by Randy A. Sansone, MD, and Lori A. Sansone, MD
Dr. R. Sansone is a professor in the Departments of Psychiatry and Internal Medicine at Wright State University School of Medicine in Dayton, Ohio, and Director of Psychiatry Education at Kettering Medical Center in Kettering, Ohio; Dr. L. Sansone is a family medicine physician (civilian) and Medical Director, Family Health Clinic, Wright-Patterson Medical Center in WPAFB, Ohio. The views and opinions expressed in this column are those of the authors and do not reflect the official policy or position of the United States Air Force, Department of Defense, or US government.

Innov Clin Neurosci. 2012;9(7–8):42–47

This ongoing column is dedicated to the challenging clinical interface between psychiatry and
primary care—two fields that are inexorably linked.

Funding: There was no funding for the development and writing of this article.

Financial Disclosures: The authors have no conflicts of interest relevant to the content of this article.

Key Words: Bone, fractures, osteoporosis, selective serotonin reuptake inhibitors, SSRIs, skeleton

ABSTRACT: Selective serotonin reuptake inhibitors are globally popular antidepressants with broad clinical indications. Despite an overall favorable side-effect profile, our examination of 19 studies, one review, and one meta-analysis indicates that these unique antidepressants appear to have negative effects on bone, particularly with regard to bone mineral density and fracture risk. These risks may be enhanced by more serotonergic agents and/or longer exposure to selective serotonin reuptake inhibitors. The magnitude of this relationship is difficult to determine due to the myriad of potential confounds in available studies, but all indicate risk. In additional support of these findings, serotonin receptors have been identified on osteoclasts, osteoblasts, and osteocyte cell lines, suggesting that serotonin may be an important regulatory agent in bone. While no formal recommendations regarding the use of selective serotonin reuptake inhibitors in risk populations are available, caution is advised in individuals with potential risk (i.e., those with osteoporosis or histories of osteoporotic fractures).

Selective serotonin reuptake inhibitors (SSRIs) are globally popular antidepressants. In addition to their generally favorable side-effect profiles compared with other classes of antidepressants, SSRIs currently have the broadest range of clinical indications approved by the United States Food and Drug Administration.1 Depending on the individual SSRI, these indications include major depression, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, and bulimia nervosa (Table 1).[1] Given their tolerability and broad clinical efficacy, however, continuing examination of risk is important. In this edition of The Interface, we examine one potential risk associated with SSRIs—their effects on bone, specifically decreased bone mineral density (BMD) and fractures.

A Sampling of Studies

To collect data, we performed a search of the PubMed and PsycINFO databases, using the search terms SSRI, bone, fractures and osteoporosis. We eliminated one study in which the article was only available in Japanese,which left us with 21 studies[2–22] dating back to 1998 (Table 2). These studies consist of retrospective, cross-sectional, prospective, review, and meta-analytic designs. With the exclusion of the review and meta-analysis, the remaining 19 studies were from the United States (9 studies), Canada (3 studies), the Netherlands (3 studies), Denmark (2 studies), the United Kingdom (1 study), and Australia (1 study). Study populations included men, women, both men and women, and male children. Using different study variables, varying approaches to statistical analyses, and controlling for various potential confounds in a number of studies, each and every study indicates a risk of reduced BMD, fracture, or both. In other words, we could not find a study that disputed this clinical association.


Importantly, the explicit magnitude of the relationship between SSRI use and decreased BMD/fracture remains somewhat undefined. One reason for this is the potential for confounds in these studies, which we will discuss. Yet, in a recent meta-analytic examination of 13 studies by Wu et al,[22] researchers concluded that despite confounds, SSRI use was associated with a significantly increased risk of fracture.

According to limited data, bone risk may vary. For example, Vestergaard13 found that paroxetine did not exhibit an increased risk of fracture when compared to the other SSRIs. This finding is somewhat unexpected given that Verdel et al[19] reported an association between fracture risk and a given antidepressant’s affinity for serotonin, with more serotonergic compounds evidencing higher risk (i.e., paroxetine is the most serotonergic SSRI). Likewise, in a review, Ginzberg and Rosero[16] found that fracture risk appeared to slightly increase over time with exposure to an SSRI.

To summarize these findings, there appears to be a higher risk of negative effects on BMD and fracture among individuals taking SSRIs, although this risk is difficult to specifically quantify. Greater risk may be associated with more serotonergic antidepressants as well as longer exposure.

Potential Confounds

From a statistical perspective, there are always potential confounds that temper findings in any study. The relationship between SSRIs and their effects on bone are no different. For example, depression itself has been associated with adverse skeletal consequences through postulated effects on the hypothalamic-pituitary-adrenal axis as well as pro-inflammatory cytokines.[23] However, in examining various studies, the effects of depression on bone are statistically inconsistent.[24] In addition, several studies have controlled for other suspected confounds (nicely outlined by Wu et al[22]), such as potential bias in claims database studies,[5 ]the possibility of physical inactivity induced by antidepressants,[25] and estrogen deficiency[26]—all with unwavering conclusions that SSRIs continue to exert negative effects on bone.

SSRIs and Bone: Pathophysiological Relationships

While the pathophysiology of SSRI effects on bone is just beginning to be elucidated and is not totally clarified,[27] serotonin appears to have major functions outside of the central nervous system.28 In this more peripheral role, serotonin may exert effects on the skeleton.[28] In support of this, serotonin receptors have been identified on osteoclasts, osteoblasts, and osteocyte cell lines,[29] suggesting that this neurotransmitter may be an important regulatory agent in bone.[30] While a number of studies have confirmed serotonergic influences on skeletal bone, they offer contrasting evidence as to its effects.[28] For our purposes, one postulated effect of serotonin is a role in bone-resorption pathways.[28] In addition, studies indicate that the inhibition of the serotonin transporter, which is the function of SSRIs, may have detrimental effects on bone mineral accrual.[31] Clearly, more research will be required before the explicit pathway is uncovered, but current evidence supports an overall negative serotonergic effect on bone regulation.


Our review of 19 studies on the effect of SSRIs on bone indicates negative effects on BMD and/or heightened fracture risk. The explicit magnitude of this effect remains unclear due to the tempering effects of various potential confounds. However, in support of this relationship, there are known negative pathophysiological effects of serotonin on bone regulation. While no recommendations are presently available, SSRI use in high-risk individuals (e.g., those with osteoporosis, history of osteoporotic fractures) is cautioned.


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