CRD summary

The review findings indicated that treatment with selective serotonin reuptake inhibitors was associated with an increased risk of bone fracture. A large number of patients were included in the review and, although there were some omissions in reporting, the authors' conclusions are likely to be reliable.

Authors' objectives

To evaluate the effect of treatment with selective serotonin re-uptake inhibitors on the risk of fractures and bone loss.

Searching

MEDLINE, EMBASE, and PsycINFO were searched for relevant articles to March 2011; search terms were reported. Dissertation Abstracts Online and the proceedings of the International Osteoporosis Foundation World Conference on Osteoporosis from 2000 to 2010 were also searched. Reference lists from retrieved studies were checked for additional references.

Study selection

Case-control and cohort studies that reported data on patients with fractures or decreases in bone mineral density, who had received treatment with selective serotonin re-uptake inhibitors, were eligible for inclusion. Cross sectional studies were excluded from the review. The primary outcome was the risk of any fracture associated with treatment with selective serotonin re-uptake inhibitors. The secondary outcome was the risk of bone loss associated with selective serotonin re-uptake inhibitor use.

The included studies were conducted in the USA, Canada, the Netherlands, Denmark and the UK. Most studies included both men and women. Most studies only included participants aged 50 years or older; some studies included only participants aged 65 years or older. The use of selective serotonin re-uptake inhibitors was estimated from interviews and verification from containers or pharmacy dispensing records in most of the cohort studies. In most studies, outcomes were assessed by assessments of bone mineral density or by interviews with patients who had self-reported fractures which were confirmed by medical or radiological records. In the case-control studies, patients were drawn from general practice research databases, civil registration systems, hospital databases, and pharmaceutical records systems. Fractures were confirmed by clinical diagnoses, radiographic reports and database records; exposures were assessed using prescription claims and prescription codes in databases.

Two reviewers independently performed the study selection; any disagreements were resolved by consensus.

Assessment of study quality

Methodological quality was assessed by two independent reviewers using a 10-point scale for the assessment of observational studies.

Data extraction

Data were extracted by two reviewers to calculate relative risks (RR), hazard ratios or odds ratios of fracture associated with selective serotonin re-uptake inhibitor use, along with 95% confidence intervals (CI). Mean difference in bone mineral density change associated with selective serotonin re-uptake inhibitor use was also calculated, along with standard deviations. When multiple estimates of fracture risk were presented, the estimate that adjusted for the largest number of confounding factors was used. Minor discrepancies between the reviewers were solved by re-checking the studies.

Methods of synthesis

Pooled risk ratios and 95% confidence intervals were calculated using fixed-effect and random-effects models. The Cochran Q-statistic was used to assess statistical heterogeneity.

A post-hoc sensitivity analysis was conducted to include studies of patients aged 50 years or older. Subgroup analyses were conducted on the basis of methodological quality scores, the control of confounding risk factors for fracture, and the use of hip fractures and non-vertebral fractures as outcomes.

The potential for publication bias was assessed by using visual appraisals of funnel plots, the Begg test and the trim-and-fill method.

Results of the review

Thirteen studies (319,148 patients) were included in the review, comprising seven cohort studies (130,637 patients) and six case control studies (188,511 patients). The results of the quality assessment were not presented, although the results of the subgroup analyses showed that 11 studies attained quality scores of 7 points or higher. Duration of follow-up ranged from four years to 8.4 years.

There were significantly higher risks of fractures observed for patients who received selective serotonin re-uptake inhibitors compared with patients with no exposure (RR 1.72, 95% CI 1.51 to 1.95; 12 studies). The fracture risk remained statistically significant for studies that controlled for important risk factors (RR 1.70, 95% CI 1.48 to 1.94; 10 studies), studies that included patients aged 50 years or older (RR 1.68, 95% CI 1.41 to 2.00; nine studies), studies that used non-vertebral fractures as an outcome (RR 1.78, 95% CI 1.43 to 2.21; eight studies), studies that used hip fracture as an outcome (RR 1.70, 95% CI 1.48 to 1.95; seven studies), and studies that scored 7 or higher in the quality assessment (RR 1.63, 95% CI 1.46 to 1.81; 11 studies).

There were no significant differences between patients who received selective serotonin re-uptake inhibitors and those who did not in bone mineral density as measured by bone loss at the hip (0.19%, 95% CI -0.15 to 0.53; two studies).

The Cochran Q statistic indicated significant heterogeneity (p<0.001).

There was some potential for publication bias as observed by the funnel plot and the Begg test, although after the trim-and-fill analysis correcting for missing data, the risk of fracture was still statistically significant (RR 1.40, 95% CI 1.22 to 1.61)

Authors' conclusions

The findings indicated that use of selective serotonin reuptake inhibitors was associated with an increased risk of fracture; these medications may have exerted an increased risk of fracture independent of depression and bone mineral density.

CRD commentary

The review addressed a clear question. Criteria for the inclusion of studies were broadly outlined. Appropriate databases were searched without language restriction. There were attempts made to identify unpublished studies. Steps were taken at each stage of the review to minimise reviewer errors and biases.

Methodological quality of the included studies was assessed, but little information was provided on the results of the quality assessment. The combination of results in a meta-analysis may not have been justified as there was evidence of significant heterogeneity and the results from cohort and case control studies were associated with a number of potential biases, not all of which may have been accounted for in the analyses. The authors acknowledged that the associations observed may have been confounded by other factors such as other medications.

In general, a large number of patients were included in the review and, although there were some omissions in reporting, the authors' conclusions are likely to be reliable

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that additional studies were required to account for confounding factors including cognition, physical functioning, other medications when evaluating the relationship between treatment with selective serotonin re-uptake inhibitors and the risk of fracture.

Funding

Not stated.

Bibliographic details

Wu Q, Bencaz AF, Hentz JG, Crowell MD. Selective serotonin reuptake inhibitor treatment and risk of fractures: a meta-analysis of cohort and case-control studies. Osteoporosis International 2012; 23(1): 365-375. [PubMed: 21904950]

Original Paper URL

http://www.springerlink.com/content/k0u6726p65674v13/

Indexing Status

Subject indexing assigned by NLM

MeSH

Aged; Antidepressive Agents /adverse effects; Bone Density /drug effects; Case-Control Studies; Cohort Studies; Female; Fractures, Bone /chemically induced; Humans; Male; Middle Aged; Osteoporosis /chemically induced; Osteoporotic Fractures /chemically induced; Publication Bias; Risk Assessment /methods; Serotonin Uptake Inhibitors /adverse effects

AccessionNumber

12012011978

Database entry date

23/10/2012

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.