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The association of melatonin use and hip fracture: a matched cohort study

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Abstract

Summary

By using propensity-score matched cohorts, we compared the risk of incident hip fracture between melatonin initiators and hypnotic benzodiazepines initiators. The initiation of melatonin was not associated with an increased risk of hip fracture.

Introduction

Melatonin is hypothesized to suppress bone loss, but a previous study reported an increased risk of hip fracture among melatonin users compared with non-users, which was however susceptible to confounding by indication. This study aimed to compare the risk of hip fracture between melatonin initiators and initiators of its active comparators, i.e., hypnotic benzodiazepines.

Methods

Among individuals aged 40 years or older without a history of hip fracture or cancer in the IQVIA Medical Research Database (IMRD) in the UK (2000–2018), a propensity score-matched cohort study was conducted to examine the association of melatonin initiation vs. hypnotic benzodiazepines initiation with the risk of hip fracture.

Results

After propensity score matching, 9,038 patients were included (4,519 melatonin initiators and 4,519 hypnotic benzodiazepines initiators). During the entire follow-up, 41 cases of hip fracture occurred in the melatonin cohort, and 51 cases occurred in the hypnotic benzodiazepines cohort. The absolute rate difference in hip fracture between melatonin initiators and hypnotic benzodiazepines initiators was -0.8 (95% CI: -1.9 to 0.3) per 1000 person-years and the multivariable-adjusted hazard ratio (HR) of hip fracture for melatonin initiators was 0.78 (95% CI: 0.51 to 1.17).

Conclusion

In this population-based cohort study, the risk of hip fracture among melatonin initiators was not higher, if not lower, than that among hypnotic benzodiazepines initiators.

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Data availability

The data that support the findings of this study are available from the IQVIA Medical Research Database (IMRD).

References

  1. Parker M, Johansen A (2006) Hip fracture. BMJ (Clin Res ed) 333:27–30

    Article  Google Scholar 

  2. Salkeld G, Cameron I, Cumming R, Easter S, Seymour J, Kurrle S, Quine S (2000) Quality of life related to fear of falling and hip fracture in older women: a time trade off study. BMJ (Clin Res ed) 320:341–346

    Article  CAS  Google Scholar 

  3. Brauer C, Coca-Perraillon M, Cutler D, Rosen A (2009) Incidence and mortality of hip fractures in the United States. JAMA 302:1573–1579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wenk M, Frey S (2021) Elderly hip fracture patients: surgical timing and factors to consider. Curr Opin Anaesthesiol 34:33–39

    Article  PubMed  Google Scholar 

  5. Burge R, Dawson-Hughes B, Solomon D, Wong J, King A, Tosteson A (2007) Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Mineral Res Off J Am Soc Bone Mineral Res 22:465–475

    Article  Google Scholar 

  6. Williams S, Daigle S, Weiss R, Wang Y, Arora T, Curtis J (2021) Economic Burden of Osteoporosis-Related Fractures in the US Medicare Population. Ann Pharmacother 55:821–829

    Article  PubMed  Google Scholar 

  7. Park H, Kim S, Sohn H, Kwon J (2019) The Association between Polypharmacy and Hip Fracture in Osteoporotic Women: A Nested Case-Control Study in South Korea. Clin Drug Investig 39:63–71

    Article  CAS  PubMed  Google Scholar 

  8. Poly T, Islam M, Yang H, Wu C, Li Y (2019) Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies. Osteoporos Int J Established Result Coop between Eur Found Osteoporos Natl Osteoporos Found USA 30:103–114

    Article  CAS  Google Scholar 

  9. Woolcott J, Richardson K, Wiens M, Patel B, Marin J, Khan K, Marra C (2009) Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Arch Intern Med 169:1952–1960

    Article  PubMed  Google Scholar 

  10. Redman J (1997) Circadian entrainment and phase shifting in mammals with melatonin. J Biol Rhythms 12:581–587

    Article  CAS  PubMed  Google Scholar 

  11. Claustrat B, Leston J (2015) Melatonin: Physiological effects in humans. Neurochirurgie 61:77–84

    Article  CAS  PubMed  Google Scholar 

  12. Gomes Domingos A, Hermsdorff H, Bressan J (2019) Melatonin intake and potential chronobiological effects on human health. Crit Rev Food Sci Nutr 59:133–140

    Article  CAS  PubMed  Google Scholar 

  13. Jiménez-Delgado A, Ortiz G, Delgado-Lara D, González-Usigli H, González-Ortiz L, Cid-Hernández M, Cruz-Serrano J, Pacheco-Moisés F (2021) Effect of Melatonin Administration on Mitochondrial Activity and Oxidative Stress Markers in Patients with Parkinson’s Disease. Oxid Med Cell Longev 2021:5577541

    Article  PubMed  PubMed Central  Google Scholar 

  14. Albreiki M, Middleton B, Hampton S (2021) The effect of melatonin on glucose tolerance, insulin sensitivity, and lipid profiles after a late evening meal in healthy young males. J Pineal Res 71:e12770

  15. Kim C, Yoo Y (2013) Fluid shear stress and melatonin in combination activate anabolic proteins in MC3T3-E1 osteoblast cells. J Pineal Res 54:453–461

    Article  PubMed  Google Scholar 

  16. Sharan K, Lewis K, Furukawa T, Yadav V (2017) Regulation of bone mass through pineal-derived melatonin-MT2 receptor pathway. J Pineal Res 63:e12423

  17. Zhou L, Chen X, Yan J et al (2017) Melatonin at pharmacological concentrations suppresses osteoclastogenesis via the attenuation of intracellular ROS. Osteoporos Int 28:3325–3337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Egermann M, Gerhardt C, Barth A, Maestroni GJ, Schneider E, Alini M (2011) Pinealectomy affects bone mineral density and structure–an experimental study in sheep. BMC Musculoskelet Disord 12:271

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kim HJ, Kim HJ, Bae MK, Kim YD (2017) Suppression of osteoclastogenesis by melatonin: a melatonin receptor-independent action. Int J Mol Sci 18:1142

  20. Li X, Li Z, Wang J et al (2019) Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment. FASEB J 33:10126–10139

    Article  CAS  PubMed  Google Scholar 

  21. Nakano M, Ikegame M, Igarashi-Migitaka J, Maruyama Y, Suzuki N, Hattori A (2019) Suppressive effect of melatonin on osteoclast function via osteocyte calcitonin. J Endocrinol 242:13–23

    Article  CAS  PubMed  Google Scholar 

  22. Amstrup A, Sikjaer T, Heickendorff L, Mosekilde L, Rejnmark L (2015) Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial. J Pineal Res 59:221–229

    Article  CAS  PubMed  Google Scholar 

  23. Frisher M, Gibbons N, Bashford J, Chapman S, Weich S (2016) Melatonin, hypnotics and their association with fracture: a matched cohort study. Age Ageing 45:801–806

    Article  PubMed  Google Scholar 

  24. Amstrup A, Sikjaer T, Mosekilde L, Rejnmark L (2015) The effect of melatonin treatment on postural stability, muscle strength, and quality of life and sleep in postmenopausal women: a randomized controlled trial. Nutr J 14:102

    Article  PubMed  PubMed Central  Google Scholar 

  25. Read J (1990) Read clinical classification. BMJ (Clin Res ed) 301:45

    Article  CAS  Google Scholar 

  26. First Databank (2018) Multilex. First Databank. http://www.folbhealth.co.uk/solutions/multilex. Accessed 20 Feb 2018

  27. Lewis J, Schinnar R, Bilker W, Wang X, Strom B (2007) Validation studies of the health improvement network (THIN) database for pharmacoepidemiology research. Pharmacoepidemiol Drug Saf 16:393–401

    Article  PubMed  Google Scholar 

  28. Atkin T, Comai S, Gobbi G (2018) Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery. Pharmacol Rev 70:197–245

    Article  CAS  PubMed  Google Scholar 

  29. Krystal A, Prather A, Ashbrook L (2019) The assessment and management of insomnia: an update. World Psychiatry Off J World Psychiatric Assoc (WPA) 18:337–352

    Google Scholar 

  30. Collins G, Mallett S, Altman D (2011) Predicting risk of osteoporotic and hip fracture in the United Kingdom: prospective independent and external validation of QFractureScores. BMJ (Clin Res ed) 342:d3651

    Article  Google Scholar 

  31. Misra D, Zhang Y, Peloquin C, Choi H, Kiel D, Neogi T (2014) Incident long-term warfarin use and risk of osteoporotic fractures: propensity-score matched cohort of elders with new onset atrial fibrillation. Osteoporos Int J established result Coop between Eur Found Osteoporos Natl Osteoporos Found USA 25:1677–1684

    Article  CAS  Google Scholar 

  32. Misra D, Peloquin C, Kiel D, Neogi T, Lu N, Zhang Y (2017) Intermittent Nitrate Use and Risk of Hip Fracture. Am J Med 130:229.e215-229.e220

    Article  Google Scholar 

  33. Austin P, Lee D, Fine J (2016) Introduction to the Analysis of Survival Data in the Presence of Competing Risks. Circulation 133:601–609

    Article  PubMed  PubMed Central  Google Scholar 

  34. Rod N, Lange T, Andersen I, Marott J, Diderichsen F (2012) Additive interaction in survival analysis: use of the additive hazards model. Epidemiology 23:733–737

    Article  PubMed  Google Scholar 

  35. NHS Business Services Authority (2016) Prescription Cost Analysis (PCA) Data. http://www.nhsbsa.nhs.uk/PrescriptionServices/3494.aspx. Accessed 6 June 2016

  36. Ferracioli-Oda E, Qawasmi A, Bloch M (2013) Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One 8:e63773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Radio N, Doctor J, Witt-Enderby P (2006) Melatonin enhances alkaline phosphatase activity in differentiating human adult mesenchymal stem cells grown in osteogenic medium via MT2 melatonin receptors and the MEK/ERK (1/2) signaling cascade. J Pineal Res 40:332–342

    Article  CAS  PubMed  Google Scholar 

  38. Park K, Kang J, Lee E, Kim J, Rhee Y, Kim M, Jeong S, Park Y, Kim S (2011) Melatonin promotes osteoblastic differentiation through the BMP/ERK/Wnt signaling pathways. J Pineal Res 51:187–194

    Article  CAS  PubMed  Google Scholar 

  39. Rafat A, Mohammadi Roushandeh A, Alizadeh A, Hashemi-Firouzi N, Golipoor Z (2019) Comparison of The Melatonin Preconditioning Efficacy between Bone Marrow and Adipose-Derived Mesenchymal Stem Cells. Cell J 20:450–458

    PubMed  Google Scholar 

  40. Maria S, Samsonraj R, Munmun F et al (2018) Biological effects of melatonin on osteoblast/osteoclast cocultures, bone, and quality of life: implications of a role for MT2 melatonin receptors, MEK1/2, and MEK5 in melatonin-mediated osteoblastogenesis. J Pineal Res. https://doi.org/10.1111/jpi.12465

  41. Koyama H, Nakade O, Takada Y, Kaku T, Lau K (2002) Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. J Bone Mineral Res Off J Am Soc Bone Mineral Res 17:1219–1229

    Article  CAS  Google Scholar 

  42. Kotlarczyk M, Lassila H, O’Neil C, D’Amico F, Enderby L, Witt-Enderby P, Balk J (2012) Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women. J Pineal Res 52:414–426

    Article  CAS  PubMed  Google Scholar 

  43. Maria S, Swanson M, Enderby L, D’Amico F, Enderby B, Samsonraj R, Dudakovic A, van Wijnen A, Witt-Enderby P (2017) Melatonin-micronutrients Osteopenia Treatment Study (MOTS): a translational study assessing melatonin, strontium (citrate), vitamin D3 and vitamin K2 (MK7) on bone density, bone marker turnover and health related quality of life in postmenopausal osteopenic women following a one-year double-blind RCT and on osteoblast-osteoclast co-cultures. Aging 9:256–285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Okawa M, Uchiyama M, Ozaki S, Shibui K, Kamei Y, Hayakawa T, Urata J (1998) Melatonin treatment for circadian rhythm sleep disorders. Psychiatry Clin Neurosci 52:259–260

    Article  CAS  PubMed  Google Scholar 

  45. Malhotra S, Sawhney G, Pandhi P (2004) The therapeutic potential of melatonin: a review of the science. MedGenMed Medscape Gen Med 6:46

    Google Scholar 

  46. Lewiecki E (2004) Management of osteoporosis. Clin Mol Allergy CMA 2:9

    Article  PubMed  Google Scholar 

  47. Marks R, Allegrante J, Ronald MacKenzie C, Lane J (2003) Hip fractures among the elderly: causes, consequences and control. Ageing Res Rev 2:57–93

    Article  PubMed  Google Scholar 

  48. Blais L, Ernst P, Suissa S (1996) Confounding by indication and channeling over time: the risks of beta 2-agonists. Am J Epidemiol 144:1161–1169

    Article  CAS  PubMed  Google Scholar 

  49. Donnelly K, Bracchi R, Hewitt J, Routledge PA, Carter B (2017) Benzodiazepines, Z-drugs and the risk of hip fracture: A systematic review and meta-analysis. PLoS One 12:e0174730

    Article  PubMed  PubMed Central  Google Scholar 

  50. Poly T, Islam M, Yang H, Li Y (2020) Association between benzodiazepines use and risk of hip fracture in the elderly people: A meta-analysis of observational studies. Joint Bone Spine 87:241–249

    Article  CAS  PubMed  Google Scholar 

  51. Cumming RG, Le Couteur DG (2003) Benzodiazepines and risk of hip fractures in older people: a review of the evidence. CNS Drugs 17:825–837

    Article  CAS  PubMed  Google Scholar 

  52. Ponkilainen V, Kuitunen I, Liukkonen R, Vaajala M, Reito A, Uimonen M (2022) The incidence of musculoskeletal injuries: a systematic review and meta-analysis. Bone Joint Res 11:814–825

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (U21A20352, 81930071, 82072502, 81902265, 81902264); Wu Jieping Medical Foundation (320.6750.2020–03-11); the Key Research and Development Program of Hunan Province (2021SK2017); the Project Program of the National Clinical Research Center for Geriatric Disorders (grant 2020LNJJ03 to Xiangya Hospital); the Science and Technology Program of Hunan Province (2019RS2010) and the Natural Science Foundation of Hunan Province (2022JJ40835, 2020JJ5907).

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Authors and Affiliations

  1. Health Management Center, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Tuo Yang

  2. Department of Orthopedics, Xiangya Hospital, Central South University, 87 Xiangya Road, 410008, Changsha, Hunan, China

    Tuo Yang, Xiang Ding & Yilin Xiong

  3. Hunan Key Laboratory of Joint Degeneration and Injury, Changsha, 410008, Hunan, China

    Jing Wu & Bin Zhou

  4. Hunan Engineering Research Center of Osteoarthritis, Changsha, Hunan, China

    Yilin Xiong

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  1. Tuo Yang
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  2. Jing Wu
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  3. Xiang Ding
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  4. Bin Zhou
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Corresponding authors

Correspondence to Bin Zhou or Yilin Xiong.

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Ethical approval and informed consent

The scientific review committee for the IQVIA Medical Research Database (21SRC027) and the institutional review board at Xiangya Hospital approved this study (2018091077), with waiver of informed consent.

Conflict of interest

Tuo Yang, Jing Wu, Xiang Ding, Bin Zhou and Yilin Xiong declare that they have no conflict of interest.

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Yang, T., Wu, J., Ding, X. et al. The association of melatonin use and hip fracture: a matched cohort study. Osteoporos Int 34, 1127–1135 (2023). https://doi.org/10.1007/s00198-023-06740-8

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