Risk of fractures in patients treated with selective serotonin reuptake inhibitors (SSRI)

Selective serotonin reuptake inhibitors (SSRIs) are recommended for the treatment of anxiety and depression in children, adolescents, and adults. Treatment with SSRIs, as well as underlying clinical depression, have been suggested to lead to an increased risk of fracture, potentially mediated by a change in bone metabolism and/or risk of falls.

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SBU Enquiry Service

Consists of structured literature searches to highlight studies that can address questions received by the SBU Enquiry Service from Swedish healthcare or social service providers. We assess the risk of bias in systematic reviews and when needed also quality and transferability of results in health economic studies. Relevant references are compiled by an SBU staff member, in consultation with an external expert when needed.

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Published: Report no: ut202127 Registration no: SBU 2021/420

Question

What systematic reviews are there on the risk of fractures or changed bone mineral density in people in long-term SSRI treatment?

Identified literature

One relevant systematic review with moderate risk of bias was identified (Table 1) [1]. The systematic review reported on the risk of fracture in adults treated with either SSRIs or Selective norepinephrine reuptake inhibitors (SNRIs).

In addition, 26 relevant primary studies reporting on either risk of fracture or changes in bone mineral density in people treated with either SSRI or SNRI were also identified (Table 2) [2–27]. The primary studies have not been assessed for risk of bias.

Table 1. Systematic reviews with low/medium risk of bias
Included studies Population/Intervention Outcome and Results
Khanassov et al, (2018) [1]
Selective serotonin reuptake inhibitor and selective serotonin and norepinephrine reuptake inhibitor use and risk of fractures in adults: A systematic review and meta-analysis.
Qualitative analysis:
33 studies, 11 case-control, 22 cohorts

Quantitative meta-analysis:
23 studies, 9 case control, 14 cohort

Setting:
Europe, 16 studies
US, 11 studies
Canada, 4 studies
Asia, 2 studies
Israel, 1 study		 Population:
Adults on an SSRI or SNRI, with or without a formal diagnosis of depression

Exposure:
SSRI (29 studies) or SNRI (7 studies)

Comparison:
Non-users (22 studies), other antidepressants, different level of adherence or past use (9 studies)

Outcome:
Fracture (any type of fracture at any anatomical sites either self‐reported or identified in the hospital records)		 Risk of fracture SSRI vs control:

All studies (n=23):
RR 1.67 (95% CI, 1.56 to 1.79)

Case-control studies (n=9):
RR 1.74 (95% CI, 1.50 to 2.02)

Cohort studies (n=14):
RR 1.63 (95%, CI 1.49 to 1.79)

Studies adjusted for depression (n=10):
RR 1.62 (95% CI, 1.39 to 1.90)

Studies not adjusted for depression (n=12):
RR 1.73 (95% CI, 1.60 to 1.87)

Association fracture & age (meta-regression):
OR 1.006; p=0.173
Authors' conclusion:
“There is sufficient albeit nonrandomized evidence that use of SSRIs substantially increases fracture risk in adults, from at least age 40 years and above, particularly when used over long periods; but counter to expectations, the degree of increased risk is largely independent of age.”

 

Table 2. Primary studies published 2016-2021
Author
Year, Reference		 Study type Population Relevant exposure
Outcome: Fracture
Albrecht et al
2018, [3]		 Retrospective cohort Older adults (≥65) hospitalized with traumatic brain injury SSRI, SNRI
Brinton et al
2019, [4]		 Retrospective cohort US veterans SSRI
Bruun et al
2018, [5]		 Case control Hip fracture patients aged ≥65 years SSRI
Brännström et al
2019, [6]		 Case control Age >65 years SSRI, SNRI
Carrière et al
2016, [8]		 Prospective cohort Age >65 years SSRI
Cheng et al
2016, [9]		 Case control Patients with depression SSRI
Coupland et al
2018, [10]		 Prospective cohort Age 20–64 years with depression SSRI
Gorgas et al
2021, [11]		 Case control Age 50–95 with hip fracture SSRI
Hung et al
2017, [13]		 Case control Random sample of hip fracture patients SSRI
Leach et al
2017, [28]		 Case control Australian war veterans >65 years of age SSRI
Munson et al
2018, [17]		 Retrospective cohort Older adults with fragility fracture SSRI
Ozen et al
2019, [18]		 Retrospective cohort Patients with rheumatoid arthritis SSRI
Pisa et al
2020, [19]		 Case control Older adults without previous hip fracture SSRI
Souverein et al
2016, [22]		 Retrospective cohort Antidepressant users SSRI
Tamblyn et al
2020, [23]		 Retrospective cohort Older adults SSRI, SNRI
Torvinen-Kiiskinen et al
2017, [24]		 Retrospective cohort Alzheimers patients SSRI, SNRI
Vangala et al
2020, [25]		 Case control Maintenance hemodialysis patients SSRI
Wang et al
2016, [26]		 Case control Patients with fractures SSRI, SNRI
Wright et al
2018, [27]		 Prospective cohort Community-dwelling men SSRI
Outcome: Bone mineral density
Agarwal et al
2020, [2]		 Cross sectional Female adults ≥65 years old SSRI, SNRI
Calarge et al
2017, [7]		 Prospective cohort 15–20 years with depression or anxiety SSRI
Ham et al
2017, [12]		 Prospective cohort Age >45 years SSRI
Kang et al
2021, [14]		 Case control Newly diagnosed osteoporosis or osteopenia SSRI
Larsson et al
2018, [15]		 Case control Older women SSRI
Rauma et al
2016, [20]		 Retrospective cohort Women 57–67 years of age SSRI
Saraykar et al
2018. [21]		 Cross sectional Older women with high risk of fragility fractures SSRI

References

  1. Khanassov V, Hu J, Reeves D, van Marwijk H. Selective serotonin reuptake inhibitor and selective serotonin and norepinephrine reuptake inhibitor use and risk of fractures in adults: A systematic review and meta-analysis. Int J Geriatr Psychiatry. 2018;33(12):1688-708.
  2. Agarwal S, Germosen C, Kil N, Bucovsky M, Colon I, Williams J, et al. Current anti-depressant use is associated with cortical bone deficits and reduced physical function in elderly women. Bone. 2020;140.
  3. Albrecht JS, Rao V, Perfetto EM, Daniel Mullins C. Safety of Antidepressant Classes Used Following Traumatic Brain Injury Among Medicare Beneficiaries: A Retrospective Cohort Study. Drugs Aging. 2018;35(8):763-72.
  4. Brinton DL, Simpson AN, Fominaya CE, LaRue AC. Impact of selective serotonin reuptake inhibitors in the veteran population: 10-year risk outcomes. J Comp Eff Res. 2019;8(6):431-40. Available from: https://doi.org/10.2217/cer-2018-0085.
  5. Bruun SB, Petersen I, Kristensen NR, Cronin-Fenton D, Pedersen AB. Selective serotonin reuptake inhibitor use and mortality, postoperative complications, and quality of care in hip fracture patients: A danish nationwide cohort study. Clin Epidemiol. 2018;10:1053-71.
  6. Brännström J, Lövheim H, Gustafson Y, Nordström P. Association between Antidepressant Drug Use and Hip Fracture in Older People before and after Treatment Initiation. JAMA Psychiatry. 2019;76(2):172-9.
  7. Calarge CA, Mills JA, Janz KF, Burns TL, Schlechte JA, Coryell WH, et al. The Effect of Depression, Generalized Anxiety, and Selective Serotonin Reuptake Inhibitors on Change in Bone Metabolism in Adolescents and Emerging Adults. J Bone Miner Res. 2017;32(12):2367-74. Available from: https://doi.org/10.1002/jbmr.3238.
  8. Carrière I, Farré A, Norton J, Wyart M, Tzourio C, Noize P, et al. Patterns of selective serotonin reuptake inhibitor use and risk of falls and fractures in community-dwelling elderly people: the Three-City cohort. Osteoporos Int. 2016;27(11):3187-95.
  9. Cheng BH, Chen PC, Yang YH, Lee CP, Huang KE, Chen VC. Effects of depression and antidepressant medications on hip fracture: A population-based cohort study in Taiwan. Medicine (Baltimore). 2016;95(36):e4655. Available from: https://doi.org/10.1097/MD.0000000000004655.
  10. Coupland, C., Hill T, Morriss R, Moore M, Arthur A, et al. Antidepressant use and risk of adverse outcomes in people aged 20-64 years: Cohort study using a primary care database. BMC Med. 2018;16(1).
  11. Gorgas MQ, Torres F, Vives R, Lopez-Rico I, Capella D, Pontes C. Effects of selective serotonin reuptake inhibitors and other antidepressant drugs on the risk of hip fracture: a case-control study in an elderly Mediterranean population. Eur J Hosp Pharm. 2021;28(1):28-32. Available from: https://doi.org/10.1136/ejhpharm-2019-001893.
  12. Ham AC, Aarts N, Noordam R, Rivadeneira F, Ziere G, Zillikens MC, et al. Use of Selective Serotonin Reuptake Inhibitors and Bone Mineral Density Change: A Population-Based Longitudinal Study in Middle-Aged and Elderly Individuals. J Clin Psychopharmacol. 2017;37(5):524-30.
  13. Hung SC, Lin CH, Hung HC, Lin CL, Lai SW. Use of Selective Serotonin Reuptake Inhibitors and Risk of Hip Fracture in the Elderly: A Case-Control Study in Taiwan. J Am Med Dir Assoc. 2017;18(4):350-4.
  14. Kang S, Han M, Park CI, Jung I, Kim EH, Boo YJ, et al. Use of serotonin reuptake inhibitors and risk of subsequent bone loss in a nationwide population-based cohort study. Sci Rep. 2021;11(1):13461.
  15. Larsson B, Mellstrom D, Johansson L, Nilsson AG, Lorentzon M, Sundh D. Normal Bone Microstructure and Density But Worse Physical Function in Older Women Treated with Selective Serotonin Reuptake Inhibitors, a Cross-Sectional Population-Based Study. Calcif Tissue Int. 2018;103(3):278-88. Available from: https://doi.org/10.1007/s00223-018-0427-z.
  16. Leach MJ, Pratt NL, Roughead EE. Risk of Hip Fracture in Older People Using Selective Serotonin Reuptake Inhibitors and Other Psychoactive Medicines Concurrently: A Matched Case–Control Study in Australia. Drugs Real World Outcomes. 2017;4(2):87-96.
  17. Munson JC, Bynum JPW, Bell JE, McDonough C, Wang Q, Tosteson T, et al. Impact of prescription drugs on second fragility fractures among US Medicare patients. Osteoporos Int. 2018;29(12):2771-9.
  18. Ozen G, Pedro S, Wolfe F, Michaud K. Medications associated with fracture risk in patients with rheumatoid arthritis. Ann Rheum Dis. 2019;78(8):1041-7.
  19. Pisa FE, Reinold J, Kollhorst B, Haug U, Schink T. Individual Antidepressants and the Risk of Fractures in Older Adults: A New User Active Comparator Study. Clin Epidemiol. 2020;12:667-78. Available from: https://doi.org/10.2147/CLEP.S222888.
  20. Rauma PH, Honkanen RJ, Williams LJ, Tuppurainen MT, Kroger HP, Koivumaa-Honkanen H. Effects of antidepressants on postmenopausal bone loss - A 5-year longitudinal study from the OSTPRE cohort. Bone. 2016;89:25-31. Available from: https://doi.org/10.1016/j.bone.2016.05.003.
  21. Saraykar S, John V, Cao B, Hnatow M, Ambrose CG, Rianon N. Association of Selective Serotonin Reuptake Inhibitors and Bone Mineral Density in Elderly Women. J Clin Densitom. 2018;21(2):193-9. Available from: https://doi.org/10.1016/j.jocd.2017.05.016.
  22. Souverein PC, Abbing-Karahagopian V, Martin E, Huerta C, de Abajo F, Leufkens HGM, et al. Understanding inconsistency in the results from observational pharmacoepidemiological studies: The case of antidepressant use and risk of hip/femur fractures. Pharmacoepidemiol Drug Saf. 2016;25:88-102.
  23. Tamblyn R, Bates DW, Buckeridge DL, Dixon WG, Girard N, Haas JS, et al. Multinational Investigation of Fracture Risk with Antidepressant Use by Class, Drug, and Indication. J Am Geriatr Soc. 2020;68(7):1494-503.
  24. Torvinen-Kiiskinen S, Tolppanen AM, Koponen M, Tanskanen A, Tiihonen J, Hartikainen S, et al. Antidepressant use and risk of hip fractures among community-dwelling persons with and without Alzheimer's disease. Int J Geriatr Psychiatry. 2017;32(12):e107-e15.
  25. Vangala C, Niu J, Montez-Rath ME, Yan J, Navaneethan SD, Winkelmayer WC. Selective Serotonin Reuptake Inhibitor Use and Hip Fracture Risk Among Patients on Hemodialysis. Am J Kidney Dis. 2020;75(3):351-60.
  26. Wang CY, Fu SH, Wang CL, Chen PJ, Wu FLL, Hsiao FY. Serotonergic antidepressant use and the risk of fracture: a population-based nested case–control study. Osteoporos Int. 2016;27(1):57-63.
  27. Wright NC, Hooker ER, Nielson CM, Ensrud KE, Harrison SL, Orwoll ES, et al. The epidemiology of wrist fractures in older men: the Osteoporotic Fractures in Men (MrOS) study. Osteoporos Int. 2018;29(4):859-70. Available from: https://doi.org/10.1007/s00198-017-4349-9.
  28. Leach MJ, Pratt NL, Roughead E. The risk of hip fracture in older people after switching between or concurrently using mirtazapine and other antidepressants. Pharmacoepidemiol Drug Saf. 2017;26:164.

 

Literature search

Embase via Elsevier 2 September 2021

SSRI and osteoporosis
The final search result, usually found at the end of the documentation, forms the list of abstracts.

/de = Term from the EMTREE controlled vocabulary; /exp = Includes terms found below this term in the EMTREE hierarchy
/mj = Major Topic; :ab = Abstract; :au = Author; :ti = Article Title; :ti,ab = Title or abstract; * = Truncation; ' ' = Citation Marks; searces for an exact phrase; NEAR/n = Requests terms that are within 'n' words of each other in either direction; NEXT/n = Requests terms that are within 'n' words of each other in the order specified
  Search terms Items found
Population:
1. 'bone density'/exp OR 'bone demineralization'/exp OR 'osteolysis'/exp OR 'fracture'/de OR 'fragility fracture'/de 330 743
2. (bone NEAR/4 (loss OR fragil* OR mass OR density OR demineralization)):ti,ab,kw 137 310
3. osteoporo*:ti,ab,kw OR osteolysi*:ti,ab,kw OR fracture*:ti,ab,kw OR decalcificat*:ti,ab,kw 424 199
4. 1 OR 2 OR 3  
Intervention: SSRI/SNRI
5. 'serotonin uptake inhibitor'/exp 294 122
6. 'antidepressant agent'/de 103 924
7. (((serotonin OR noradrenaline OR norepinephrine OR '5 ht' OR '5 hydroxytryptamine') NEAR/3 (uptake OR reuptake) NEAR/3 inhibitor*):ti,ab,kw) OR 'anti depress*':ti,ab,kw OR ssri:ti,ab,kw OR snri:ti,ab,kw 36 573
8. fluvoxamin*:ti,ab,kw OR fluoxetin*:ti,ab,kw OR paroxetin*:ti,ab,kw OR sertralin*:ti,ab,kw OR citalopram:ti,ab,kw OR escitalopram:ti,ab,kw OR vilazodon*:ti,ab,kw OR trazodon*:ti,ab,kw 40 577
9. desvenlafaxin*:ti,ab,kw OR duloxetin*:ti,ab,kw OR venlafaxin*:ti,ab,kw OR levomilnacipran:ti,ab,kw OR milnacipran:ti,ab,kw OR renboxetin:ti,ab,kw OR edronax:ti,ab,kw 11 683
10. 5 OR 6 OR 7 OR 8 OR 9  
Study types: systematic reviews
11. 'systematic review'/exp OR 'meta analysis'/exp OR 'systematic review':ti,ab,kw OR 'meta analysis':ti,ab,kw OR metaanalysis:ti,ab,kw  
Combined sets
12. 4 AND 10 5 161
13. 11 AND 12 266
Final result
14.   266

Medline via OvidSP 2 September 2021

SSRI and osteoporosis
The final search result, usually found at the end of the documentation, forms the list of abstracts.

.ab. = Abstract; .ab,ti. = Abstract or title; .af. = All fields; Exp = Term from the Medline controlled vocabulary, including terms found below this term in the MeSH hierarchy; .sh. = Term from the Medline controlled vocabulary; .ti. = Title; / = Term from the Medline controlled vocabulary, but does not include terms found below this term in the MeSH hierarchy; * = Focus (if found in front of a MeSH-term); * or $ = Truncation (if found at the end of a free text term); .mp = Text, heading word, subject area node, title; “ “ = Citation Marks; searches for an exact phrase; ADJn = Positional operator that lets you retrieve records that contain your terms (in any order) within a specified number (n) of words of each other.
  Search terms Items found
Population: Osteoporosis
1. exp Osteoporosis/ or exp Bone Demineralization, Pathologic/ or Bone density/ or Osteoporotic Fractures/ or Osteolysis/ [osteoporosis MeSH] 103 161
2. (osteoporo* or osteolysi* or fracture* or decalcificat* or (bone adj3 (loss or fragil* or mass or density or demineralization))).tw,kw 384 664
3. 1 or 2 403 658
Intervention: SSRI/SNRI
4. exp Serotonin Uptake Inhibitors/ or exp Antidepressive Agents/ or exp "Serotonin and Noradrenaline Reuptake Inhibitors"/ [SSRI & SNRI] 165143
5. (((serotonin or 5-HT or 5-Hydroxytryptamine or noradrenaline or norepinephrine) adj2 (uptake or reuptake) adj2 inhibitor*) or (anti-depress* or anti depress*)).tw,kw. [SSRI SNRI] 22155
6. Fluvoxamine/ or Fluoxetine/ or Paroxetine/ or Sertraline/ or Citalopram/ or Vilazodone Hydrochloride/ or Trazodone/ [SSRI] 22444
7. Desvenlafaxine Succinate/ or Duloxetine Hydrochloride/ or Venlafaxine Hydrochloride/ or exp Milnacipran/ [SNRI] 4791
8. (Fluvoxamin* or fluoxetin* or paroxetin* or Sertralin* or citalopram or escitalopram or vilazodon* or trazodon*).tw,kw. [SSRI] 28773
9. (desvenlafaxin* or duloxetin* or venlafaxin*or levomilnacipran or milnacipran or Renboxetin or edronax).tw,kw [SNRI] 3484
10. or/4-9 177747
Study types: systematic reviews
11. (Systematic Review or Meta-Analysis).pt. or Cochrane Database Syst Rev.ja. or ((systematic adj3 review) or "meta analys*" or metaanalys*).ti,ab 351528
Combined sets
12. 3 and 10 742
13. 11 and 12 41
Final result
14. 13 41

Scopus via Elsevier 2 September 2021

SSRI and osteoporosis
The final search result, usually found at the end of the documentation, forms the list of abstracts.

TITLE-ABS-KEY = Title or abstract or keywords; ALL = All fields; PRE/n = "precedes by". The first term in the search must precede the second by a specified number of terms (n).; W/n = "Within". The terms in the search must be within a specified number of terms (n) in any order.; * = Truncation; “ “ = Citation Marks; searches for an exact phrase; LIMIT-TO (SRCTYPE, "j" = Limit to source type journal; LIMIT-TO (DOCTYPE, "ar" = Limit to document type article; LIMIT-TO (DOCTYPE, "re" = Limit to document type review
  Search terms Items found
Population: Bone loss
1. TITLE-ABS-KEY ( osteoporo* OR osteolysi* OR decalcificat* OR fracture* ) 996 564
2. TITLE-ABS-KEY ( bone W/3 ( loss OR fragil* OR mass OR density OR demineralization ) ) 164 592
3. 1 OR 2 1 062 787
Intervention: SSRI/SNRI
4. TITLE-ABS-KEY ( ( ( serotonin OR noradrenaline OR norepinephrine OR 5-ht OR 5-hydroxytryptamine ) W/2 ( uptake OR reuptake ) W/2 inhibitor* ) OR anti-depress* OR ssri OR snri ) 66 801
5. TITLE-ABS-KEY ( fluvoxamin* OR fluoxetin* OR paroxetin* OR sertralin* OR citalopram OR escitalopram OR vilazodon* OR trazodon* OR venlafaxin* OR desvenlafaxin* OR duloxetin* OR levomilnacipran OR milnacipran OR renboxetin OR edronax ) 104 734
6. 4 OR 5 134 334
Study types: Systematic reviews
7. ( TITLE-ABS-KEY ( ( systematic W/2 review ) OR "meta analys*" OR metaanalys* ) OR ( SRCTITLE ( cochrane ) ANDDOCTYPE ( re ) ) )  
Combined sets
8. 3 AND 6 2 595
9. 7 AND 8 216
Final result
10.   216
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