Polypharmacy and risk of fractures in older adults: A systematic review

Abstract

Background: Fractures have serious health consequences in older adults. While some medications are individually associated with increased risk of falls and fractures, it is not clear if this holds true for the use of many medications (polypharmacy). We aimed to identify what is known about the association between polypharmacy and the risk of fractures in adults aged ≥65 and to examine the methods used to study this association.

Methods: We conducted a systematic review with narrative synthesis of studies published up to October 2023 in PubMed, Embase, CINAHL, PsychINFO, Cochrane Library, Web of Science, and the grey literature. Two independent reviewers screened titles, abstracts, and full texts, then performed data extraction and quality assessment.

Results: Among the 31 studies included, 11 different definitions of polypharmacy were used and were based on three medication counting methods (concurrent use 15/31, cumulative use over a period 6/31, daily average 3/31, and indeterminate 7/31). Overall, polypharmacy was frequent and associated with higher fracture risk. A dose–response relationship between increasing number of medications and increased risk of fractures was observed. However, only seven studies adjusted for major confounders (age, sex, and chronic disease). The quality of the studies ranged from poor to high.

Conclusions: Polypharmacy appears to be a relevant modifiable risk factor for fractures in older individuals that can easily be used to identify those at risk. The diversity of medication calculation methods and definitions of polypharmacy highlights the importance of a detailed methodology to understand and compare results.

Keywords

fractures / geriatrics / pharmacoepidemiology / polypharmacy / systematic review

References

[1] Chowdhury SR, Chandra Das D, Sunna TC, Beyene J, Hossain A. Global and regional prevalence of multimorbidity in the adult population in community settings: a systematic review and meta-analysis. eClinicalMedicine. 2023; 57:101860.

[2] Reider L, Pollak A, Wolff JL, Magaziner J, Levy JF. National trends in extremity fracture hospitalizations among older adults between 2003 and 2017. J Am Geriatr Soc. 2021; 69(9): 2556-2565.

[3] Barcelos A, Lopes DG, Canhão H, da Cunha Branco J, Rodrigues AM. Multimorbidity is associated with fragility fractures in women 50 years and older: a nationwide cross-sectional study. Bone Rep 2021; 15:101139.

[4] Ong T, Kantachuvesiri P, Sahota O, Gladman JR. Characteristics and outcomes of hospitalised patients with vertebral fragility fractures: a systematic review. Age Ageing. 2018; 47(1): 17-25.

[5] World Health Organization. WHO Global Report on Falls Prevention in Older Age. WHO; 2007.

[6] Davies LE, Spiers G, Kingston A, Todd A, Adamson J, Hanratty B. Adverse outcomes of polypharmacy in older people: systematic review of reviews. J Am Med Dir Assoc. 2020; 21(2): 181-187.

[7] Bradley SM. Falls in older adults. Mt Sinai J Med. 2011; 78(4): 590-595.

[8] Woolcott JC, Richardson KJ, Wiens MO, et al. Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Arch Intern Med. 2009; 169(21): 1952-1960.

[9] Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res. 2004; 19(6): 893-899.

[10] Lee RH, Lyles KW, Colón-Emeric C. A review of the effect of anticonvulsant medications on bone mineral density and fracture risk. Am J Geriatr Pharmacother. 2010; 8(1): 34-46.

[11] Rejnmark L, Vestergaard P, Mosekilde L. Fracture risk in patients treated with loop diuretics. J Intern Med. 2006; 259(1): 117-124.

[12] Gajic-Veljanoski O, Phua CW, Shah PS, Cheung AM. Effects of long-term low-molecular-weight heparin on fractures and bone density in non-pregnant adults: a systematic review with meta-analysis. J Gen Intern Med. 2016; 31: 947-957.

[13] Elaine WY, Bauer SR, Bain PA, Bauer DC. Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med. 2011; 124(6): 519-526.

[14] Eastell R, Adams JE, Coleman RE, et al. Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol. 2008; 26(7): 1051-1057.

[15] Crivellari D, Sun Z, Coates AS, et al. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1–98 trial. J Clin Oncol. 2008; 26(12): 1972-1979.

[16] Coleman RE, Banks LM, Girgis SI, et al. Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. Lancet Oncol. 2007; 8(2): 119-127.

[17] Bruning P, Pit M, de Jong-Bakker M, Van den Ende A, Hart A, Van Enk A. Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br J Cancer. 1990; 61(2): 308-310.

[18] World Health Organization. Medication Safety in Polypharmacy. WHO; 2019.

[19] Gnjidic D, Hilmer SN, Blyth FM, et al. Polypharmacy cutoff and outcomes: five or more medicines were used to identify community-dwelling older men at risk of different adverse outcomes. J Clin Epidemiol. 2012; 65(9): 989-995.

[20] Turner JP, Jamsen KM, Shakib S, Singhal N, Prowse R, Bell JS. Polypharmacy cut-points in older people with cancer: how many medications are too many? Support Care Cancer. 2016; 24(4): 1831-1840.

[21] Helgadóttir B, Laflamme L, Monárrez-Espino J, Möller J. Medication and fall injury in the elderly population; do individual demographics, health status and lifestyle matter? BMC Geriatr. 2014; 14(1): 1-8.

[22] Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Int J Surg. 2021; 88:105906.

[23] Scottish Intercollegiate Guidelines Network. SIGN 50: A Guideline Developer's Handbook. SIGN; 2011.

[24] Ma L-L, Wang Y-Y, Yang Z-H, Huang D, Weng H, Zeng X-T. Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: what are they and which is better? Mil Med Res. 2020; 7(1): 7.

[25] Kalaycioglu I, Rioux B, Briard JN, et al. Inter-rater reliability of risk of bias tools for non-randomized studies. Syst Rev. 2023; 12(1): 227.

[26] Minary A, Lambert-Kuhn E, Gourieux B, Bonnomet F, Vogel T, Lang P-O. Médicaments majorant le risque de chute: étude prospective au CHRU de Strasbourg. NPG Neurologie-Psychiatrie-Gériatrie. 2016; 16(94): 217-225.

[27] Reinold J, Braitmaier M, Riedel O, Haug U. Potential of health insurance claims data to predict fractures in older adults: a prospective cohort study. Clin Epidemiol. 2022; 14: 1111-1122.

[28] Uematsu T, Kawakami Y, Nojiri S, et al. Association between number of medications and hip fractures in Japanese elderly using conditional logistic LASSO regression. Sci Rep. 2023; 13(1):16831.

[29] Montali F, Campaniello G, Benatti M, Rastelli G, Pedrazzoni M, Cervellin G. Impact of different drug classes on clinical severity of falls in an elderly population: epidemiological survey in a trauma center. J Clin Gerontol Geriatr. 2015; 6(2): 63-67.

[30] Andersen CU, Lassen PO, Usman HQ, Albertsen N, Nielsen LP, Andersen S. Prevalence of medication-related falls in 200 consecutive elderly patients with hip fractures: a cross-sectional study. BMC Geriatr. 2020; 20(1): 1-9.

[31] Kabue S, Liu V, Dyer W, Raebel M, Nichols G, Schmittdiel J. Identifying common predictors of multiple adverse outcomes among elderly adults with type-2 diabetes. Med Care. 2019; 57(9): 702-709.

[32] Mueller C, Molokhia M, Perera G, et al. Polypharmacy in people with dementia: associations with adverse health outcomes. Exp Gerontol. 2018; 106: 240-245.

[33] Formiga F, Navarro M, Duaso E, et al. Factors associated with hip fracture-related falls among patients with a history of recurrent falling. Bone. 2008; 43(5): 941-944.

[34] Machado-Duque ME, Castaño-Montoya JP, Medina-Morales DA, Castro-Rodríguez A, González-Montoya A, Machado-Alba JE. Drugs with anticholinergic potential and risk of falls with hip fracture in the elderly patients: a case–control study. J Geriatr Psychiatry Neurol. 2018; 31(2): 63-69.

[35] Rossini M, Viapiana O, Adami S, et al. Medication use before and after hip fracture: a population-based cohort and case-control study. Drugs Aging. 2014; 31: 547-553.

[36] Park H-Y, Kim S, Sohn HS, Kwon J-W. The association between polypharmacy and hip fracture in osteoporotic women: a nested case–control study in South Korea. Clin Drug Investig. 2019; 39: 63-71.

[37] Lai S-W, Liao K-F, Liao C-C, Muo C-H, Liu C-S, Sung F-C. Polypharmacy correlates with increased risk for hip fracture in the elderly: a population-based study. Medicine. 2010; 89(5): 295-299.

[38] García Molina O, Olmos Jimenez R, Castellote de Varona F, Mendoza Otero F, Arocas Casañ V, de la Rubia Nieto MA. Polypharmacy related to increased risk of hip fracture in elderly patients. Eur J Clin Pharmacol. 2014; 16(2): 117-123.

[39] Polan C, Meyer H-L, Burggraf M, et al. Geriatric proximal femur fractures during the COVID-19 pandemic—fewer cases, but more comorbidities. Geriatr Orthop Surg Rehabil. 2021; 12: 1-7.

[40] Lin PY, Huang HH, Yen DH. Comprehensive geriatric assessment in the emergency department for identifying elderly individuals at risk of hip fracture. J Acute Med. 2022; 12(3): 113-121.

[41] Cartei A, Mossello E, Ceccofiglio A, et al. Independent, differential effects of delirium on disability and mortality risk after hip fracture. J Am Med Dir Assoc. 2022; 23(4): 654.e1-659.e1.

[42] Borsari V, Veronesi F, Carretta E, Fini M. Multimorbidity and polytherapy in patients with femoral neck fracture: a retrospective observational study. J Clin Med. 2022; 11(21): 6405.

[43] Olesen AE, Schacksen CS, Nielsen IM, Nielsen LP, Andersen S, Andersen CU. Significantly higher use of polypharmacy in elderly with hip fracture treated with psychotropics. Dan Med J. 2022; 69(10):A12210945.

[44] Lu W-H, Wen Y-W, Chen L-K, Hsiao F-Y. Effect of polypharmacy, potentially inappropriate medications and anticholinergic burden on clinical outcomes: a retrospective cohort study. CMAJ. 2015; 187(4): E130-E137.

[45] Alyazeedi A, Fouad Algendy A, Sharabash M, Karawia A. Prevalence, determinants and associated risk of potentially inappropriate prescribing for older adults in Qatar: a national retrospective study. Clin Interv Aging. 2019; 14: 1889-1899.

[46] Umıt EG, Baysal M, Bas V, Asker I, Kırkızlar O, Demır AM. Polypharmacy and potentially inappropriate medication use in older patients with multiple myeloma, related to fall risk and autonomous neuropathy. J Oncol Pharm Pract. 2020; 26(1): 43-50.

[47] Duman Atilla O, Tur FC, Aksay E, Dogan T, Eyler Y, Akin S. Clinical factors in geriatric blunt trauma/Geriatrik kunt travma hastalarinin klinik ozellikleri. Turk J Emerg Med. 2012; 12(3): 123-128.

[48] Bambina E, Mestivier E, Berod T. Chutes et identification des facteurs de risques médicamenteux chez le sujet âgé: apport du bilan médicamenteux optimisé à l'entrée d'hospitalisation. Le Pharmacien Hospitalier et Clinicien. 2017; 52(1): 21-25.

[49] Müller M, Ricklin ME, Weiler S, Exadaktylos AK, Arampatzis S. Emergency medicine in the extreme geriatric era: a retrospective analysis of patients aged in their mid 90s and older in the emergency department. Geriatr Gerontol Int. 2018; 18(3): 415-420.

[50] Chen JS, Simpson JM, March LM, et al. Fracture risk assessment in frail older people using clinical risk factors. Age Ageing. 2008; 37(5): 536-541.

[51] Roitto HM, Aalto UL, Öhman H, et al. Association of medication use with falls and mortality among long-term care residents: a longitudinal cohort study. BMC Geriatr. 2023; 23(1): 375.

[52] Komorita Y, Ohkuma T, Iwase M, et al. Polypharmacy and bone fracture risk in patients with type 2 diabetes: the Fukuoka Diabetes Registry. Diabetes Res Clin Pract. 2021; 181:109097.

[53] LeBlanc ES, Rosales AG, Balasubramanian A, et al. Risk factors for fracture among current, persistent users of bisphosphonates. Osteoporos Int. 2015; 26(2): 713-725.

[54] Hauff J, Rottenkolber M, Oehler P, et al. Single and combined use of fall-risk-increasing drugs and fracture risk: a population-based case-control study. Age Ageing. 2023; 52(6):afad079.

[55] Nagai T, Nagaoka M, Tanimoto K, Tomizuka Y, Uei H, Nakanishi K. Relationship between potentially inappropriate medications and functional prognosis in elderly patients with distal radius fracture: a retrospective cohort study. J Orthop Surg Res. 2020; 15: 1-8.

[56] Cox N, Ilyas I, Roberts HC, Ibrahim K. Exploring the prevalence and types of fall-risk-increasing drugs among older people with upper limb fractures. Int J Pharm Pract. 2023; 31(1): 106-112.

[57] Wakasugi M, Yokoseki A, Wada M, et al. Polypharmacy, chronic kidney disease, and incident fragility fracture: a prospective cohort study. J Bone Miner Metab. 2022; 40(1): 157-166.

[58] Leslie WD, Lix LM, Johansson H, Oden A, McCloskey E, Kanis JA. Independent clinical validation of a Canadian FRAX tool: fracture prediction and model calibration. J Bone Miner Res. 2010; 25(11): 2350-2358.

[59] Harvey NC, Odén A, Orwoll E, et al. Falls predict fractures independently of FRAX probability: a meta-analysis of the osteoporotic fractures in men (MrOS) study. J Bone Miner Res. 2018; 33(3): 510-516.

[60] Ganz DA, Latham NK. Prevention of falls in community-dwelling older adults. N Engl J Med. 2020; 382(8): 734-743.

[61] Gutiérrez-Valencia M, Izquierdo M, Cesari M, Casas-Herrero Á, Inzitari M, Martínez-Velilla N. The relationship between frailty and polypharmacy in older people: a systematic review. Br J Clin Pharmacol. 2018; 84(7): 1432-1444.

[62] Milos V, Bondesson Å, Magnusson M, Jakobsson U, Westerlund T, Midlöv P. Fall risk-increasing drugs and falls: a cross-sectional study among elderly patients in primary care. BMC Geriatr. 2014; 14: 1-7.

[63] Turner JP, Tervonen HE, Shakib S, Singhal N, Prowse R, Bell JS. Factors associated with use of falls risk-increasing drugs among patients of a geriatric oncology outpatient clinic in Australia: a cross-sectional study. J Eval Clin Pract. 2017; 23(2): 361-368.

[64] Laflamme L, Monárrez-Espino J, Johnell K, Elling B, Möller J. Type, number or both? A population-based matched case-control study on the risk of fall injuries among older people and number of medications beyond fall-inducing drugs. PLoS ONE. 2015; 10(3):e0123390.

[65] Gagnon M-E, Mésidor M, Simard M, et al. A comparative analysis of medication counting methods to assess polypharmacy in medico-administrative databases. 2024. (submitted).

[66] Sutton-Tyrrell K. Assessing bias in case-control studies. Proper selection of cases and controls. Stroke. 1991; 22(7): 938-942.

[67] Rothman KJ, Greenland S, Lash TL. Modern Epidemiology. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008.

[68] Nunan D, Aronson J, Bankhead C. Catalogue of bias: attrition bias. BMJ Evid Based Med. 2018; 23(1): 21-22.

[69] Sun G-W, Shook TL, Kay GL. Inappropriate use of bivariable analysis to screen risk factors for use in multivariable analysis. J Clin Epidemiol. 1996; 49(8): 907-916.

[70] Pazzagli L, Linder M, Zhang M, et al. Methods for time-varying exposure related problems in pharmacoepidemiology: an overview. Pharmacoepidemiol Drug Saf. 2018; 27(2): 148-160.

[71] Button KS, Ioannidis JP, Mokrysz C, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013; 14(5): 365-376.

[72] Kristman VL, Manno M, Côté P. Methods to account for attrition in longitudinal data: do they work? A simulation study. Eur J Epidemiol. 2005; 20: 657-662.

[73] Talbot D, Massamba VK. A descriptive review of variable selection methods in four epidemiologic journals: there is still room for improvement. Eur J Epidemiol. 2019; 34(8): 725-730.

[74] Talbot D, Diop A, Lavigne-Robichaud M, Brisson C. The change in estimate method for selecting confounders: a simulation study. Stat Methods Med Res. 2021; 30(9): 2032-2044.

[75] Schneeweiss S, Rassen JA, Glynn RJ, Avorn J, Mogun H, Brookhart MA. High-dimensional propensity score adjustment in studies of treatment effects using health care claims data. Epidemiology. 2009; 20(4): 512.

[76] Greenland S, Senn SJ, Rothman KJ, et al. Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations. Eur J Epidemiol. 2016; 31: 337-350.

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