27(11):3301–7.
68. Leder BZ, Tsai JN, Uihlein AV, et al. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): Extension of a randomised controlled trial. Lancet 2015;386(9999):1147–55.
69. Cheng C, Wentworth K, Shoback DM. New frontiers in osteoporosis therapy. Annu Rev Med 2020;71:12.1–12.12.