Bisphosphonate drug holidays:​ risk of fractures and mortality in a prospective cohort study

Pfeilschifter, Johannes<sup>1</sup>; Steinebach, Inga<sup>1</sup>; Trampisch, Hans J.<sup>1</sup>; Rudolf, Henrik<sup>1</sup>

Affiliations

¹Department of Medical Informatics, Biometry and Epidemiology, Ruhr University Bochum, D-44780 Bochum, Germany

Abstract and keywords

Purpose: This study examined osteoporotic fractures and mortality in patients pretreated with bisphosphonates (BPs) during BP holidays and ongoing BP use.

Methods: Interview-based prospective observational study in a cohort of 1973 patients with BP treatment for at least 80% of the total time of the preceding 4 years. Patients were recruited from 146 primarily endocrinological, orthopedic and rheumatological practices and clinics across Germany between May 2013 and June 2015. Outcomes were analyzed by Cox proportional hazards regression in relation to treatment status at the time of the first interview (model 1) or using time-dependent treatment variables (model 2). Temporal changes in fracture risk during BP holidays were evaluated by comparisons among 3 incremental levels of simple moving averages of BP treatment during the preceding 12 months (BP-SMA levels 0%, >0% to <50%, and ≥50%).

Results: For an observation period of up to 25 months, the adjusted hazard ratios (HRs) in model 1 for BP holidays compared to ongoing BP use were 0.87 (95% confidence interval [CI] 0.59–1.28) for major osteoporotic fractures (MOFs), 0.95 (95% CI 0.70–1.28) for any clinical osteoporotic fracture, 0.96 (95% CI 0.55–1.68) for clinical vertebral fractures, and 0.86 (95% CI 0.50–1.48) for mortality. The risk of MOFs was higher for the BP-SMA level 0%, corresponding to a time >12 months since the start of a BP holiday, than for the BP-SMA level >0% to <50%, corresponding mainly to a time >6 to ≤12 months since the start of a BP holiday (adjusted HR 2.28, 95% CI 1.07–4.86). We found an interaction between prevalent vertebral fractures (PVFs) and BP-SMA-related time to first MOF for BP-SMA as a continuous variable (p for interaction 0.046 in the adjusted model). The adjusted HR for MOFs for the BP-SMA level 0% compared to the BP-SMA level >0% to <50% was 3.53 (95% CI 1.19–10.51) with a PVF but was 1.44 (95% CI 0.49–4.22) without a PVF.

Conclusions: Fracture risk and mortality in patients with preceding BP treatment did not significantly differ between BP holidays and ongoing BP use for an observation period up to 25 months when outcomes were analyzed in relation to treatment at the time of the first interview. However, in the presence of a PVF, the risk of MOFs was higher for a BP-SMA level corresponding to a time >12 months since the start of a BP holiday than for a BP-SMA level corresponding mainly to a time >6 to ≤12 months since the start of a BP holiday. The presence of a PVF may increase the relative risk of MOFs associated with a longer BP holiday.

Keywords: Osteoporosis; Bisphosphonates; Bisphosphonate holiday; Long-term treatment; Fractures

Links

DOI: 10.1016/j.bone.2020.115431

PubMed: 32422299

WoS: 000557876000003

History

Received: 2019-12-1

Revised: 2020-05-13

Accepted: 2020-05-13

Online: 2020-05-15

Cited Works (15)

Year	Entry
2006	Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the fracture intervention trial long-term extension (FLEX): a randomized trial. JAMA. December 27, 2006;296(24):2927-2938.
2017	Compston J, Cooper A, Cooper C, Gittoes N, Gregson C, Harvey N, Hope S, Kanis JA, McCloskey EV, Poole KES, Reid DM, Selby P, Thompson F, Thurston A, Vine N; The National Osteoporosis Guideline Group (NOGG). UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos. December 2017;12(1):1-24.
1999	Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. June 1999;94(446):496-509.
2012	Dell RM, Adams AL, Greene DF, Funahashi TT, Silverman SL, Eisemon EO, Zhou H, Burchette RJ, Ott SM. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res. December 2012;27(12):2544-2550.
2018	Reid IR, Horne AM, Mihov B, Stewart A, Garratt E, Wong S, Wiessing KR, Bolland MJ, Bastin S, Gamble GD. Fracture prevention with zoledronate in older women with osteopenia. NEJM. December 20, 2018;379(25):2407-2416.
2000	Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA III, Berger M. Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res. April 2000;15(4):721-739.
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.
2008	Russell RGG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. June 2008;19(6):733-759.
2015	Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O'Ryan F, Reid IR, Ruggiero SL, Taguchi A, Tetradis S, Watts NB, Brandi ML, Peters E, Guise T, Eastell R, Cheung AM, Morin SN, Masri B, Cooper C, Morgan SL, Obermayer-Pietsch B, Langdahl BL, Al Dabagh R, Davison KS, Kendler DL, Sándor GK, Josse RG, Bhandari M, El Rabbany M, Pierroz DD, Sulimani R, Saunders DP, Brown JP, Compston J; International Task Force on Osteonecrosis of the Jaw. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. January 2015;30(1):3-23.
1987	Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis. January 1, 1987;40(5):373-383.
2014	Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O'Ryan F. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw: 2014 update. J Oral Maxillofac Surg. October 2014;72(10):1938-1956.
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.
2011	Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. NEJM. May 5, 2011;364(18):1728-1737.
2012	Bala Y, Depalle B, Farlay D, Douillard T, Meille S, Follet H, Chapurlat R, Chevalier J, Boivin G. Bone micromechanical properties are compromised during long-term alendronate therapy independently of mineralization. J Bone Miner Res. April 2012;27(4):825-834.
2016	Adler RA, Fuleihan GE-H, Bauer DC, Camacho PM, Clarke BL, Clines GA, Compston JE, Drake MT, Edwards BJ, Favus MJ, Greenspan SL, McKinney R Jr, Pignolo RJ, Sellmeyer DE. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016;31(1):16-35.