The Portuguese state of the art on osteoporosis and fracture risk: an update on the treatment options

Abstract

Osteoporosis and fragility fractures are serious public health problems, which greatly impact individual health and the economy of other health services. Pharmacological treatment is still one of the main elements of clinical intervention, combined with non-pharmacological measures, in preventing the occurrence of fragility fractures. The emergence of promising new pharmacological options in the treatment of osteoporosis seems to renew expectations in the prevention of complications and a subsequent reduction in morbidity and mortality, including symptomatic treatment, improved physical function and a better quality of life. This review aims to provide updated information on the pharmacological treatment of osteoporosis in the adult population. A comprehensive PubMed search was performed to review the current evidence on osteoporosis treatment. Of the 378 articles identified from the initial queries, the final review included 80 articles. Currently, the following pharmacological options are available: antiresorptive (bisphosphonates, denosumab, postmenopausal hormone replacement therapy and selective oestrogen receptor modulators), bone-forming agents (essentially, teriparatide and abaloparatide) and the new dual-action therapy (romosozumab), recently approved by the US Food and Drug Administration and the European Medicines Agency, but which is not yet an option in Portugal. Therapeutic selection is essentially based on assessment of cost-effectiveness, since current evidence does not suggest any differences between the distinctive classes in reducing the risk of fractures, but this analysis is limited by the scarcity of comparative intraclass studies. Notwithstanding, romosozumab, as a dual effect therapy, is promising in resolving the physiological limitations resulting from the merely unilateral action of antiresorptive agents and bone-forming agents in the inseparable relationship between bone formation and resorption. However, its cardiovascular safety raises some concerns, and this topic is still being debated. The underdiagnosis and the undertreatment of osteoporosis remain one of the greatest challenges of the 21st century. Over the years, new drugs have appeared that have tried to address these problems with a direct impact on the health of populations, but a long way remains to be come in optimising their effectiveness, safety and tolerability.

Key words

osteoporosis - bone density conservation agents - denosumab - romosozumab - abaloparatide

Schlüsselwörter

Osteoporose - Mittel zur Erhaltung der Knochendichte - Denosumab - Romosozumab - Abaloparatid

Publication History

Article published online:
24 October 2023

• References

• 1 Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet 2019; 393: 364-376 DOI: 10.1016/S0140-6736(18)32112-3.
• 2 Kanis JA. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporos Int 1994; 4: 368-381 DOI: 10.1007/BF01622200.
• 3 Sozen T, Ozisik L, Basaran NC. An overview and management of osteoporosis. Eur J Rheumatol 2017; 4: 46-56 DOI: 10.5152/eurjrheum.2016.048.
• 4 Marques A, Lourenco O, da Silva JA. et al. The burden of osteoporotic hip fractures in Portugal: costs, health related quality of life and mortality. Osteoporos Int 2015; 26: 2623-2630 DOI: 10.1007/s00198-015-3171-5.
• 5 Hernlund E, Svedbom A, Ivergard 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 DOI: 10.1007/s11657-013-0136-1.
• 6 Iolascon G, Moretti A, Toro G. et al. Pharmacological Therapy of Osteoporosis: What's New?. Clin Interv Aging 2020; 15: 485-491 DOI: 10.2147/CIA.S242038.
• 7 Qaseem A, Forciea MA, McLean RM. et al. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann Intern Med 2017; 166: 818-839 DOI: 10.7326/M15-1361.
• 8 Khosla S, Hofbauer LC. Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol 2017; 5: 898-907 DOI: 10.1016/S2213-8587(17)30188-2.
• 9 Rodrigues AM, Canhao H, Marques A. et al. Portuguese recommendations for the prevention, diagnosis and management of primary osteoporosis – 2018 update. Acta Reumatol Port 2018; 43: 10-31
• 10 Johansson H, Kanis JA, Oden A. et al. BMD, clinical risk factors and their combination for hip fracture prevention. Osteoporos Int 2009; 20: 1675-1682 DOI: 10.1007/s00198-009-0845-x.
• 11 Curtis EM, Moon RJ, Dennison EM. et al. Recent advances in the pathogenesis and treatment of osteoporosis. Clin Med (Lond) 2016; 16: 360-364 DOI: 10.7861/clinmedicine.16-4-360.
• 12 Direção Geral de Saúde. Norma nº 004/2019, 14/08/2019 – Prevenção e Tratamento da Deficiência de Vitamina D. Available at: https://www.dgs.pt/directrizes-da-dgs/normas-ecirculares-normativas/norma-n-0042019-de-14082019-pdf.aspx. Access on November, 2020
• 13 Langdahl BL. Overview of treatment approaches to osteoporosis. Br J Pharmacol 2020; DOI: 10.1111/bph.15024.
• 14 Barrionuevo P, Kapoor E, Asi N. et al. Efficacy of Pharmacological Therapies for the Prevention of Fractures in Postmenopausal Women: A Network Meta-Analysis. J Clin Endocrinol Metab 2019; 104: 1623-1630 DOI: 10.1210/jc.2019-00192.
• 15 Langdahl B, Ferrari S, Dempster DW. Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis. Ther Adv Musculoskelet Dis 2016; 8: 225-235 DOI: 10.1177/1759720X16670154.
• 16 Kerschan-Schindl K. Romosozumab: a novel bone anabolic treatment option for osteoporosis?. Wien Med Wochenschr 2020; 170: 124-131 DOI: 10.1007/s10354-019-00721-5.
• 17 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: 209-217 DOI: 10.1007/s00198-012-2068-9.
• 18 Wen F, Du H, Ding L. et al. Clinical efficacy and safety of drug interventions for primary and secondary prevention of osteoporotic fractures in postmenopausal women: Network meta-analysis followed by factor and cluster analysis. PLoS One 2020; 15: e0234123 DOI: 10.1371/journal.pone.0234123.
• 19 Seeman E, Martin TJ. Antiresorptive and anabolic agents in the prevention and reversal of bone fragility. Nat Rev Rheumatol 2019; 15: 225-236 DOI: 10.1038/s41584-019-0172-3.
• 20 Kanis JA, Cooper C, Rizzoli R. et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2019; 30: 3-44 DOI: 10.1007/s00198-018-4704-5.
• 21 Lems WF, Dreinhofer KE, Bischoff-Ferrari H. et al. EULAR/EFORT recommendations for management of patients older than 50 years with a fragility fracture and prevention of subsequent fractures. Ann Rheum Dis 2017; 76: 802-810 DOI: 10.1136/annrheumdis-2016-210289.
• 22 Marques A, Lourenco O, Ortsater G. et al. Cost-Effectiveness of Intervention Thresholds for the Treatment of Osteoporosis Based on FRAX((R)) in Portugal. Calcif Tissue Int 2016; 99: 131-141 DOI: 10.1007/s00223-016-0132-8.
• 23 Harris ST, Watts NB, Genant HK. et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 1999; 282: 1344-1352 DOI: 10.1001/jama.282.14.1344.
• 24 Black DM, Cummings SR, Karpf DB. et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996; 348: 1535-1541 DOI: 10.1016/s0140-6736(96)07088-2.
• 25 Chesnut CH, Skag A, Christiansen C. et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004; 19: 1241-1249 DOI: 10.1359/JBMR.040325.
• 26 Rodan GA, Fleisch HA. Bisphosphonates: mechanisms of action. J Clin Invest 1996; 97: 2692-2696 DOI: 10.1172/JCI118722.
• 27 Rogers MJ, Monkkonen J, Munoz MA. Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton. Bone 2020; 139: 115493 DOI: 10.1016/j.bone.2020.115493.
• 28 Pazianas M, van der Geest S, Miller P. Bisphosphonates and bone quality. Bonekey Rep 2014; 3: 529 DOI: 10.1038/bonekey.2014.24.
• 29 Eastell R, Rosen CJ, Black DM. et al. Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society* Clinical Practice Guideline. J Clin Endocrinol Metab 2019; 104: 1595-1622 DOI: 10.1210/jc.2019-00221.
• 30 Iolascon G, Gimigliano F, Moretti A. et al. Rates and reasons for lack of persistence with anti-osteoporotic drugs: analysis of the Campania region database. Clin Cases Miner Bone Metab 2016; 13: 127-130 DOI: 10.11138/ccmbm/2016.13.2.127.
• 31 McClung MR, Zanchetta JR, Hoiseth A. et al. Denosumab densitometric changes assessed by quantitative computed tomography at the spine and hip in postmenopausal women with osteoporosis. J Clin Densitom 2013; 16: 250-256 DOI: 10.1016/j.jocd.2012.02.014.
• 32 Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 2011; 48: 677-692 DOI: 10.1016/j.bone.2010.11.020.
• 33 Bolognese MA, Teglbjaerg CS, Zanchetta JR. et al. Denosumab significantly increases DXA BMD at both trabecular and cortical sites: results from the FREEDOM study. J Clin Densitom 2013; 16: 147-153 DOI: 10.1016/j.jocd.2012.02.006.
• 34 European Medicines Agency. Summary of product characteristics. Available at www.ema.europa.eu/en/medicines/human/EPAR/prolia. Access on November, 2020
• 35 Cummings SR, San Martin J, McClung MR. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 361: 756-765 DOI: 10.1056/NEJMoa0809493.
• 36 Papapoulos S, Chapurlat R, Libanati C. et al. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 2012; 27: 694-701 DOI: 10.1002/jbmr.1479.
• 37 Ferrari S, Adachi JD, Lippuner K. et al. Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years. Osteoporos Int 2015; 26: 2763-2771 DOI: 10.1007/s00198-015-3179-x.
• 38 Papapoulos S, Lippuner K, Roux C. et al. The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study. Osteoporos Int 2015; 26: 2773-2783 DOI: 10.1007/s00198-015-3234-7.
• 39 Bone HG, Wagman RB, Brandi ML. 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; 5: 513-523 DOI: 10.1016/S2213-8587(17)30138-9.
• 40 Kendler DL, Chines A, Brandi ML. et al. The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies. Osteoporos Int 2019; 30: 71-78 DOI: 10.1007/s00198-018-4687-2.
• 41 Bilezikian JP, Lin CJF, Brown JP. et al. Long-term denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus: analyses from the FREEDOM Extension cross-over group. Osteoporos Int 2019; 30: 1855-1864 DOI: 10.1007/s00198-019-05020-8.
• 42 Langdahl BL, Teglbjaerg CS, Ho PR. et al. A 24-month study evaluating the efficacy and safety of denosumab for the treatment of men with low bone mineral density: results from the ADAMO trial. J Clin Endocrinol Metab 2015; 100: 1335-1342 DOI: 10.1210/jc.2014-4079.
• 43 Ding L, Hu J, Wang D. et al. Efficacy and Safety of First- and Second-Line Drugs to Prevent Glucocorticoid-Induced Fractures. J Clin Endocrinol Metab 2020; 105 DOI: 10.1210/clinem/dgz023.
• 44 Cummings SR, Ferrari S, Eastell R. et al. Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res 2018; 33: 190-198 DOI: 10.1002/jbmr.3337.
• 45 Reid IR, Horne AM, Mihov B. et al. Bone Loss After Denosumab: Only Partial Protection with Zoledronate. Calcif Tissue Int 2017; 101: 371-374 DOI: 10.1007/s00223-017-0288-x.
• 46 Tsourdi E, Langdahl B, Cohen-Solal M. et al. Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone 2017; 105: 11-17 DOI: 10.1016/j.bone.2017.08.003.
• 47 Migliaccio S, Francomano D, Romagnoli E. et al. Persistence with denosumab therapy in women affected by osteoporosis with fragility fractures: a multicenter observational real practice study in Italy. J Endocrinol Invest 2017; 40: 1321-1326 DOI: 10.1007/s40618-017-0701-3.
• 48 Tabatabaei-Malazy O, Salari P, Khashayar P. et al. New horizons in treatment of osteoporosis. Daru 2017; 25: 2 DOI: 10.1186/s40199-017-0167-z.
• 49 Chan CK, Mason A, Cooper C. et al. Novel advances in the treatment of osteoporosis. Br Med Bull 2016; 119: 129-142 DOI: 10.1093/bmb/ldw033.
• 50 Prior JC, Seifert-Klauss VR, Giustini D. et al. Estrogen-progestin therapy causes a greater increase in spinal bone mineral density than estrogen therapy – a systematic review and meta-analysis of controlled trials with direct randomization. J Musculoskelet Neuronal Interact 2017; 17: 146-154
• 51 Leder BZ. Parathyroid Hormone and Parathyroid Hormone-Related Protein Analogs in Osteoporosis Therapy. Curr Osteoporos Rep 2017; 15: 110-119 DOI: 10.1007/s11914-017-0353-4.
• 52 Abrahamsen B, Jorgensen HL, Laulund AS. et al. The excess risk of major osteoporotic fractures in hypothyroidism is driven by cumulative hyperthyroid as opposed to hypothyroid time: an observational register-based time-resolved cohort analysis. J Bone Miner Res 2015; 30: 898-905 DOI: 10.1002/jbmr.2416.
• 53 Direção Geral de Saúde. Norma nº 27/2011, 29/09/2011 – Tratamento Farmacológico da Osteoporose Pós-menopáusica. Available at: https://www.dgs.pt/?cr=21174. Access on November, 2020
• 54 FDA Approved Drug Products. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208743lbl.pdf. Access on November, 2020
• 55 Chew CK, Clarke BL. Abaloparatide: Recombinant human PTHrP (1-34) anabolic therapy for osteoporosis. Maturitas 2017; 97: 53-60 DOI: 10.1016/j.maturitas.2016.12.003.
• 56 Russow G, Jahn D, Appelt J. et al. Anabolic Therapies in Osteoporosis and Bone Regeneration. Int J Mol Sci 2018; 20 DOI: 10.3390/ijms20010083.
• 57 Canalis E. MANAGEMENT OF ENDOCRINE DISEASE: Novel anabolic treatments for osteoporosis. Eur J Endocrinol 2018; 178: R33-R44 DOI: 10.1530/EJE-17-0920.
• 58 Langdahl BL, Andersen JD. Treatment of Osteoporosis: Unmet Needs and Emerging Solutions. J Bone Metab 2018; 25: 133-140 DOI: 10.11005/jbm.2018.25.3.133.
• 59 Miller PD, Hattersley G, Riis BJ. et al. Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial. JAMA 2016; 316: 722-733 DOI: 10.1001/jama.2016.11136.
• 60 European Medicines Agency. Available at https://www.ema.europa.eu/en/documents/assessment-report/eladynos-epar-refusal-public-assessment-report_en.pdf. Access on December, 2020
• 61 Martin TJ, Seeman E. Abaloparatide Is an Anabolic, but Does It Spare Resorption?. J Bone Miner Res 2017; 32: 11-16 DOI: 10.1002/jbmr.3042.
• 62 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: 1147-1155 DOI: 10.1016/S0140-6736(15)61120-5.
• 63 Muschitz C, Kocijan R, Fahrleitner-Pammer A. et al. Overlapping and continued alendronate or raloxifene administration in patients on teriparatide: effects on areal and volumetric bone mineral density--the CONFORS Study. J Bone Miner Res 2014; 29: 1777-1785 DOI: 10.1002/jbmr.2216.
• 64 Kim KM, Lee SY, Rhee Y. Influence of Dosing Interval and Administration on the Bone Metabolism, Skeletal Effects, and Clinical Efficacy of Parathyroid Hormone in Treating Osteoporosis: A Narrative Review. JBMR Plus 2017; 1: 36-45 DOI: 10.1002/jbm4.10005.
• 65 McClung MR. Romosozumab for the treatment of osteoporosis. Osteoporos Sarcopenia 2018; 4: 11-15 DOI: 10.1016/j.afos.2018.03.002.
• 66 van Lierop AH, Appelman-Dijkstra NM, Papapoulos SE. Sclerostin deficiency in humans. Bone 2017; 96: 51-62 DOI: 10.1016/j.bone.2016.10.010.
• 67 McClung MR, Grauer A, Boonen S. et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014; 370: 412-420 DOI: 10.1056/NEJMoa1305224.
• 68 FDA Approved Drug Products. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761062s000lbl.pdf. Access on November, 2020
• 69 European Medicines Agency. Summary of product characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/evenity-epar-product-information_en.pdf. Access on November, 2020
• 70 Markham A. Romosozumab: First Global Approval. Drugs 2019; 79: 471-476 DOI: 10.1007/s40265-019-01072-6.
• 71 Shoback D, Rosen CJ, Black DM. et al. Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Guideline Update. J Clin Endocrinol Metab 2020; 105 DOI: 10.1210/clinem/dgaa048.
• 72 Cosman F, Crittenden DB, Adachi JD. et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med 2016; 375: 1532-1543 DOI: 10.1056/NEJMoa1607948.
• 73 Saag KG, Petersen J, Brandi ML. et al. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N Engl J Med 2017; 377: 1417-1427 DOI: 10.1056/NEJMoa1708322.
• 74 Langdahl BL, Libanati C, Crittenden DB. et al. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial. Lancet 2017; 390: 1585-1594 DOI: 10.1016/S0140-6736(17)31613-6.
• 75 Lewiecki EM, Blicharski T, Goemaere S. et al. A Phase III Randomized Placebo-Controlled Trial to Evaluate Efficacy and Safety of Romosozumab in Men With Osteoporosis. J Clin Endocrinol Metab 2018; 103: 3183-3193 DOI: 10.1210/jc.2017-02163.
• 76 Kang JH, Keller JJ, Lin HC. Bisphosphonates reduced the risk of acute myocardial infarction: a 2-year follow-up study. Osteoporos Int 2013; 24: 271-277 DOI: 10.1007/s00198-012-2213-5.
• 77 Lv F, Cai X, Yang W. et al. Denosumab or romosozumab therapy and risk of cardiovascular events in patients with primary osteoporosis: Systematic review and meta- analysis. Bone 2020; 130: 115121 DOI: 10.1016/j.bone.2019.115121.
• 78 Kaveh S, Hosseinifard H, Ghadimi N. et al. Efficacy and safety of Romosozumab in treatment for low bone mineral density: a systematic review and meta-analysis. Clin Rheumatol 2020; 39: 3261-3276 DOI: 10.1007/s10067-020-04948-1.
• 79 Ferrieres L, Degboe Y, Laroche M. et al. No impact of anti-Rank ligand and PTH analogs on cardiovascular risk in postmenopausal osteoporosis: a systematic literature review and meta-analysis. Arch Osteoporos 2020; 15: 10 DOI: 10.1007/s11657-019-0672-4.
• 80 Saag KG, Pannacciulli N, Geusens P. et al. Denosumab Versus Risedronate in Glucocorticoid-Induced Osteoporosis: Final Results of a Twenty-Four-Month Randomized, Double-Blind, Double-Dummy Trial. Arthritis Rheumatol 2019; 71: 1174-1184 DOI: 10.1002/art.40874.