Osteoporosis is a skeletal disorder that causes impairment of bone structure and strength, leading to a progressively increased risk of fragility fractures. The global prevalence of osteoporosis is increasing in the ageing population. Owing to the chronic character of osteoporosis, years or even decades of preventive measures or therapy are required. The long-term use of bone-specific pharmacological treatment options, including antiresorptive and/or osteoanabolic approaches, has raised concerns around adverse effects or potential rebound phenomena after treatment discontinuation. Imaging options, risk scores and the assessment of bone turnover during initiation and monitoring of such therapies could help to inform individualized treatment strategies. Combination therapies are currently used less often than ‘sequential’ treatments. However, all patients with osteoporosis, including those with secondary and rare causes of osteoporosis, as well as specific patient populations (for example, young adults, men and pregnant women) require new approaches for long-term therapy and disease monitoring. New pathophysiological aspects of bone metabolism might therefore help to inform and revolutionize the diagnosis and treatment of osteoporosis.
Osteoporosis and related fragility fractures are becoming increasingly common among women and men, with fewer clinical treatment studies available that include men.
The burden of fragility fractures is characterized not only by individual harm but also by high costs for health-care systems worldwide.
Osteoporosis requires long-term prevention or therapy based on specific bone medication and/or general measures; specific therapy principles encompass antiresorptive or osteoanabolic approaches or a dual approach.
Risks and benefits of antiresorptive and osteoanabolic therapies have been investigated and include rare but sometimes disabling adverse effects such as atypical femoral fractures and medication-related osteonecrosis of the jaw.
Sequential therapy options are increasingly being addressed in clinical trials more often than combination therapies, with the first results showing benefits for the maintenance of stable BMD increases and fracture risk reduction.
Future therapy directions include the application of an ‘osteoanabolics first’ approach and dosage variation in antiresorptive agents, as well as new therapy options including follicle-stimulating hormone, mesenchymal stem cells and extracellular vesicles.
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Zengin, A., Prentice, A. & Ward, K. A. Ethnic differences in bone health. Front. Endocrinol. 6, 24 (2015).
Trajanoska, K. et al. Assessment of the genetic and clinical determinants of fracture risk: genome wide association and Mendelian randomisation study. Br. Med. J. 362, k3225 (2018).
Schweighofer, N. et al. DXA-derived indices in the characterisation of sarcopenia. Nutrients 14, 186 (2022).
Herath, M., Cohen, A., Ebeling, P. R. & Milat, F. Dilemmas in the management of osteoporosis in younger adults. JBMR Plus 6, e10594 (2022).
Collins, M. T. et al. Skeletal and extraskeletal disorders of biomineralization. Nat. Rev. Endocrinol. 18, 473–489 (2022).
Kanis, J. A. et al. A systematic review of hip fracture incidence and probability of fracture worldwide. Osteoporos. Int. 23, 2239–2256 (2012).
Pepe, J. et al. Osteoporosis in premenopausal women: a clinical narrative review by the ECTS and the IOF. J. Clin. Endocrinol. Metab. 105, 2487–2506 (2020).
Vilaca, T., Eastell, R. & Schini, M. Osteoporosis in men. Lancet Diabetes Endocrinol. 10, 273–283 (2022).
Kahwati, L. C. et al. Vitamin D, calcium, OR combined supplementation for the primary prevention of fractures in community-dwelling adults: evidence report and systematic review for the US Preventive Services Task Force. JAMA 319, 1600–1612 (2018).
Weaver, C. M. et al. Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation. Osteoporos. Int. 27, 367–376 (2016).
Chevalley, T. et al. Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group. Aging Clin. Exp. Res. 34, 2603–2623 (2022).
Reid, I. R. & Bolland, M. J. Calcium and/or vitamin D supplementation for the prevention of fragility fractures: who needs it? Nutrients 12, 1011 (2020).
Ensrud, K. E. & Crandall, C. J. Osteoporosis. Ann. Intern. Med. 167, ITC17–ITC31 (2017).
Cornelissen, D. et al. Improvement of osteoporosis Care Organized by Nurses: ICON study - protocol of a quasi-experimental study to assess the (cost)-effectiveness of combining a decision aid with motivational interviewing for improving medication persistence in patients with a recent fracture being treated at the fracture liaison service. BMC Musculoskelet. Disord. 22, 913 (2021).
Bouxsein, M. L. et al. Change in bone density and reduction in fracture risk: a meta-regression of published trials. J. Bone Miner. Res. 34, 632–642 (2019).
Russell, R. G. G. Bisphosphonates: the first 40 years. Bone 49, 2–19 (2011).
Grey, A. et al. Low-dose fluoride in postmenopausal women: a randomized controlled trial. J. Clin. Endocrinol. Metab. 98, 2301–2307 (2013).
Statham, L. A. & Aspray, T. J. Odanacatib: the best osteoporosis treatment we never had? Lancet Diabetes Endocrinol. 7, 888–889 (2019).
Bolland, M. J. & Grey, A. Ten years too long: strontium ranelate, cardiac events, and the European Medicines Agency. Br. Med. J. 354, i5109 (2016).
Downs, R. W. Jr. et al. Comparison of alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women. J. Clin. Endocrinol. Metab. 85, 1783–1788 (2000).
Sun, L. M., Lin, M. C., Muo, C. H., Liang, J. A. & Kao, C. H. Calcitonin nasal spray and increased cancer risk: a population-based nested case-control study. J. Clin. Endocrinol. Metab. 99, 4259–4264 (2014).
Overman, R. A., Borse, M. & Gourlay, M. L. Salmon calcitonin use and associated cancer risk. Ann. Pharmacother. 47, 1675–1684 (2013).
Ebetino, F. H. et al. Bisphosphonates: the role of chemistry in understanding their biological actions and structure-activity relationships, and new directions for their therapeutic use. Bone 156, 116289 (2022).
Moen, M. D. & Keam, S. J. Denosumab: a review of its use in the treatment of postmenopausal osteoporosis. Drugs Aging 28, 63–82 (2011).
Hanley, D. A., Adachi, J. D., Bell, A. & Brown, V. Denosumab: mechanism of action and clinical outcomes. Int. J. Clin. Pract. 66, 1139–1146 (2012).
Weitzmann, M. N. & Pacifici, R. Estrogen deficiency and bone loss: an inflammatory tale. J. Clin. Invest. 116, 1186–1194 (2006).
Stepan, J. J., Alenfeld, F., Boivin, G., Feyen, J. H. M. & Lakatos, P. Mechanisms of action of antiresorptive therapies of postmenopausal osteoporosis. Endocr. Regul. 37, 225–238 (2003).
Gartlehner, G. et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women. JAMA 328, 1747–1767 (2018).
Nethander, M. et al. Evidence of a causal effect of estradiol on fracture risk in men. J. Clin. Endocrinol. Metab. 104, 433–442 (2018).
Yan, M. Z. et al. Raloxifene inhibits bone loss and improves bone strength through an Opg-independent mechanism. Endocrine 37, 55–61 (2010).
Riggs, B. L. & Hartmann, L. C. Selective estrogen-receptor modulators — mechanisms of action and application to clinical practice. N. Engl. J. Med. 348, 618–629 (2003).
Peng, L., Luo, Q. & Lu, H. Efficacy and safety of bazedoxifene in postmenopausal women with osteoporosis: a systematic review and meta-analysis. Medicine 96, e8659 (2017).
Rendina-Ruedy, E. & Rosen, C. J. Parathyroid hormone (PTH) regulation of metabolic homeostasis: an old dog teaches us new tricks. Mol. Metab. 60, 101480 (2022).
Martin, T. J., Sims, N. A. & Seeman, E. Physiological and pharmacological roles of PTH and PTHrP in bone using their shared receptor, PTH1R. Endocr. Rev. 42, 383–406 (2021).
Wittelsberger, A. et al. The mid-region of parathyroid hormone (1–34) serves as a functional docking domain in receptor activation. Biochemistry 45, 2027–2034 (2006).
Dobnig, H. & Turner, R. T. The effects of programmed administration of human parathyroid hormone fragment (1–34) on bone histomorphometry and serum chemistry in rats. Endocrinology 138, 4607–4612 (1997).
Neer, R. M. et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med. 344, 1434–1441 (2001).
Rauner, M., Taipaleenmäki, H., Tsourdi, E. & Winter, E. M. Osteoporosis treatment with anti-sclerostin antibodies—mechanisms of action and clinical application. J. Clin. Med. 10, 787 (2021).
Hadji, P. et al. Osteoporotic fractures and subsequent fractures: imminent fracture risk from an analysis of German real-world claims data. Arch. Gynecol. Obstet. 304, 703–712 (2021).
Ayub, N. et al. The treatment gap in osteoporosis. J. Clin. Med. 10, 3002 (2021).
Chang, L. L., Eastell, R. & Miller, P. D. Continuation of bisphosphonate therapy for osteoporosis beyond 5 years. N. Engl. J. Med. 386, 1467–1469 (2022).
Tsourdi, E. et al. Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone 105, 11–17 (2017).
Farlay, D. et al. Bone mineral and organic properties in postmenopausal women treated with denosumab for up to 10 years. J. Bone Miner. Res. 37, 856–864 (2022).
Reid, I. R. Osteoporosis treatment: focus on safety. Eur. J. Intern. Med. 24, 691–697 (2013).
Khan, A. A. et al. Case-based review of osteonecrosis of the jaw (ONJ) and application of the International Recommendations for Management from the International Task Force on ONJ. J. Clin. Densitom. 20, 8–24 (2017).
Diez-Perez, A. et al. International osteoporosis foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates. Osteoporos. Int. 28, 767–774 (2017).
Bareli, N. et al. Bisphosphonate treatment and the risk of atypical femoral fracture among patients participating in a Fracture Liaison Service of a tertiary medical center. Arch. Osteoporos. 16, 86 (2021).
Kusumbe, A. P., Ramasamy, S. K. & Adams, R. H. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507, 323–328 (2014).
Xu, R. et al. Targeting skeletal endothelium to ameliorate bone loss. Nat. Med. 24, 823–833 (2018).
Cackowski, F. C. et al. Osteoclasts are important for bone angiogenesis. Blood 115, 140–149 (2010).
Liu, X. et al. Osteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis. Nat. Commun. 12, 1832 (2021).
Santini, D. et al. Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin. Cancer Res. 9, 2893–2897 (2003).
Saul, D. & Khosla, S. Fracture healing in the setting of endocrine diseases, aging, and cellular senescence. Endocr. Rev. 43, 984–1002 (2022).
Black, D. M. et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N. Engl. J. Med. 356, 1809–1822 (2007).
Fazmin, I. T., Huang, C. L. H. & Jeevaratnam, K. Bisphosphonates and atrial fibrillation: revisiting the controversy. Ann. NY Acad. Sci. 1474, 15–26 (2020).
Rodríguez, A. J. & Abrahamsen, B. Cardiovascular safety of antifracture medications in patients with osteoporosis: a narrative review of evidence from randomized studies. JBMR Plus 5, e10628 (2021).
Poggi, C. D., Fusaro, M., Mereu, M. C., Brandi, M. L. & Cianferotti, L. Cardiovascular safety and effectiveness of bisphosphonates: from intervention trials to real-life data. Nutrients 14, 2369 (2022).
Goh, S. K. et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J. Bone Jt Surg. Ser. B 89, 349–353 (2007).
Cosman, F. et al. Romosozumab treatment in postmenopausal women with osteoporosis. N. Engl. J. Med. 375, 1532–1543 (2016).
Austin, D. C., Torchia, M. T., Klare, C. M. & Cantu, R. V. Atypical femoral fractures mimicking metastatic lesions in 2 patients taking denosumab. Acta Orthop. 88, 351–353 (2017).
Black, D. M., Condra, K., Adams, A. L. & Eastell, R. Bisphosphonates and the risk of atypical femur fractures. Bone 156, 116297 (2022).
Zhou, W., van Rooij, J. G. J., Ebeling, P. R., Verkerk, A. J. M. H. & Zillikens, M. C. The genetics of atypical femur fractures—a systematic review. Curr. Osteoporos. Rep. 19, 123–130 (2021).
Shane, E. 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. 29, 1–23 (2014).
Shane, E. et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the american society for bone and mineral research. J. Bone Miner. Res. 25, 2267–2294 (2010).
Rizzoli, R. 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. 22, 373 (2011).
Clynes, M. A. et al. The epidemiology of osteoporosis. Br. Med. Bull. 133, 105–117 (2020).
Black, D. M. et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N. Engl. J. Med. 383, 743–753 (2020).
Schilcher, J., Koeppen, V., Aspenberg, P. & Michaëlsson, K. Risk of atypical femoral fracture during and after bisphosphonate use: full report of a nationwide study. Acta Orthop. 86, 100–107 (2015).
Wang, M., Wu, Y. F. & Girgis, C. M. Bisphosphonate drug holidays: evidence from clinical trials and real-world studies. JBMR Plus 6, e10629 (2022).
Bone, H. G. 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. 5, 513–523 (2017).
Saag, K. G. et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N. Engl. J. Med. 377, 1417–1427 (2017).
Black, D. M. et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 296, 2927–2938 (2006).
Diab, D. L. & Watts, N. B. Bisphosphonate drug holiday: who, when and how long. Ther. Adv. Musculoskelet. Dis. 5, 107–111 (2013).
Marx, R. E., Sawatari, Y., Fortin, M. & Broumand, V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J. Oral. Maxillofac. Surg. 63, 1567–1575 (2005).
Taylor, K. H., Middlefell, L. S. & Mizen, K. D. Osteonecrosis of the jaws induced by anti-RANK ligand therapy. Br. J. Oral. Maxillofac. Surg. 48, 221–223 (2010).
Sacco, R., Woolley, J., Patel, G., Calasans-Maia, M. D. & Yates, J. Systematic review of medication related osteonecrosis of the jaw (MRONJ) in patients undergoing only antiangiogenic drug therapy: surgery or conservative therapy? Br. J. Oral. Maxillofac. Surg. 60, e216–e230 (2022).
Khosla, S. et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J. Bone Miner. Res. 22, 1479–1491 (2007).
Fung, P. P. L. et al. Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study. Oral. Dis. 23, 477–483 (2017).
Khan, A. A. et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J. Bone Miner. Res. 30, 3–23 (2015).
Gkouveris, I. et al. Inhibition of HMGB1/RAGE signaling reduces the incidence of medication-related osteonecrosis of the jaw (MRONJ) in mice. J. Bone Miner. Res. 37, 1775–1786 (2022).
Aguirre, J. I., Castillo, E. J. & Kimmel, D. B. Biologic and pathologic aspects of osteocytes in the setting of medication-related osteonecrosis of the jaw (MRONJ). Bone 153, 116168 (2021).
Cheng, Y. C. et al. Antiresorptive therapy and dental implant survival: an up to 20-year retrospective cohort study in women. Clin. Oral. Investig. 26, 6569–6582 (2022).
Govaerts, D. et al. Adjuvant therapies for MRONJ: a systematic review. Bone 141, 115676 (2020).
Anastasilakis, A. D. et al. Osteonecrosis of the jaw and antiresorptive agents in benign and malignant diseases: a critical review organized by the ECTS. J. Clin. Endocrinol. Metab. 107, 1441–1460 (2022).
Krege, J. H., Gilsenan, A. W., Komacko, J. L. & Kellier-Steele, N. Teriparatide and osteosarcoma risk: history, science, elimination of boxed warning, and other label updates. JBMR Plus 6, e10665 (2022).
Bernstein, Z. S., Kim, E. B. & Raje, N. Bone disease in multiple myeloma: biologic and clinical implications. Cells 11, 2308 (2022).
Schwartz, E., Reichert, Z. & Van Poznak, C. Pharmacologic management of metastatic bone disease. Bone 158, 115735 (2022).
Lee, M. & Partridge, N. C. Parathyroid hormone signaling in bone and kidney. Curr. Opin. Nephrol. Hypertens. 18, 298 (2009).
Zhan, T., Rindtorff, N. & Boutros, M. Wnt signaling in cancer. Oncogene 36, 1461–1473 (2017).
Swami, S. et al. Prevention of breast cancer skeletal metastases with parathyroid hormone. JCI Insight 2, e90874 (2017).
Koski, A. M., Sikiö, A. & Forslund, T. Teriparatide treatment complicated by malignant myeloma. BMJ Case Rep. 2010, bcr0120102681 (2010).
Gilsenan, A. et al. The Forteo Patient Registry linkage to multiple state cancer registries: study design and results from the first 8 years. Osteoporos. Int. 29, 2335–2343 (2018).
Aubry-Rozier, B., Gonzalez-Rodriguez, E., Stoll, D. & Lamy, O. Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports. Osteoporos. Int. 27, 1923–1925 (2016).
Tsourdi, E. et al. Fracture risk and management of discontinuation of denosumab therapy: a systematic review and position statement by ECTS. J. Clin. Endocrinol. Metab. 106, 264–281 (2021).
Kong, S. H. et al. Effect of denosumab on the change of osteoclast precursors compared to zoledronate treatment in postmenopausal women with osteoporosis. J. Bone Metab. 29, 93–101 (2022).
McDonald, M. M., Kim, A. S., Mulholland, B. S. & Rauner, M. New insights into osteoclast biology. JBMR Plus 5, e10539 (2021).
Saag, K. G. et al. The effect of discontinuing denosumab in patients with rheumatoid arthritis treated with glucocorticoids. Arthritis Rheumatol. 74, 604–611 (2022).
Sosa Henríquez, M., Gómez de Tejada Romero, M. J., Escudero-Socorro, M. & Torregrosa Suau, O. Hip fractures following denosumab discontinuation: three clinical cases reports. J. R. Soc. Med. 112, 472–475 (2019).
Anagnostis, P. et al. Spontaneous vertebral fractures in males with osteoporosis after denosumab discontinuation: a report of two cases. J. Clin. Rheumatol. 27, S581–S584 (2021).
Sølling, A. S., Tsourdi, E., Harsløf, T. & Langdahl, B. L. Denosumab discontinuation. Curr. Osteoporos. Rep. 21, 95–103 (2023).
Ha, J. et al. Effect of follow-up raloxifene therapy after denosumab discontinuation in postmenopausal women. Osteoporos. Int. 33, 1591–1599 (2022).
Kothawala, P., Badamgarav, E., Ryu, S., Miller, R. M. & Halbert, R. J. Systematic review and meta-analysis of real-world adherence to drug therapy for osteoporosis. Mayo Clin. Proc. 82, 1493–1501 (2007).
Hiligsmann, M. et al. Cost-effectiveness of osteoporosis screening followed by treatment: the impact of medication adherence. Value Health 13, 394–401 (2010).
Ross, S. et al. A meta-analysis of osteoporotic fracture risk with medication nonadherence. Value Health 14, 571–581 (2011).
Foessl, I. et al. Bone phenotyping approaches in human, mice and zebrafish – expert overview of the EU Cost Action GEMSTONE (“GEnomics of MusculoSkeletal traits TranslatiOnal NEtwork”). Front. Endocrinol. 12, 720728 (2021).
Dimai, H. P. Use of dual-energy X-ray absorptiometry (DXA) for diagnosis and fracture risk assessment; WHO-criteria, T- and Z-score, and reference databases. Bone 104, 39–43 (2017).
Shuhart, C. R. et al. Executive summary of the 2019 ISCD Position Development Conference on Monitoring Treatment, DXA Cross-calibration and Least Significant Change, Spinal Cord Injury, Peri-prosthetic and Orthopedic Bone Health, Transgender Medicine, and Pediatrics. J. Clin. Densitom. 22, 453–471 (2019).
Shevroja, E., Cafarelli, F. P., Guglielmi, G. & Hans, D. DXA parameters, trabecular bone score (TBS) and bone mineral density (BMD), in fracture risk prediction in endocrine-mediated secondary osteoporosis. Endocrine 74, 20–28 (2021).
Shevroja, E. et al. Bone texture assessment on lateral VFAs using the texture research investigational platform (TRIP) and its fracture discrimination ability. J. Clin. Densitom. 25, 599–605 (2022).
Haeri, N. S., Perera, S., Ferreiro, I., Hans, D. & Greenspan, S. L. Trabecular bone score in the hip: a new method to examine hip bone microarchitecture-a feasibility study. Arch. Osteoporos. 17, 126–126 (2022).
Hans, D. et al. Updated trabecular bone score accounting for the soft tissue thickness (TBSTT) demonstrated significantly improved bone microstructure with denosumab in the FREEDOM TBS post hoc analysis. Osteoporos. Int. 33, 2517–2525 (2022).
Bonnick, S. L. Dual-energy X-ray absorptiometry: interpreting reports and serial measurements. Clin. Obstet. Gynecol. 56, 677–685 (2013).
Carey, J. J., Chih-Hsing, W. P. & Bergin, D. Risk assessment tools for osteoporosis and fractures in 2022. Best Pract. Res. Clin. Rheumatol. 36, 101775 (2022).
Vandenput, L. et al. Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan. Osteoporos. Int. 33, 2103–2136 (2022).
Vlot, M. C. et al. Clinical utility of bone markers in various diseases. Bone 114, 215–225 (2018).
Eastell, R. et al. Bone turnover markers: are they clinically useful? Eur. J. Endocrinol. 178, R19–R31 (2018).
Boonen, S. et al. Postmenopausal osteoporosis treatment with antiresorptives: effects of discontinuation or long-term continuation on bone turnover and fracture risk-A perspective. J. Bone Miner. Res. 27, 963–974 (2012).
Drake, M. T., Clarke, B. L. & Khosla, S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin. Proc. 83, 1032–1045 (2008).
Odvina, C. V. et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J. Clin. Endocrinol. Metab. 90, 1294–1301 (2005).
Dimai, H. P. & Fahrleitner-Pammer, A. Osteoporosis and fragility fractures: currently available pharmacological options and future directions. Best Pract. Res. Clin. Rheumatol. 36, 101780 (2022).
Adams, A. L. et al. Bisphosphonate drug holiday and fracture risk: a population-based cohort study. J. Bone Miner. Res. 33, 1252–1259 (2018).
Curtis, J. R. et al. Duration of bisphosphonate drug holidays and associated fracture risk. Med. Care 58, 419–426 (2020).
Malluche, H. H. et al. Bone quality and fractures in women with osteoporosis treated with bisphosphonates for 1 to 14 years. JBMR 5, e10549 (2021).
Diez-Perez, A. et al. Treatment failure in osteoporosis. Osteoporos. Int. 23, 2769–2774 (2012).
Miller, P. D. et al. Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. J. Clin. Endocrinol. Metab. 101, 3163–3170 (2016).
Kanis, J. A. et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos. Int. 30, 3 (2019).
Cipriani, C. & Bilezikian, J. P. Osteoanabolics versus antiresorptives: which first? J. Clin. Endocrinol. Metab. 105, 964–965 (2020).
Samadfam, R., Xia, Q. & Goltzman, D. Pretreatment with anticatabolic agents blunts but does not eliminate the skeletal anabolic response to parathyroid hormone in oophorectomized mice. Endocrinology 148, 2778–2787 (2007).
Ettinger, B., San Martin, J., Crans, G. & Pavo, I. Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J. Bone Miner. Res. 19, 745–751 (2004).
Boonen, S. et al. Effects of previous antiresorptive therapy on the bone mineral density response to two years of teriparatide treatment in postmenopausal women with osteoporosis. J. Clin. Endocrinol. Metab. 93, 852–860 (2008).
Miller, P. D. et al. Early responsiveness of women with osteoporosis to teriparatide after therapy with alendronate or risedronate. J. Clin. Endocrinol. Metab. 93, 3785–3793 (2008).
Geusens, P. et al. Effects of teriparatide compared with risedronate on the risk of fractures in subgroups of postmenopausal women with severe osteoporosis: the VERO trial. J. Bone Miner. Res. 33, 783–794 (2018).
Leder, B. Z. et al. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial. Lancet 386, 1147–1155 (2015).
Cosman, F. et al. Romosozumab and antiresorptive treatment: the importance of treatment sequence. Osteoporos. Int. 33, 1243–1256 (2022).
Kendler, D. L. et al. Bone mineral density gains with a second 12-month course of romosozumab therapy following placebo or denosumab. Osteoporos. Int. 30, 2437 (2019).
Langdahl, B. L. 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 390, 1585–1594 (2017).
Li, N. et al. An updated systematic review of cost-effectiveness analyses of drugs for osteoporosis. Pharmacoeconomics 39, 181–209 (2021).
Black, D. M. et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N. Engl. J. Med. 349, 1207–1215 (2003).
Walker, M. D. et al. Combination therapy with risedronate and teriparatide in male osteoporosis. Endocrine 44, 237–246 (2013).
Cosman, F. et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis. J. Bone Miner. Res. 26, 503–511 (2011).
Leder, B. Z. et al. Two years of denosumab and teriparatide administration in postmenopausal women with osteoporosis (the DATA Extension Study): a randomized controlled trial. J. Clin. Endocrinol. Metab. 99, 1694–1700 (2014).
Mäkitie, O. & Zillikens, M. C. Early-onset osteoporosis. Calcif. Tissue Int. 110, 546–561 (2022).
Ferrari, S. et al. Osteoporosis in young adults: pathophysiology, diagnosis, and management. Osteoporos. Int. 23, 2735–2748 (2012).
Kim, S. J., Baker, B. S., Sharma-Ghimire, P., Bemben, D. A. & Bemben, M. G. Association between bone-specific physical activity scores and pQCT-derived measures of bone strength and geometry in healthy young and middle-aged premenopausal women. Arch. Osteoporos. 13, 83 (2018).
Hammoud, E. et al. Influence of sarcopenia on bone health parameters in a group of eumenorrheic obese premenopausal women. J. Bone Miner. Metab. 38, 385–391 (2020).
Goshtasebi, A. et al. Adolescent use of combined hormonal contraception and peak bone mineral density accrual: a meta-analysis of international prospective controlled studies. Clin. Endocrinol. 90, 517–524 (2019).
Hardcastle, S. A. “Pregnancy and lactation associated osteoporosis”. Calcif. Tissue Int. 110, 531–545 (2022).
Cohen, A. et al. Women with pregnancy and lactation-associated osteoporosis (PLO) have low bone remodeling rates at the tissue level. J. Bone Miner. Res. 34, 1552–1561 (2019).
Butscheidt, S. et al. Relevant genetic variants are common in women with pregnancy and lactation-associated osteoporosis (PLO) and predispose to more severe clinical manifestations. Bone 147, 115911 (2021).
Kovacs, C. S. Maternal mineral and bone metabolism during pregnancy, lactation, and post-weaning recovery. Physiol. Rev. 96, 449–547 (2016).
Cooke-Hubley, S. et al. Parity and lactation are not associated with incident fragility fractures or radiographic vertebral fractures over 16 years of follow-up: Canadian Multicentre Osteoporosis Study (CaMos). Arch. Osteoporos. 14, 49 (2019).
MacHairiotis, N., Ntali, G., Kouroutou, P. & Michala, L. Clinical evidence of the effect of bisphosphonates on pregnancy and the infant. Horm. Mol. Biol. Clin. Investig. 40, 20190021 (2019).
Sokal, A. et al. Pregnancy and newborn outcomes after exposure to bisphosphonates: a case-control study. Osteoporos. Int. 30, 221–229 (2019).
Wang, X. F., Duan, Y., Beck, T. J. & Seeman, E. Varying contributions of growth and ageing to racial and sex differences in femoral neck structure and strength in old age. Bone 36, 978–986 (2005).
Orwoll, E. S. & Klein, R. F. Osteoporosis in men. Endocr. Rev. 16, 87–116 (1995).
Boonen, S. et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N. Engl. J. Med. 367, 1714–1723 (2012).
Orwoll, E. et al. Alendronate for the treatment of osteoporosis in men. N. Engl. J. Med. 343, 604–610 (2000).
Boonen, S. et al. Once-weekly risedronate in men with osteoporosis: results of a 2-year, placebo-controlled, double-blind, multicenter study. J. Bone Miner. Res. 24, 719–725 (2009).
Orwoll, E. et al. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J. Clin. Endocrinol. Metab. 97, 3161–3169 (2012).
Langdahl, B. L. 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. 100, 1335–1342 (2015).
Smith, M. R. et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N. Engl. J. Med. 361, 745–755 (2009).
Orwoll, E. S. et al. The effect of teriparatide [human parathyroid hormone (1–34)] therapy on bone density in men with osteoporosis. J. Bone Miner. Res. 18, 9–17 (2003).
Michael Lewiecki, E. et al. A phase III randomized placebo-controlled trial to evaluate efficacy and safety of Romosozumab in men with osteoporosis. J. Clin. Endocrinol. Metab. 103, 3183–3193 (2018).
Duarte, M. P. et al. Prevalence of low bone mineral density (T-score ≤ −2.5) in the whole spectrum of chronic kidney disease: a systematic review and meta-analysis. Osteoporos. Int. 34, 467–477 (2023).
Khosla, S., Samakkarnthai, P., Monroe, D. G. & Farr, J. N. Update on the pathogenesis and treatment of skeletal fragility in type 2 diabetes mellitus. Nat. Rev. Endocrinol. 17, 685–697 (2021).
Ferrari, S. L. et al. Diagnosis and management of bone fragility in diabetes: an emerging challenge. Osteoporos. Int. 29, 2585–2596 (2018).
Laurent, M. R. et al. Prevention and treatment of glucocorticoid-induced osteoporosis in adults: consensus recommendations from the Belgian Bone Club. Front. Endocrinol. 13, 908727 (2022).
Costantini, A. et al. Early-onset osteoporosis: rare monogenic forms elucidate the complexity of disease pathogenesis beyond type I collagen. J. Bone Miner. Res. 37, 1623–1641 (2022).
Chu, H. et al. Comparative effectiveness of bisphosphonate treatments for the prevention of re-fracture in glucocorticoid-induced osteoporosis: protocol for a systematic review and meta-analysis. BMJ Open 12, e062537 (2022).
Langdahl, B. L., Uitterlinden, A. G. & Ralston, S. H. Where is bone science taking us? Best Pract. Res. Clin. Rheumatol. 36, 101791 (2022).
Fuggle, N. et al. Novel formulations of oral bisphosphonates in the treatment of osteoporosis. Aging Clin. Exp. Res. 34, 2625–2634 (2022).
Jiang, Y., Zhang, P., Zhang, X., Lv, L. & Zhou, Y. Advances in mesenchymal stem cell transplantation for the treatment of osteoporosis. Cell Prolif. 54, e12956 (2021).
Lu, L. et al. Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: a prospective, randomized, double-blind, active-controlled, phase IIb clinical trial. Stem Cell Res. Ther. 10, 143 (2019).
US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT05152381 (2022).
Colombo, M., Raposo, G. & Théry, C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30, 255–289 (2014).
Qin, Y., Wang, L., Gao, Z., Chen, G. & Zhang, C. Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo. Sci. Rep. 6, 21961 (2016).
Shen, M. et al. Injection of synthetic mesenchymal stem cell mitigates osteoporosis in rats after ovariectomy. J. Cell. Mol. Med. 22, 3751–3757 (2018).
Tkach, M. & Théry, C. Communication by extracellular vesicles: where we are and where we need to go. Cell 164, 1226–1232 (2016).
Sun, L. et al. FSH directly regulates bone mass. Cell 125, 247–260 (2006).
Østergren, P. B. et al. Metabolic consequences of gonadotropin-releasing hormone agonists vs orchiectomy: a randomized clinical study. BJU Int. 123, 602–611 (2019).
Guo, Y. et al. Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol. Cell Res. 29, 151–166 (2019).
Xiong, J. et al. FSH blockade improves cognition in mice with Alzheimer’s disease. Nature 603, 470–476 (2022).
Gera, S. et al. FSH-blocking therapeutic for osteoporosis. eLife 11, e78022 (2022).
Dincel, A. S. & Jørgensen, N. R. New emerging biomarkers for bone disease: sclerostin and Dickkopf-1 (DKK1). Calcif. Tissue Int. 112, 243–257 (2023).
Madel, M. B. et al. Immune function and diversity of osteoclasts in normal and pathological conditions. Front. Immunol. 10, 1408 (2019).
Forgetta, V. et al. Development of a polygenic risk score to improve screening for fracture risk: a genetic risk prediction study. PLoS Med. 17, e1003152 (2020).
Grillari, J. et al. Circulating miRNAs in bone health and disease. Bone 145, 115787 (2021).
Messner, Z. et al. Circulating miRNAs respond to denosumab treatment after 2 years in postmenopausal women with osteoporosis—the MiDeTe study. J. Clin. Endocrinol. Metab. 108, 1154–1165 (2022).
Heilmeier, U. et al. Circulating serum microRNAs including senescent miR-31-5p are associated with incident fragility fractures in older postmenopausal women with type 2 diabetes mellitus. Bone 158, 116308 (2022).
Nevola, K. T. et al. miRNA mechanisms underlying the association of beta blocker use and bone mineral density. J. Bone Miner. Res. 36, 110–122 (2021).
Chen, S., Liu, D., Zhou, Z. & Qin, S. Role of long non-coding RNA H19 in the development of osteoporosis. Mol. Med. 27, 122 (2021).
Alfonzo, M. C., Al Saedi, A., Fulzele, S. & Hamrick, M. W. Extracellular vesicles as communicators of senescence in musculoskeletal aging. JBMR Plus 6, e10686 (2022).
Liberman, U. A. et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N. Engl. J. Med. 333, 1437–1444 (1995).
Schnitzer, T. et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Aging Clin. Exp. Res. 12, 1–12 (2000).
Black, D. M. et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348, 1535–1541 (1996).
Axelsson, K. F., Wallander, M., Johansson, H., Lundh, D. & Lorentzon, M. Hip fracture risk and safety with alendronate treatment in the oldest-old. J. Intern. Med. 282, 546–559 (2017).
McClung, M. R., Balske, A., Burgio, D. E., Wenderoth, D. & Recker, R. R. Treatment of postmenopausal osteoporosis with delayed-release risedronate 35 mg weekly for 2 years. Osteoporos. Int. 24, 301–310 (2013).
McClung, M. R. et al. Effect of risedronate on the risk of hip fracture in elderly women. N. Engl. J. Med. 344, 333–340 (2001).
Reginster, J. Y. et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) study group. Osteoporos. Int. 11, 83–91 (2000).
Harris, S. T. 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 282, 1344–1352 (1999).
Miller, P. D. et al. Long-term fracture rates seen with continued ibandronate treatment: pooled analysis of DIVA and MOBILE long-term extension studies. Osteoporos. Int. 25, 349–357 (2014).
Harris, S. T., Blumentals, W. A. & Miller, P. D. Ibandronate and the risk of non-vertebral and clinical fractures in women with postmenopausal osteoporosis: results of a meta-analysis of phase III studies. Curr. Med. Res. Opin. 24, 237–245 (2008).
Delmas, P. D. et al. Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporos. Int. 15, 792–798 (2004).
Chesnut, C. H. et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J. Bone Miner. Res. 19, 1241–1249 (2004).
Lyles, K. W. et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N. Engl. J. Med. 357, 1799–1809 (2007).
Recker, R. R. et al. Comparative effects of raloxifene and alendronate on fracture outcomes in postmenopausal women with low bone mass. Bone 40, 843–851 (2007).
Delmas, P. D. et al. Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone 33, 522–532 (2003).
Ettinger, B. et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) investigators. JAMA 282, 637–645 (1999).
Ellis, A. G. et al. Indirect comparison of bazedoxifene vs oral bisphosphonates for the prevention of vertebral fractures in postmenopausal osteoporotic women. Curr. Med. Res. Opin. 30, 1617–1626 (2014).
Ellis, A. G. et al. Bazedoxifene versus oral bisphosphonates for the prevention of nonvertebral fractures in postmenopausal women with osteoporosis at higher risk of fracture: a network meta-analysis. Value Health 17, 424–432 (2014).
De Villiers, T. J. et al. Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial. Osteoporos. Int. 22, 567–576 (2011).
Kanis, J. A., Johansson, H., Oden, A. & McCloskey, E. V. Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Bone 44, 1049–1054 (2009).
Kendler, D. L. et al. Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet 391, 230–240 (2018).
McCloskey, E. V., Fitzpatrick, L. A., Hu, M. Y., Williams, G. & Kanis, J. A. Effect of abaloparatide on vertebral, nonvertebral, major osteoporotic, and clinical fractures in a subset of postmenopausal women at increased risk of fracture by FRAX probability. Arch. Osteoporos. 14, 15 (2019).
Miller, P. D. et al. Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial. JAMA 316, 722–733 (2016).
Reginster, J. Y. et al. Abaloparatide for risk reduction of nonvertebral and vertebral fractures in postmenopausal women with osteoporosis: a network meta-analysis. Osteoporos. Int. 30, 1465–1473 (2019).
Cummings, S. R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 361, 756–765 (2009).
Broadwell, A. et al. Denosumab safety and efficacy among participants in the FREEDOM extension study with mild to moderate chronic kidney disease. J. Clin. Endocrinol. Metab. 106, 397–409 (2021).
Geusens, P. et al. The effect of 1 year of romosozumab on the incidence of clinical vertebral fractures in postmenopausal women with osteoporosis: results from the FRAME study. JBMR Plus 3, e10211 (2019).
Zhu, L., Jiang, X., Sun, Y. & Shu, W. Effect of hormone therapy on the risk of bone fractures: a systematic review and meta-analysis of randomized controlled trials. Menopause 23, 461–470 (2016).
Bagger, Y. Z. et al. Two to three years of hormone replacement treatment in healthy women have long-term preventive effects on bone mass and osteoporotic fractures: the PERF study. Bone 34, 728–735 (2004).
Banks, E., Beral, V., Reeves, G., Balkwill, A. & Barnes, I. Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women. JAMA 291, 2212–2220 (2004).
Anderson, G. L. et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291, 1701–1712 (2004).
Rossouw, J. E. et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288, 321–333 (2002).
Hadji, P., Ryan, K. A., Yu, C. R., Mirkin, S. & Komm, B. S. CE/BZA effects on bone and quality of life in European postmenopausal women: a pooled analysis. Climacteric 19, 482–487 (2016).
Cauley, J. A. et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 290, 1729–1738 (2003).
Torgerson, D. J. & Bell-Syer, S. E. M. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA 285, 2891–2897 (2001).
Kanis, J. A. et al. An assessment of intervention thresholds for very high fracture risk applied to the NOGG guidelines: a report for the National Osteoporosis Guideline Group (NOGG). Osteoporos. Int. 32, 1951–1960 (2021).
Eastell, R. et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 104, 1595–1622 (2019).
Shoback, D. et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J. Clin. Endocrinol. Metab. 105, dgaa048 (2020).
Camacho, P. M. et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis — 2020 update. Endocr. Pract. 26 (Suppl. 1), 1–46 (2020).
Kanis, J. A. et al. Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures. Osteoporos. Int. 31, 1–12 (2020).
Naylor, K. E. et al. Response of bone turnover markers to three oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO study. Osteoporos. Int. 27, 21–31 (2016).
Eastell, R. & Szulc, P. Use of bone turnover markers in postmenopausal osteoporosis. Lancet Diabetes Endocrinol. 5, 908–923 (2017).
B.O.-P. declares lecture fees from Immundiagnostic Systems, Eli Lilly, Gedeon Richter, Institut Allergosan, anwerina, Merck Sharp & Dome, Roche, UCB and unrestricted research grants from CBmed, Immundiagnostic Systems, Infineon, Institut Allergosan, Kinderwunschinstitut, SelenoMed, ViennaLab and Winclove. H.P.D. declares lecture and consultancy fees from Amgen, Braincon, Daiichi-Sankyo, Eli Lilly, Gedeon Richter, Genericon, Medtronic, Merck Sharp & Dohme, Novartis, Nycomed, Sanabo, Servier, Sinapharm, Stada and UCB. I.F. was a part-time employee (Medical Oncology, Amgen Austria) during the writing of the first draft, but not thereafter, all outside of the present work.
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Foessl, I., Dimai, H.P. & Obermayer-Pietsch, B. Long-term and sequential treatment for osteoporosis. Nat Rev Endocrinol 19, 520–533 (2023). https://doi.org/10.1038/s41574-023-00866-9