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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2010 Sep;95(9):4124–4132. doi: 10.1210/jc.2010-0861

Update in Serotonin and Bone

Michael Bliziotes 1
PMCID: PMC2936065  PMID: 20823465

Abstract

Context: Serotonin (5-HT) may be an important regulatory agent in bone, and agents that modify 5-HT signaling, such as selective serotonin reuptake inhibitors (SSRIs), are in widespread clinical use.

Evidence Acquisition: Evidence was obtained by PubMed search and the author’s knowledge of the field.

Evidence Synthesis: Recent data suggest that gut-derived 5-HT may mediate the skeletal effects of LDL receptor-related protein 5, stimulating intense interest in a novel mechanism for regulating bone mass. However, the specific biochemical nature of serotonergic pathways influencing bone and their direct and/or indirect effects on bone metabolism are still unclear. The weight of epidemiological evidence suggests that SSRIs are associated with reduced bone mass, increased bone loss, and increased risk of fractures. Interpretation of these studies is complicated by the confounding effects of depression, the usual indication for treatment with SSRIs. The mechanisms for putative SSRI-induced deleterious effects on the skeleton are unknown, and are likely multifactorial.

Conclusions: 5-HT may have regulatory effects on bone. Initial preclinical data suggest that its effects may be deleterious and may be regulated by low-density lipoprotein receptor-related protein 5. These studies need confirmation, as well as elucidation, of the biochemical pathways utilized and the feedback loops involved among bone, gut, and perhaps brain. Paradoxically, targeting of 5-HT synthesis and/or signaling in selective tissues may hold promise as an anabolic intervention for bone. Epidemiological data suggest that clinicians should be vigilant about detection of bone disease in patients who are using SSRIs.

Serotonin (5-HT) may be an important regulatory agent in bone, and selective serotonin reuptake inhibitors are associated with reduced bone mass and fractures.

In 2001, two groups identified a functional signaling system in bone for the centrally acting neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] (1,2). 5-HT is a monoamine compound classically referred to as “serotonin” due to early observations identifying it as a serum agent (sero-) affecting vascular tone (-tonin) (3). Evidence regarding the participation of the serotonergic signaling system in bone physiology has accumulated slowly, but a recent publication from Yadav et al. has provided an unexpected twist and stimulated intense interest in a novel mechanism for regulating bone mass (4,5,6). However, the specific biochemical nature of serotonergic pathways influencing bone and their direct and/or indirect effects on bone metabolism are still unclear. This review will describe recent preclinical evidence for an effect of 5-HT and altered 5-HT signaling on bone metabolism as well as the current clinical knowledge resulting from epidemiological studies of bone mass and fractures in individuals using selective serotonin reuptake inhibitors (SSRIs).

Central and Peripheral Effects of 5-HT

5-HT exhibits separate central and peripheral function depending on its site of synthesis. 5-HT is synthesized in two steps from the essential amino acid tryptophan, with the rate-limiting step being catalyzed by tryptophan hydroxylase (TPH). Two isoforms of TPH exist: Tph1 is expressed in the periphery, and Tph2 is expressed in the brain (7). Because 5-HT does not freely cross the blood-brain barrier due to its positive charge at physiological pH, centrally and peripherally synthesized 5-HT can function in relative isolation. This has enabled the investigation and (potential) therapeutic targeting of the independent central and peripheral effects of 5-HT.

5-HT is synthesized and released by neurons of the brain raphe nuclei to influence a range of behavioral, physiological, and cognitive functions. These effects are mediated by seven families of membrane-bound 5-HT receptors (5-HT1 to 5-HT7). Spatial and temporal 5-HT signaling is tightly regulated by a plasma membrane 5-HT transporter (5-HTT; also known as SERT). The 5-HTT regulates the spatial and temporal effects of 5-HT activity by actively transporting 5-HT into cells using transmembrane ion gradients and an internal negative membrane potential (Fig. 1A). Central 5-HT signaling is a frequent therapeutic target because it is hypothesized to play a key role in major depressive disorder and other affective conditions (8). Pharmaceutical agents that antagonize the 5-HTT, such as SSRIs, are clinically popular because they potentiate 5-HT activity (Fig. 1B) and have been shown to effectively relieve depressive symptoms (9).

Figure 1.

Figure 1

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A, 5-HT signaling within the central nervous system. 5-HT is synthesized by presynaptic neurons and stored in vesicles. Released 5-HT activates postsynaptic receptors to stimulate the postsynaptic neuron. Membrane-bound 5-HTTs uptake released 5-HT to control the duration of 5-HT effects and recycle or degrade 5-HT. B, The effects of 5-HTT inhibition using a SSRI on 5-HT signaling. Inhibition of the 5-HTT prevents uptake of 5-HT, resulting in its accumulation within the synaptic cleft and the prolonging of receptor activation. Osteoblasts, osteoclasts, and osteocytes express the 5-HTT, and SSRIs inhibit 5-HT uptake in bone cells in the same manner as in neurons. [Reprinted from S. J. Warden et al.: Bone 46:4–12, 2010 (73), with permission from Elsevier.]

5-HT has major functions outside the central nervous system, with 95% of 5-HT located in the periphery. Peripheral 5-HT is produced using TPH1 by enterochromaffin cells in the gastrointestinal (GI) tract where it functions as a paracrine factor to stimulate peristalsis and mucus secretion (10). As in the central nervous system, 5-HT signaling within the GI tract is regulated by the 5-HTT (11). A proportion of 5-HT synthesized within the GI tract is rapidly taken up by platelets using the platelet 5-HTT. Platelets cannot synthesize 5-HT because they do not express Tph. Platelets store 5-HT in dense granules and release it upon activation to stimulate platelet aggregation and blood clotting after tissue injury, as well as an array of other physiological effects including blood vessel constriction or dilation (depending on the 5-HT receptors activated), and smooth muscle cell hypertrophy and hyperplasia (12). The remaining circulating 5-HT (<5% of total) is free in the plasma. The function of this extracellular 5-HT remains unknown, but it may conceivably act as a hormone.

Emerging Role of 5-HT Signaling in the Skeleton

Recent evidence suggests that 5-HT has peripheral effects beyond the GI tract and cardiovascular system, including effects within the skeleton (13). 5-HT receptors have been identified in all the major bone cell types (osteoblasts, osteocytes, and osteoclasts), and stimulation of these receptors influences bone cell activities (1,2,14,15,16). Similarly, each major bone cell type possesses a 5-HTT, which is highly specific for 5-HT uptake into these cells (1,14,15,16). These findings indicate that bone cells possess functional pathways for both responding to and regulating the uptake of 5-HT.

Several in vitro studies have confirmed the functionality of 5-HT signaling in bone cells, with mixed effects reported (13). Some suggest a direct stimulatory effect of 5-HT on bone formation pathways (2,15,16,17), whereas others have found inhibitory effects (2,6). Dose-dependent contrasting effects of 5-HT signaling on bone resorption pathways have also been observed (14,16).

Gut-Derived 5-HT Mediates the Skeletal Effects of LDL Receptor-Related Protein 5 (LRP5)

The source of 5-HT used by bone cells has been unclear. Bone cells may produce 5-HT themselves as osteoblasts, osteocytes, and osteoclasts all express Tph1 (6,15,16). However, autocrine/paracrine 5-HT signaling has yet to be confirmed in bone with bone cells not secreting measurable levels of 5-HT (6). Instead, recent evidence provided by Yadav et al. (6) suggests that 5-HT derived from the GI tract and transported through the circulation is the major source for skeletal 5-HT. This is an important observation because it suggests that 5-HT functions as an endocrine signaling molecule and may be a potential target for novel therapeutics. The finding was enhanced by the concomitant observation that gut-derived 5-HT acted as a downstream mediator for the entire skeletal effects of LRP5 (Fig. 2).

Figure 2.

Figure 2

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Model of the Lrp5-dependent regulation of bone formation through inhibition of tph1 expression and 5-HT synthesis in enterochromaffin cells. 5-HT binds to Htr1b in osteoblasts and inhibits cyclic AMP response element binding protein (Creb) expression and function, resulting in reduced osteoblast proliferation. Lrp5 favors bone formation and bone mass accrual through this pathway. [Reprinted from V. K. Yadav et al.: Cell 135:825–837, 2008 (6), with permission from Elsevier.]

Interest in the skeletal effects of LRP5 was initially prompted by the discoveries that loss- and gain-of-function mutations in its gene cause osteoporosis pseudoglioma syndrome and a high bone mass (HBM) phenotype, respectively (18,19,20). These effects are commonly believed to result from LRP5 modulation of Wnt/β-catenin signaling in osteoblasts (21). These observations have directed recent research and drug discovery efforts toward the Wnt/β-catenin signaling pathway, which has resulted in the discovery of additional mediators in the pathway and the development of potentially anabolic compounds such as neutralizing antibodies for sclerostin and Dickkopf-1 (22,23).

Yadav et al. (6) performed an impressive series of studies to identify the existence of the LRP5–5-HT–osteoblast pathway, with their initial motivation being to better understand the skeletal role of LRP5. They observed that Tph1 was the most differentially expressed gene in Lrp5−/− bones and that Lrp5−/− mice also had overexpression of Tph1 in the duodenum as well as elevated circulating levels of 5-HT. Establishing a link between the elevated 5-HT and bone, 5-HT inhibited ex vivo proliferation of osteoblasts from both Lrp5−/− and wild-type mice. However, interpretation of the ex vivo osteoblast experiment must be tempered by the fact that only a single 5-HT concentration (50 μm) was used, a concentration up to 50,000 times greater than estimated in vivo platelet-free plasma 5-HT concentrations (1 nm) (24). Lrp5−/− mice fed a low-tryptophan diet or treated with an inhibitor of 5-HT synthesis (parachlorophenylalanine) exhibited reduced circulating 5-HT levels and normalization of their skeletal phenotype. In contrast to other studies (e.g. see Ref. 25), parachlorophenylalanine did not lower brain 5-HT levels, making the interpretation of this drug’s effects problematic. These combined findings provide preliminary evidence that elevated circulating 5-HT contributes to the decreased bone formation and mass observed in Lrp5−/− mice.

To further investigate the link between LRP5, 5-HT, and bone, Yadav et al. (6) generated mice with either gut- or osteoblast-specific loss- or gain-of-function of Lrp5. Gut-specific deletion of Lrp5 recapitulated the high circulating 5-HT and skeletal phenotype of Lrp5−/− mice, whereas osteoblast-specific deletion did not. Conversely, overexpression of Lrp5 in the gut via the insertion of cDNA encoding the HBM mutation of Lrp5 (G171V) decreased circulating 5-HT levels and generated a HBM phenotype, whereas osteoblast-specific overexpression of Lrp5 did not. These findings support Lrp5 regulating bone formation indirectly via effects in the gut as opposed to via direct effects on osteoblasts.

The final component of the work of Yadav et al. (6) was to identify the mechanism by which 5-HT influences osteoblasts. Yadav et al. (6) found three 5-HT receptors to be expressed in osteoblasts—5-HT1B, 2A, and 2B. Mice with either global deletion of Htr2a or osteoblast-specific deletion of Htr2b did not display skeletal phenotypes. The same was not true for mice with global or osteoblast-specific deletion of at least one allele of the Htr1b gene. These latter animals displayed a similar HBM phenotype to mice with the HBM mutation of Lrp5 (G171V) in the gut, suggesting that the 5-HT1B receptor mediates 5-HT effects in osteoblasts. This was confirmed in vitro with studies of primary osteoblast cultures.

Although Yadav et al. (6) have presented an impressive case for LRP5 acting on bone through an increase in gut-derived 5-HT, direct skeletal effects of gain-of-function mutations in Lrp5 have been observed (26). The data of Yadav et al. (6) are also difficult to reconcile with the observed integral role of LRP5 in skeletal mechanotransduction. Sawakami et al. (27) found the skeletal anabolic response to mechanical loading to be completely blocked in Lrp5−/− mice. Thus, LRP5 appears to have both direct and indirect skeletal effects. However, definitive conclusions still await corroborating evidence.

Extending previous work from his laboratory, Karsenty’s group explored the interaction between leptin and 5-HT in the regulation of bone mass, energy expenditure, and appetite (28). Their data demonstrate, surprisingly, that brainstem-derived serotonin (BDS) favors bone mass accrual after its binding to 5-HT2C receptors on ventromedial hypothalamic neurons (Fig. 3). Previously, it was assumed that leptin exerted its effects directly on the hypothalamus because the leptin receptor (ObRb) is expressed in several hypothalamic nuclei. Most unexpectedly, leptin inhibited the 5-HT-induced central increase in bone mass by reducing 5-HT synthesis and firing of serotonergic neurons. Accordingly, whereas abrogating BDS synthesis corrects the bone phenotype caused by leptin deficiency, inactivation of the leptin receptor in serotonergic neurons recapitulates it fully. These experiments suggest a molecular basis for the central control of bone mass. They also lend credence to the dual nature of 5-HT activity depending on the site of synthesis (central vs. peripheral). According to this hypothesis, gut-derived 5-HT has a negative influence on bone mass, whereas BDS is positive. This raises several important questions, including the potential for treatment of low bone mass disease states by selectively targeting peripherally derived 5-HT.

Figure 3.

Figure 3

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Model of the leptin-dependent regulation of bone mass and appetite. Leptin inhibits release of BDS, which favors bone mass accrual. [Reprinted from V. Yadav et al.: Cell 138:976–989, 2009 (28), with permission from Elsevier.]

As further proof of the concept that interventions targeting gut-derived 5-HT might be beneficial for bone, Yadav et al. (29) synthesized and used LP533401, a small molecule inhibitor of both Tph-1 and Tph-2, to prevent or treat osteoporosis in mice. LP533401 does not cross the blood-brain barrier, so in vivo its effects are limited to Tph-1 in the periphery (25). Oral administration of LP533401 once daily for up to 6 wk acted prophylactically or therapeutically, in a dose-dependent manner, to treat osteoporosis in ovariectomized rodents. The change in bone mass was associated with an isolated increase in bone formation and reductions in serum 5-HT concentrations. In rats, LP533401 was as effective as PTH in preventing the bone microarchitectural changes after ovariectomy. These results provide a proof of principle that inhibiting gut-derived 5-HT biosynthesis could become a new anabolic treatment for osteoporosis.

In vitro studies have confirmed the functionality of 5-HT signaling in bone cells, and studies with transgenic and knockout mice have implicated peripheral 5-HT as detrimental to the skeleton, whereas brain-derived 5-HT may be beneficial. What about agents currently in clinical use that perturb serotonergic signaling, the SSRIs? In vivo studies into the skeletal effect of 5-HT signaling were initiated by the observation that mice with a null mutation in the 5-htt gene that encodes the 5-HTT possessed a consistent skeletal phenotype of reduced mass, altered architecture, and inferior mechanical properties (13). This potential detrimental effect of enhanced 5-HT signaling has been supported by numerous preclinical studies investigating the skeletal effects of SSRIs (30,31,32,33,34). These studies found young and adult rodents treated for 4 wk with daily doses of an SSRI (fluoxetine, 5–20 mg/kg) to also exhibit reduced bone mass, altered skeletal architecture, and reduced bone mechanical properties. These changes resulted from a reduction in bone formation in growing animals treated with the SSRI or possessing a null mutation in the 5-htt gene (31), and reduced bone formation and increased resorption in adult animals treated with the SSRI (30). Altered loading does not appear responsible for the negative skeletal effects of 5-HTT inhibition and altered 5-HT signaling. In addition, 5-htt null mutant mice did not display significant differences from wild-type animals in any of the skeletally relevant hormones or biochemical markers assessed (31).

Additional Questions Regarding Skeletal 5-HT Signaling

Yadav et al. (6) clearly demonstrated that 5-HT influences the skeleton; however, these results require confirmation, and many questions remain. It remains unknown as to how LRP5 affects Tph1 expression in enterochromaffin cells of the gut, with no identified ligand for gut LRP5 mediating a currently unknown molecular pathway leading to altered Tph1 expression. It also remains to be shown how 5-HT synthesized in the gut reaches bone cells to activate 5-HT receptors. Yadav et al. (6) demonstrated 5-HT transport to be via the circulatory system, as is evident from elevated serum 5-HT levels. However, assessment of serum 5-HT levels provides only a picture of whole-blood (intra- and extracellular) 5-HT levels. As indicated earlier, most circulating 5-HT (>95%) is stored intracellularly in platelets in dense granules. This sequestered 5-HT is unlikely to be the source for the skeletal effects of 5-HT because it is released only after platelet activation, which occurs during clotting. Instead, the more likely source of skeletal 5-HT is the small amount (<5% of circulating 5-HT) in the plasma. The influence of LRP5 on circulating platelet-free plasma levels of 5-HT is currently unknown, and the consequences of LRP5-mediated elevation of circulating 5-HT on other peripheral 5-HT-sensitive systems (including the GI tract and cardiovascular system) also require consideration.

The negative skeletal effects of elevated circulating 5-HT observed by Yadav et al. (6) also do not explain the negative skeletal effects of SSRIs. Administration of a single-dose of an SSRI (fluoxetine) transiently increases plasma 5-HT levels (24); however, chronic administration of the same SSRI over 1–2 wk results in substantial reductions in both whole-blood and plasma 5-HT levels (24,35). Applying the findings of Yadav et al. (6), the reduction in circulating 5-HT with chronic SSRI administration suggests that these agents would lead to increased osteoblast proliferation and bone formation and a HBM phenotype. Preclinical and clinical studies indicate the opposite, and thus, other explanations for the negative skeletal effects of SSRIs need to be explored. One possible scenario is that SSRIs impact the skeleton by directly inhibiting the 5-HTT located on bone cell membranes. This may increase local 5-HT levels, despite decreased circulating 5-HT, by reducing its removal from the bone cell microenvironment.

Clinical Evidence for a Relationship between Serum 5-HT and Bone Health

In light of the in vitro and preclinical evidence suggesting that circulating 5-HT has effects on bone, what is the clinical evidence that such a relationship exists? Mödder et al. (36) measured serum 5-HT levels in a population-based sample of 275 women and related these to skeletal parameters assessed by dual-energy x-ray absorptiometry (DXA), quantitative computed tomography (QCT), and high-resolution peripheral QCT (pQCT). Significant inverse associations were discovered between serum 5-HT levels and 1) femur neck total and trabecular volumetric bone mineral density (BMD) and trabecular thickness in all women; 2) femur neck trabecular volumetric BMD in premenopausal women; and 3) bone volume/tissue volume and trabecular thickness at the radius in postmenopausal women not on hormone therapy. These associations remained significant in multivariable models that included age and body mass index, consistent with an independent effect of circulating 5-HT levels on bone mass/structure at these sites. The associations, although statistically significant, were weak. This may be due to the use of serum (rather than platelet-poor plasma) for the 5-HT measurements and noncontrolled dietary intake of tryptophan in the study subjects.

Clinical Evidence for a Relationship between SSRI Use and Bone Health

SSRIs are a class of medications that selectively and potently block 5-HTT. They are widely used for treatment of major depressive disorders as well as several other psychiatric conditions. Several studies in varied populations have demonstrated an effect of SSRIs on BMD. Cross-sectional studies support an association between SSRIs and lower BMD in men (37,38) and women (38,39,40). Adjusted differences in BMD between SSRI users and nonusers range from 2.4 to 6.2% across anatomic sites (37,38,40). More important for demonstrating causal associations, longitudinal studies have shown that SSRI users have at least a 1.6-fold greater decline in BMD compared with those not taking SSRIs (39). Contrasting results from the National Health and Nutrition Examination Survey and the Women’s Health Initiative show no association between antidepressant use and BMD (41,42).

An association between antidepressants and increased risk of fracture is supported by case-control studies using large administrative datasets from Denmark (43), Manitoba, Canada (44), Michigan (45), and Ontario, Canada (46). Vestergaard et al. (43) demonstrated increased odds of hip and any fracture for users of either tricyclic antidepressants (TCA) or SSRIs [adjusted odds ratio, 1.15–1.40 for all antidepressants; 95% confidence interval (CI), 0.99–1.30 for TCAs (not significant) and 1.08–1.62 for SSRIs across dosages], as did Bolton (OR, 1.45 for SSRI users; 95% CI, 1.32–1.59) (43,44). However, database studies can be problematic because of the inability to control for unmeasured variables (i.e. depressive symptoms).

Among several prospective cohort studies, men from the Osteoporotic Fractures in Men (MrOS) cohort have an overall increased risk for nonspine fracture (47,48). In the Canadian Multicenter Osteoporosis Study (CaMOS) cohort, older men and women taking SSRIs had higher rates of fracture over 5 yr compared with nonusers (hazard ratio, 2.1; 95% CI, 1.3–3.4) (38). Among men and women in Rotterdam age 55 and older, the risk was increased 2-fold (hazard ratio, 2.35; 95% CI, 1.32–1.48) for nonvertebral fracture (49). In the Women’s Health Initiative, antidepressants were associated with increased risk of any fracture and nonclinical vertebral fracture, but not hip or wrist (42). Thus, associations between SSRIs and bone density, bone loss, or fractures as outcomes have been demonstrated in several distinct populations, using various study designs.

A few studies have examined SSRI dose and fracture risk with varied results (38,43,44). Among users of all antidepressants, Vestergaard et al. (43) demonstrated progressive increases in relative risk for any fracture, hip fracture, and spine fracture as the antidepressant dose increased across levels of defined daily dose (DDD): from less than 0.15 DDD to 0.15–0.75 DDD and 0.75 or greater DDD. SSRIs showed increases in the relative risk of fracture across doses for all categories of fracture, but results were significant only for hip fracture (43). Bolton also demonstrated a dose effect for SSRIs using the Manitoba dataset. Odds ratios for fracture among men and women over age 50 using SSRIs increased significantly across tertiles of SSRI dose (P < 0.05) (44). The CaMOS study observed a dose-dependent effect for SSRIs: 1.5-fold increase in risk of fragility fracture for each unit increase in the daily dose of SSRI (38). A linear increase in risk with increasing dose was not observed with the Rotterdam cohort (49).

The relationship between duration of SSRI use and fracture risk has also been evaluated. Richards et al. (38) demonstrated higher fracture risk among men and women using SSRIs at baseline and 5 yr later. An earlier study using the UK General Practice Research Database suggested higher risk within the first 15 d of treatment (50). Ziere et al. (49) evaluated both dose and duration in the Rotterdam cohort and observed increased fracture risk with increasing duration of SSRI treatment. One explanation for these findings is that SSRIs may contribute to fracture through falls early in the course of treatment and through a direct bone mechanism later in the course of treatment.

Limitations of Current Studies on SSRI Effect on Bone

Complicating the interpretation of current SSRI studies in terms of causality are several methodological issues, inherent to epidemiological studies. One is the issue of confounding by indication, which can exist if a disease and the treatment both have potential to be associated with the outcome of interest (51). In this case, depression has also been associated with low bone density in some (39,52,53,54,55,56,57,58) but not all (42,59,60,61,62,63) studies; mixed results have also been observed for an association between depression and falls (61,62,64,65,66) and depression and fractures (42,57,60,61,62,67,68,69). Within a particular study, it can be difficult to determine whether the disease state (depression) or the treatment (SSRIs) is responsible for the effects seen. Most studies of SSRIs have used a measure of depressive symptoms (SF-12 or SF-36, Center for Epidemiologic Studies 10-item Depression scale, Beck Depression Inventory, Geriatric Depression Scale, and others). Only one study of SSRIs and bone health assessed participants with a more rigorous research measure, the structured clinical interview, and adjusted for the presence of either past or current depression that met DSM-IV diagnostic criteria (40).

Depression and SSRIs have the potential to impact bone through distinct mechanistic pathways (Fig. 4). For instance, SSRIs could influence bone through reduced bone formation, increased bone resorption, or both or through falls. The skeletal response to SSRIs could be modulated by genetic differences in the 5-HTT. Depression could influence bone through inflammation, physical inactivity, falls, decreased outdoor exposure (and therefore lower vitamin D levels), hypercortisolism, or hypogonadism. Theoretically, when a person has persistent depressive symptoms and is taking an SSRI, he or she could be at higher risk based on overlapping pathways. Those with depressive symptoms that are in remission after treatment with an SSRI and those using SSRIs for nondepressive illness may be at lower risk.

Figure 4.

Figure 4

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Mechanisms for the effects of depression and SSRI treatment on bone loss and fracture. Depressed individuals and SSRI users may have several reasons for bone loss, related to either their depression, or their SSRI use, or both. SSRI users may have persistent symptoms of depression, may be in remission from depression, or may be using SSRIs for a nondepressive condition. [Modified from E. M. Haney et al.: Bone 46:13–17, 2010 (74).]

The relationship between SSRIs and fall risk is not clear. On one hand, several studies show that SSRI use is associated with an increase in fall risk and that this risk is higher than for other types of antidepressants, namely TCAs (65,70,71,72). Conversely, other studies show that SSRIs confer equivalent or lower fall risk to TCAs (64,66). Undermining the interpretation of these studies is the failure to clarify the dose of medication, the indication, and the frailty of the individual patient. In geriatric practice, TCAs are generally avoided because of their side effect profile and potential for drug-drug interactions (50). If used at all (e.g. for insomnia or chronic pain), they are often given in doses well below those required to treat depression. In addition, SSRIs vary with respect to their potency for inhibiting the 5-HTT. Whether this variation among medications within a class is associated with variation in fall risk has not been studied. Resolution of remaining questions about SSRIs and their contribution to bone loss, falls, and fractures will require randomized controlled trials with careful assessment of depression and depressive symptoms.

Implications for Screening and Population Health

The evidence now seems sufficient to consider adding SSRIs to the list of medications that contribute to osteoporosis. This would imply that clinicians consider bone density testing for people on SSRIs, or those on SSRIs with certain additional risk factors, for their risk of fracture. At least, it seems appropriate to expect that everyone taking SSRIs have at least some discussion about bone health with their provider. It is too early to suggest that all SSRI users be tested with DXA (in the absence of other risk factors), but the question could be addressed with trials comparing routine DXA testing (or pQCT testing, where available) with usual care (measuring/supplementing vitamin D, calcium supplementation, exercise) using fracture outcomes.

Conclusion

Mounting evidence supports 5-HT as an important regulatory agent in bone. Efforts to confirm the serotonergic effects on bone, the biochemical pathways used, and the feedback loops involved among bone, gut, and perhaps brain are under way. Whether targeting of 5-HT signaling can also be developed as an intervention for bone, without compromise to other 5-HT sensitive systems, will be determined with further work. Similarly, further work is required to establish the full skeletal effects of agents currently being used to modulate 5-HT signaling for the management of conditions in other systems. This includes the clinically popular SSRIs, which inhibit the 5-HTT for the management of major depressive disorder and other affective conditions. An important clinical implication of the work on 5-HT signaling through LRP5 is the potential for identifying novel therapeutic targets. These questions should continue to fuel the recent surge in interest in neuroendocrine regulation of the skeleton.

Footnotes

This work was supported by National Institutes of Health Grant AR-052018 (to M.B.).

Disclosure Summary: The author has no disclosures.

Abbreviations: BDS, Brainstem-derived serotonin; BMD, bone mineral density; CI, confidence interval; DDD, defined daily dose; DXA, dual-energy x-ray absorptiometry; GI, gastrointestinal; HBM, high bone mass; 5-HT, serotonin (5-hydroxytryptamine); 5-HTT, 5-HT transporter; LRP5, LDL receptor-related protein 5; pQCT, peripheral QCT; QCT, quantitative computed tomography; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TPH, tryptophan hydroxylase.

References

  1. Bliziotes MM, Eshleman AJ, Zhang XW, Wiren KM 2001 Neurotransmitter action in osteoblasts: expression of a functional system for serotonin receptor activation and reuptake. Bone 29:477–486 [DOI] [PubMed] [Google Scholar]
  2. Westbroek I, van der Plas A, de Rooij KE, Klein-Nulend J, Nijweide PJ 2001 Expression of serotonin receptors in bone. J Biol Chem 276:28961–28968 [DOI] [PubMed] [Google Scholar]
  3. Rapport MM, Green AA, Page IH 1948 Serum vasoconstrictor (serotonin). IV. Isolation and characterization. J Biol Chem 176:1243–1251 [PubMed] [Google Scholar]
  4. Rosen CJ 2009 Serotonin rising—the bone, brain, bowel connection. N Engl J Med 360:957–959 [DOI] [PubMed] [Google Scholar]
  5. Rosen CJ 2009 Breaking into bone biology: serotonin’s secrets. Nat Med 15:145–146 [DOI] [PubMed] [Google Scholar]
  6. Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G 2008 Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135:825–837 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Walther DJ, Peter JU, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M 2003 Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299:76 [DOI] [PubMed] [Google Scholar]
  8. aan het Rot M, Mathew SJ, Charney DS 2009 Neurobiological mechanisms in major depressive disorder. CMAJ 180:305–313 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Arroll B, Macgillivray S, Ogston S, Reid I, Sullivan F, Williams B, Crombie I 2005 Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann Fam Med 3:449–456 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gershon MD, Tack J 2007 The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132:397–414 [DOI] [PubMed] [Google Scholar]
  11. Wade PR, Chen J, Jaffe B, Kassem IS, Blakely RD, Gershon MD 1996 Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J Neurosci 16:2352–2364 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ni W, Watts SW 2006 5-Hydroxytryptamine in the cardiovascular system: focus on the serotonin transporter (SERT). Clin Exp Pharmacol Physiol 33:575–583 [DOI] [PubMed] [Google Scholar]
  13. Warden SJ, Bliziotes MM, Wiren KM, Eshleman AJ, Turner CH 2005 Neural regulation of bone and the skeletal effects of serotonin (5-hydroxytryptamine). Mol Cell Endocrinol 242:1–9 [DOI] [PubMed] [Google Scholar]
  14. Battaglino R, Fu J, Späte U, Ersoy U, Joe M, Sedaghat L, Stashenko P 2004 Serotonin regulates osteoclast differentiation through its transporter. J Bone Miner Res 19:1420–1431 [DOI] [PubMed] [Google Scholar]
  15. Bliziotes M, Eshleman A, Burt-Pichat B, Zhang XW, Hashimoto J, Wiren K, Chenu C 2006 Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells. Bone 39:1313–1321 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gustafsson BI, Thommesen L, Stunes AK, Tommeras K, Westbroek I, Waldum HL, Slørdahl K, Tamburstuen MV, Reseland JE, Syversen U 2006 Serotonin and fluoxetine modulate bone cell function in vitro. J Cell Biochem 98:139–151 [DOI] [PubMed] [Google Scholar]
  17. Locker M, Bitard J, Collet C, Poliard A, Mutel V, Launay JM, Kellermann O 2006 Stepwise control of osteogenic differentiation by 5-HT2B receptor signaling: nitric oxide production and phospholipase A2 activation. Cell Signal 18:628–639 [DOI] [PubMed] [Google Scholar]
  18. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP 2002 High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521 [DOI] [PubMed] [Google Scholar]
  19. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Jüppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen- Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML 2001 LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523 [DOI] [PubMed] [Google Scholar]
  20. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, Van Eerdewegh P, Recker RR, Johnson ML 2002 A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high bone-mass trait. Am J Hum Genet 70:11–19 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Baron R, Rawadi G 2007 Targeting the Wnt/β-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 148:2635–2643 [DOI] [PubMed] [Google Scholar]
  22. Glantschnig H, Hampton R, Wei N, Scott K, Nantermet P, Zhao J, Chen F, Fisher J, Su Q, Pennypacker B, Cusick T, Sandhu P, Reszka A, Strohl W, Flores O, Wang F, Kimmel D, An Z2008 Fully human anti-DKK1 antibodies increase bone formation and resolve osteopenia in mouse models of estrogen-deficiency induced bone loss. J Bone Miner Res 23(Suppl 1):S60–S61 [Google Scholar]
  23. Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu QT, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C 2009 Sclerostin antibody treatment increases bone formation, bone mass and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 24:578–588 [DOI] [PubMed] [Google Scholar]
  24. Rothman RB, Zolkowska D, Baumann MH 2008 Serotonin (5-HT) transporter ligands affect plasma 5-HT in rats. Ann NY Acad Sci 1139:268–284 [DOI] [PubMed] [Google Scholar]
  25. Liu Q, Yang Q, Sun W, Vogel P, Heydorn W, Yu XQ, Hu Z, Yu W, Jonas B, Pineda R, Calderon-Gay V, Germann M, O'Neill E, Brommage R, Cullinan E, Platt K, Wilson A, Powell D, Sands A, Zambrowicz B, Shi ZC 2008 Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract. J Pharmacol Exp Ther 325:47–55 [DOI] [PubMed] [Google Scholar]
  26. Babij P, Zhao W, Small C, Kharode Y, Yaworsky PJ, Bouxsein ML, Reddy PS, Bodine PV, Robinson JA, Bhat B, Marzolf J, Moran RA, Bex F 2003 High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res 18:960–974 [DOI] [PubMed] [Google Scholar]
  27. Sawakami K, Robling AG, Ai M, Pitner ND, Liu D, Warden SJ, Li J, Maye P, Rowe DW, Duncan RL, Warman ML, Turner CH 2006 The Wnt coreceptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment. J Biol Chem 281:23698–23711 [DOI] [PubMed] [Google Scholar]
  28. Yadav VK, Oury F, Suda N, Liu ZW, Gao XB, Confavreux C, Klemenhagen KC, Tanaka KF, Gingrich JA, Guo XE, Tecott LH, Mann JJ, Hen R, Horvath TL, Karsenty G 2009 A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 138:976–989 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P 2010 Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat Med 16:308–312 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Warden SJ, Nelson IR, Fuchs RK, Bliziotes MM, Turner CH 2008 Serotonin (5-hydroxytryptamine) transporter inhibition causes bone loss in adult mice independently of estrogen deficiency. Menopause 15:1176–1183 [DOI] [PubMed] [Google Scholar]
  31. Warden SJ, Robling AG, Sanders MS, Bliziotes MM, Turner CH 2005 Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology 146:685–693 [DOI] [PubMed] [Google Scholar]
  32. Westbroek I, Waarsing JH, van Leeuwen JP, Waldum H, Reseland JE, Weinans H, Syversen U, Gustafsson BI 2007 Long-term fluoxetine administration does not result in major changes in bone architecture and strength in growing rats. J Cell Biochem 101:360–368 [DOI] [PubMed] [Google Scholar]
  33. Warden SJ, Hassett SM, Bond JL, Rydberg J, Grogg JD, Hilles EL, Bogenschutz ED, Smith HD, Fuchs RK, Bliziotes MM, Turner CH 2010 Psychotropic drugs have contrasting skeletal effects that are independent of their effects on physical activity levels. Bone 46:985–992 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Bonnet N, Bernard P, Beaupied H, Bizot JC, Trovero F, Courteix D, Benhamou CL 2007 Various effects of antidepressant drugs on bone microarchitecture, mechanical properties and bone remodeling. Toxicol Appl Pharmacol 221:111–118 [DOI] [PubMed] [Google Scholar]
  35. Zolkowska D, Baumann MH, Rothman RB 2008 Chronic fenfluramine administration increases plasma serotonin (5-hydroxytryptamine) to nontoxic levels. J Pharmacol Exp Ther 324:791–797 [DOI] [PubMed] [Google Scholar]
  36. Mödder UI, Achenbach SJ, Amin S, Riggs BL, Melton 3rd LJ, Khosla S 2010 Relation of serum serotonin levels to bone density and structural parameters in women. J Bone Miner Res 25:415–422 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Haney EM, Parimi N, Diem SJ, Ensrud K, Cauley JA, Orwoll ES, Bliziotes MM 2007 SSRI use is associated with increased risk of fracture among older men. J Bone Miner Res 22 (Suppl 1):S45 [Google Scholar]
  38. Richards JB, Papaioannou A, Adachi JD, Joseph L, Whitson HE, Prior JC, Goltzman D, CMOSRSG 2007 The impact of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med 167:188–194 [DOI] [PubMed] [Google Scholar]
  39. Diem SJ, Blackwell TL, Stone KL, Yaffe K, Haney EM, Bliziotes MM, Ensrud KE 2007 Use of antidepressants and rates of hip bone loss in older women: the Study of Osteoporotic Fractures. Arch Intern Med 167:1240–1245 [DOI] [PubMed] [Google Scholar]
  40. Williams LJ, Henry MJ, Berk M, Dodd S, Jacka FN, Kotowicz MA, Nicholson GC, Pasco JA 2008 Selective serotonin reuptake inhibitor use and bone mineral density in women with a history of depression. Int Clin Psychopharmacol 23:84–87 [DOI] [PubMed] [Google Scholar]
  41. Kinjo M, Setoguchi S, Schneeweiss S, Solomon DH 2005 Bone mineral density in subjects using central nervous system-active medications. Am J Med 118:1414 [DOI] [PubMed] [Google Scholar]
  42. Spangler L, Scholes D, Brunner RL, Robbins J, Reed SD, Newton KM, Melville JL, Lacroix AZ 2008 Depressive symptoms, bone loss, and fractures in postmenopausal women. J Gen Intern Med 23:567–574 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Vestergaard P, Rejnmark L, Mosekilde L 2006 Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int 17:807–816 [DOI] [PubMed] [Google Scholar]
  44. Bolton JM, Metge C, Lix L, Prior H, Sareen J, Leslie WD 2008 Fracture risk from psychotropic medications: a population-based analysis. J Clin Psychopharmacol 28:384–391 [DOI] [PubMed] [Google Scholar]
  45. Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton 3rd LJ 1987 Psychotropic drug use and the risk of hip fracture. N Engl J Med 316:363–369 [DOI] [PubMed] [Google Scholar]
  46. Liu B, Anderson G, Mittmann N, To T, Axcell T, Shear N 1998 Use of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet 351:1303–1307 [DOI] [PubMed] [Google Scholar]
  47. Haney EM, Chan BK, Diem SJ, Ensrud KE, Cauley JA, Barrett-Connor E, Orwoll E, Bliziotes MM 2007 Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med 167:1246–1251 [DOI] [PubMed] [Google Scholar]
  48. Lewis CE, Ewing SK, Taylor BC, Shikany JM, Fink HA, Ensrud KE, Barrett-Connor E, Cummings SR, Orwoll E 2007 Predictors of non-spine fracture in elderly men: the MrOS Study. J Bone Miner Res 22:211–219 [DOI] [PubMed] [Google Scholar]
  49. Ziere G, Dieleman JP, van der Cammen TJ, Hofman A, Pols HA, Stricker BH 2008 Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures. J Clin Psychopharmacol 28:411–417 [DOI] [PubMed] [Google Scholar]
  50. Hubbard R, Farrington P, Smith C, Smeeth L, Tattersfield A 2003 Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture. Am J Epidemiol 158:77–84 [DOI] [PubMed] [Google Scholar]
  51. Psaty BM, Koepsell TD, Lin D, Weiss NS, Siscovick DS, Rosendaal FR, Pahor M, Furberg CD 1999 Assessment and control for confounding by indication in observational studies. J Am Geriatr Soc 47:749–754 [DOI] [PubMed] [Google Scholar]
  52. Coelho R, Silva C, Maia A, Prata J, Barros H 1999 Bone mineral density and depression: a community study in women. J Psychosom Res 46:29–35 [DOI] [PubMed] [Google Scholar]
  53. Eskandari F, Martinez PE, Torvik S, Phillips TM, Sternberg EM, Mistry S, Ronsaville D, Wesley R, Toomey C, Sebring NG, Reynolds JC, Blackman MR, Calis KA, Gold PW, Cizza G 2007 Low bone mass in premenopausal women with depression. Arch Intern Med 167:2329–2336 [DOI] [PubMed] [Google Scholar]
  54. Jacka FN, Pasco JA, Henry MJ, Kotowicz MA, Dodd S, Nicholson GC, Berk M 2005 Depression and bone mineral density in a community sample of perimenopausal women: Geelong Osteoporosis Study. Menopause 12:88–91 [DOI] [PubMed] [Google Scholar]
  55. Mussolino ME, Jonas BS, Looker AC 2004 Depression and bone mineral density in young adults: results from NHANES III. Psychosom Med 66:533–537 [DOI] [PubMed] [Google Scholar]
  56. Robbins J, Hirsch C, Whitmer R, Cauley J, Harris T 2001 The association of bone mineral density and depression in an older population. J Am Geriatr Soc 49:732–736 [DOI] [PubMed] [Google Scholar]
  57. Silverman SL, Shen W, Minshall ME, Xie S, Moses KH 2007 Prevalence of depressive symptoms in postmenopausal women with low bone mineral density and/or prevalent vertebral fracture: results from the Multiple Outcomes of Raloxifene Evaluation (MORE) study. J Rheumatol 34:140–144 [PubMed] [Google Scholar]
  58. Wong SY, Lau EM, Lynn H, Leung PC, Woo J, Cummings SR, Orwoll E 2005 Depression and bone mineral density: is there a relationship in elderly Asian men? Results from MrOs (Hong Kong). Osteoporos Int 16:610–615 [DOI] [PubMed] [Google Scholar]
  59. Reginster JY, Deroisy R, Paul I, Hansenne M, Ansseau M 1999 Depressive vulnerability is not an independent risk factor for osteoporosis in postmenopausal women. Maturitas 33:133–137 [DOI] [PubMed] [Google Scholar]
  60. Søgaard AJ, Joakimsen RM, Tverdal A, Fønnebø V, Magnus JH, Berntsen GK 2005 Long-term mental distress, bone mineral density and non-vertebral fractures. The Tromso Study. Osteoporos Int 16:887–897 [DOI] [PubMed] [Google Scholar]
  61. Whitson HE, Sanders L, Pieper CF, Gold DT, Papaioannou A, Richards JB, Adachi JD, Lyles KW 2008 Depressive symptomatology and fracture risk in community-dwelling older men and women. Aging Clin Exp Res 20:585–592 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Whooley MA 1999 Depression and medical illness. Ann Epidemiol 9:281–282 [DOI] [PubMed] [Google Scholar]
  63. Whooley MA, Cauley JA, Zmuda JM, Haney EM, Glynn NW 2004 Depressive symptoms and bone mineral density in older men. J Geriatr Psychiatry Neurol 17:88–92 [DOI] [PubMed] [Google Scholar]
  64. Ensrud KE, Blackwell TL, Mangione CM, Bowman PJ, Whooley MA, Bauer DC, Schwartz AV, Hanlon JT, Nevitt MC 2002 Central nervous system-active medications and risk for falls in older women. J Am Geriatr Soc 50:1629–1637 [DOI] [PubMed] [Google Scholar]
  65. Kerse N, Flicker L, Pfaff JJ, Draper B, Lautenschlager NT, Sim M, Snowdon J, Almeida OP 2008 Falls, depression, and antidepressants in later life: a large primary care appraisal. PLoS ONE 3:e2423 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Thapa PB, Gideon P, Cost TW, Milam AB, Ray WA 1998 Antidepressants and the risk of falls among nursing home residents. N Engl J Med 339:875–882 [DOI] [PubMed] [Google Scholar]
  67. Ensrud KE, Blackwell T, Mangione CM, Bowman PJ, Bauer DC, Schwartz A, Hanlon JT, Nevitt MC, Whooley MA 2003 Central nervous system active medications and risk for fractures in older women. Arch Intern Med 163:949–957 [DOI] [PubMed] [Google Scholar]
  68. Forsén L, Meyer HE, Søgaard AJ, Naess S, Schei B, Edna TH 1999 Mental distress and risk of hip fracture. Do broken hearts lead to broken bones? J Epidemiol Community Health 53:343–347 [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Tolea MI, Black SA, Carter-Pokras OD, Kling MA 2007 Depressive symptoms as a risk factor for osteoporosis and fractures in older Mexican American women. Osteoporos Int 18:315–322 [DOI] [PubMed] [Google Scholar]
  70. French DD, Campbell R, Spehar A, Cunningham F, Bulat T, Luther SL 2006 Drugs and falls in community-dwelling older people: a national veterans study. Clin Ther 28:619–630 [DOI] [PubMed] [Google Scholar]
  71. Hartikainen S, Lönnroos E, Louhivuori K 2007 Medication as a risk factor for falls: critical systematic review. J Gerontol A Biol Sci Med Sci 62:1172–1181 [DOI] [PubMed] [Google Scholar]
  72. Sterke CS, Verhagen AP, van Beeck EF, van der Cammen TJM 2008 The influence of drug use on fall incidents among nursing home residents: a systematic review. Int Psychogeriatr 20:890–910 [DOI] [PubMed] [Google Scholar]
  73. Warden SJ, Robling AG, Haney EM, Turner CH, Bliziotes MM 2010 The emerging role of serotonin (5-hydroxytryptamine) in the skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5). Bone 46:4–12 [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Haney EM, Warden SJ, Bliziotes MM 2010 Effects of selective serotonin reuptake inhibitors on bone health in adults: time for recommendations about screening, prevention and management? Bone 46:13–17 [DOI] [PMC free article] [PubMed] [Google Scholar]

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