www.nature.com/scientificreports OPEN Use of serotonin reuptake inhibitors and risk of subsequent bone loss in a nationwide population‑based cohort study Sunyoung Kang1,6, Minkyung Han2,6, Chun Il Park3, Inkyung Jung4, Eun Hwa Kim2, Young Jun Boo1, Jee In Kang1,5* & Se Joo Kim1,5* This study examined whether the use of SRIs is associated with an increased risk of bone loss using a nested case–control design with a nationwide population–based cohort in Korea. Using the Korean National Health Screening Cohort, subjects newly diagnosed with osteoporosis or osteopenia (n = 55,799) were matched with controls (n = 278,995) at a ratio of 1:5. We stratifed the participants by their time‑dependent use of SRIs and sex and controlled for various confounders, including lifestyle habits, laboratory data, and comorbidities. Conditional logistic regression showed that both recent and former users of SRIs had an increased risk of subsequent bone loss compared with non‑users: men [recent users: odds ratio (OR) 1.35, 95% confdential interval (CI) 1.20, 1.53; former‑users: OR 1.10, 95% CI 1.01, 1.20]; women (recent users: OR 1.38, 95% CI 1.28–1.48; former‑users: OR 1.07, 95% CI 1.02, 1.21). The use of SRIs was associated with an increased risk of bone loss in both men and women. In particular, the association was stronger in recent users. These fndings provide population‑ level evidence for the risk of bone loss associated with SRI exposure and highlight the importance of monitoring the bone health of SRI users. Te use of antidepressants, especially serotonin reuptake inhibitors (SRIs), has become increasingly common in recent decades all around the world1–5. Reports of low bone mineral density (BMD)6–8 and bone fractures9–19 in people taking antidepressants have raised the concern that SRIs could have adverse efects on bone. A meta- analysis of 16 studies reported that users of selective serotonin reuptake inhibitors (SSRIs) are 1.61 times more likely to develop bone fractures than non-users (Relative risk 1.61 95% CI 1.49, 1.74)15. In addition, some studies found that the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) can be associated with an increased risk of bone fractures16,17. Although those fracture-risk fndings suggest a possible link between use of SRIs and bone health, any real connection between them remains unclear20, and the risk of bone fractures among people taking antidepressants could be related to other factors, such as falls and depressive status. Findings about the adverse efects of SRI use on BMD are limited and mixed. Although several studies reported that a history of taking SSRIs predicted decreased BMD in both men and women 6–8,18, some studies found no signifcant association between them21,22. A meta‐analysis of 4 studies examining the association between antidepressants and BMD in women showed that antidepressant was not associated with lower or higher BMD23. A cohort study (173 men and 323 women) reported that taking antidepressants was associated with low BMD in women (Coefcient -0.141, 95% CI -0.263, -0.020) but not in men (Coefcient 0.073, 95% CI -0.086, 0.232)22. Moreover, current users of antidepressants were reported to show a signifcantly higher risk of osteoporotic fractures than former users 17. Tese inconsistent results across studies might be attributable to small sample sizes, diferent study designs, sample characteristics such as sex diferences, diferent duration of antidepressant use, and sampling bias. More research into the independent efect of SRIs on bone health in a 1Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. 2Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea. 3Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea. 4Division of Biostatistics, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea. 5Department of Psychiatry, Yonsei University College of Medicine, Yonsei-ro 50-1, Seodaemun-gu, Seoul 03722, Republic of Korea. 6These authors contributed equally: Sunyoung Kang and Minkyung Han. *email: [email protected]; [email protected] Scientifc Reports | (2021) 11:13461 | https://doi.org/10.1038/s41598-021-92821-9 1 Vol.:(0123456789) www.nature.com/scientificreports/ Figure 1. Flow chart of the study process. large unbiased clinical sample controlled for various confounders is needed to improve the safety of SRI treat- ment and the healthcare quality. In this study, we used a nationwide population-based Korean cohort to examine whether the use of SRIs is associated with subsequent bone loss. We used a nested case–control design with a 1:5 matching ratio of cases to controls and stratifed the participants according to their time-dependent use of SRIs and their sex. In addition, we controlled for various potential confounders such as laboratory test results and lifestyle factors that could afect bone health. Results We identifed 388,979 individuals who had received a medical check-up between Jan 2004 and Dec 2006. We excluded participants with a previous diagnosis related to bone loss (n = 51,151) or exposure to SRIs during the wash out period (n = 35,508). Using a 1:5 matching ratio of cases to controls, controls without any diag- nosis related to bone loss (n = 278,995) were randomly selected for each case in the group with low bone mass [n = 55,799; 43,313 Women (77.6%); mean (SD) age, 58.0 (9.4) years]. A detailed fow chart is provided in Fig. 1. Te baseline characteristics of the study sample are presented in Table 1. Te rate of participants who never used SRIs was lower in subjects with a new diagnosis of low bone density than in those without such a diagnosis. At the same time, subjects in the case group were more likely to be classifed as former or recent users of SRIs than those in the control group. In both sexes, subjects in the case group were more likely than the controls to take glucocorticoids, GnRH agonists, anticonvulsants, thiazolidinediones, antipsychotics, benzodiazepine, and TCA. Men and women who were newly diagnosed with low bone density had a higher prevalence than controls of using androgen deprivation therapy and aromatase inhibitors, respectively. Subjects with low bone density were more likely to take DMPA and estrogen or a combination of estrogen and progesterone, but those outcomes occurred only in women. Te low bone density group was also more likely than the controls to report high CCI, low systolic and diastolic blood pressures, low fasting blood glucose level, and low total cholesterol level; and perform little exercise. Te case group presented with lower hemoglobin levels and higher AST than the controls, but this outcome occurred only in men. Participants with osteoporosis had lower urine protein and ALT levels, and those results were driven by women. Scientifc Reports | (2021) 11:13461 | https://doi.org/10.1038/s41598-021-92821-9 2 Vol:.(1234567890) www.nature.com/scientificreports/ Total Men Women Low bone density Normal Low bone density Normal Low bone density Normal Characteristic (n = 55,799)a (n = 278,995)a P-value (n = 12,486) (n = 62,430) P-value (n = 43,313) (n = 216,565) P-value Age, mean ± SD 58.0 ± 9.4 58.0 ± 9.4 61.0 ± 9.6 61.0 ± 9.6 57.1 ± 9.1 57.1 ± 9.1 Serotonin reuptake inhibitors < 0.001 < 0.001 < 0.001 use Never used, no. (%) 51,186 (91.7) 263,413 (94.4) 11,296 (90.5) 58,777 (94.2) 39,890 (92.1) 204,636 (94.5) Former user, no. (%) 3151 (5.7) 11,358 (4.1) 755 (6.0) 2574 (4.1) 2396 (5.5) 8784 (4.1) Recent user, no. (%) 1462 (2.6) 4224 (1.5) 435 (3.5) 1079 (1.7) 1027 (2.4) 3145 (1.4) Medicationd Glucocorticoids, no. (%) 46,024 (82.5) 203,843 (73.1) < 0.001 10,610 (85.0) 47,318 (75.8) < 0.001 35,414 (81.8) 156,525 (72.3) < 0.001 Aromatase inhibitors, no. (%)b 225 (0.4) 199 (0.1) < 0.001 225 (0.5) 199 (0.1) < 0.001 Androgen deprivation therapy, 126 (0.2) 278 (0.1) < 0.001 126 (1.0) 278 (0.5) < 0.001 no. (%)b GnRH agonists, no. (%) 201 (0.4) 402 (0.1) < 0.001 134 (1.1) 266 (0.4) < 0.001 67 (0.2) 136 (0.1) < 0.001 Anticonvulsants, no. (%) 3819 (6.8) 13,355 (4.8) < 0.001 1129 (9.0) 3540 (5.7) < 0.001 2690 (6.2) 9815 (4.5) < 0.001 Tiazolidinediones, no. (%) 1072 (1.9) 4625 (1.7) < 0.001 386 (3.1) 1638 (2.6) 0.004 686 (1.6) 2987 (1.4) 0.001 DMPA, no. (%)c 794 (1.4) 2739 (1.0) < 0.001 1 (0.0) 0 (0.0) 0.167 793 (1.8) 2739 (1.3) < 0.001 Antipsychotics, no. (%) 2184 (3.9) 8231 (3.0) < 0.001 671 (5.4) 2089 (3.4) < 0.001 1513 (3.5) 6142 (2.8) < 0.001 Benzodiazepine, no. (%) 43,877 (78.6) 186,829 (67.0) < 0.001 9888 (79.2) 41,627 (66.7) < 0.001 33,989 (78.5) 145,202 (67.1) < 0.001 TCA c, no. (%) 10,855 (19.5) 35,226 (12.6) < 0.001 2658 (21.3) 8128 (13.0) < 0.001 8197 (18.9) 27,098 (12.5) < 0.001 Estrogen or estrogen + proges- 6175 (11.1) 18,678 (6.7) < 0.001 5 (0.0) 27 (0.0) 1 6170 (14.3) 18,651 (8.6) < 0.001 terone combination, no.