Denosumab and mortality in a real-world setting:​ a comparative study

Alarkawi, Dunia<sup>1</sup>; Tran, Thach<sup>1</sup>; Chen, Weiwen<sup>1,2</sup>; March, Lyn M.<sup>3,4</sup>; Blyth, Fiona M.<sup>5</sup>; Blank, Robert D.<sup>1</sup>; Bliuc, Dana<sup>1,6,*</sup>; Center, Jacqueline R.<sup>1,2,*</sup>

Affiliations

¹Skeletal Diseases Program, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia

²Clinical School, Faculty of Medicine, St Vincent’s Hospital, University of New South Wales, Sydney, Australia

³Institute of Bone and Joint Research, Kolling Institute, Sydney, Australia

⁴Clinical School, Royal North Shore Hospital, St Leonards, Australia

⁵Clinical School, Concord Repatriation General Hospital, Sydney, Australia

⁶School of Population Health, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, Australia

Abstract and keywords

Denosumab (Dmab) is increasingly prescribed worldwide. Unlike bisphosphonates (BPs), its effect on mortality has yet to be well explored. This study examined the association between Dmab and all-cause mortality compared with no treatment in subjects with a fracture and BPs in subjects without a fracture. The study population was from the Sax Institute's 45 and Up Study (n = 267,357), a prospective population-based cohort with questionnaire data linked to hospital admissions (Admitted Patients Data Collection [APDC] data were linked by the Centre for Health Record Linkage), medication records (Pharmaceutical Benefits Scheme [PBS] provided by Services Australia), and stored securely (secure data access was provided through the Sax Institute's Secure Unified Research Environment [SURE]). The new-user cohort design with propensity-score (PS) matching was implemented. In the fracture cohort, Dmab and oral BP users were matched 1:2 to no treatment (Dmab: 617 women, 154 men; oral BPs: 615 women, 266 men). In the no-fracture cohort, Dmab users were matched 1:1 with oral BPs and zoledronic acid (Zol) users (Dmab:oral BPs: 479 men, 1534 women; Dmab:Zol: 280 men, 625 women). Mortality risk was measured using sex-specific pairwise multivariable Cox models. In the fracture cohort, compared with no treatment, Dmab was associated with 48% lower mortality in women (hazard ratio [HR] = 0.52, 95% confidence interval [CI] 0.36–0.72) but not in men. Oral BPs were associated with 44% lower mortality in both sexes (women HR = 0.56, 95% CI 0.42–0.77; men HR = 0.56, 95% CI 0.40–0.78). In the no-fracture cohort, compared with BPs, Dmab was associated with 1.5- to 2.5-fold higher mortality than oral BPs (women HR = 1.49, 95% CI 1.13–1.98; men HR = 2.74; 95% CI 1.82–4.11) but similar mortality to Zol. Dmab in women and oral BPs were associated with lower post-fracture mortality than no treatment. However, Dmab users had generally higher mortality than oral BP users in those without fractures.

Keywords: ANTIRESORPTIVES; OSTEOPOROSIS; AGING; EPIDEMIOLOGY; STATISTICAL METHODS

Links

DOI: 10.1002/jbmr.4930

PubMed: 37915252

WoS: 001126669000001

History

Received: 2023-01-18

Revised: 2023-10-13

Cited Works (16)

Year	Entry
2007	Center JR, Bliuc D, Nguyen TV, Eisman JA. Risk of subsequent fracture after low-trauma fracture in men and women. JAMA. January 24, 2007;297(4):387-394.
2020	Rogers MJ, Mönkkönen J, Munoz MA. Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton. Bone. October 2020;139:115493.
2011	Cawthon PM. Gender differences in osteoporosis and fractures. Clin Orthop Relat Res. August 2011;469:1900-1905.
2017	McClung MR, Wagman RB, Miller PD, Wang A, Lewiecki EM. Observations following discontinuation of long-term denosumab therapy. Osteoporos Int. May 2017;28(5):1723-1732.
2009	Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. NEJM. August 20, 2009;361(8):756-765.
2010	Haentjens P, Magaziner J, Colón-Emeric CS, Vanderschueren D, Milisen K, Velkeniers B, Boonen S. Meta-analysis: excess mortality after hip fracture among older women and men. Ann Intern Med. March 16, 2010;152(6):380-390.
2011	Center JR, Bliuc D, Nguyen ND, Nguyen TV, Eisman JA. Osteoporosis medication and reduced mortality risk in elderly women and men. J Clin Endocrinol Metab. April 2011;96(4):1006-1014.
2010	Bolland MJ, Grey AB, Gamble GD, Reid IR. Effect of osteoporosis treatment on mortality: a meta-analysis. J Clin Endocrinol Metab. March 2010;95(3):1174-1181.
2020	Alarkawi D, Bliuc D, Tran T, Ahmed LA, Emaus N, Bjørnerem A, Jørgensen L, Christoffersen T, Eisman JA, Center JR. Impact of osteoporotic fracture type and subsequent fracture on mortality: the Tromsø Study. Osteoporos Int. January 2020;31(1):119-130.
2014	Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. October 2014;25(10):2359-2381.
2017	Tsourdi E, Langdahl B, Cohen-Solal M, Aubry-Rozier B, Eriksen EF, Guañabens N, Obermayer-Pietsch B, Ralston SH, Eastell R, Zillikens MC. Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone. December 2017;105:11-17.
2004	Elliot-Gibson V, Bogoch ER, Jamal SA, Beaton DE. Practice patterns in the diagnosis and treatment of osteoporosis after a fragility fracture: a systematic review. Osteoporos Int. October 2004;15(10):767-778.
2018	Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen J-EB, McClung M, Roux C, Törring O, Valter I, Wang AT, Brown JP. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. February 2018;33(2):190-198.
1998	Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. May 1998;12(9):1260-1268.
2009	Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA. February 4, 2009;301(5):513-521.
2007	Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S; HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture. NEJM. November 1, 2007;357(18):1799-1809.