Fracture Risk From Psychotropic Medications
Department of Psychiatry, University of Manitoba, Winnipeg, Manitoba, Canada. Journal of clinical psychopharmacology
(Impact Factor: 3.24).
09/2008; 28(4):384-91. DOI: 10.1097/JCP.0b013e31817d5943
Selective serotonin reuptake inhibitors (SSRIs), benzodiazepines, and antipsychotics have each been associated with an increased risk of fracture in older individuals. The aim of this study was to better define the magnitude of fracture risk with psychotropic medications and to determine whether a dose-effect relationship exists.
Population-based administrative databases were used to examine psychotropic medication exposure and fractures in persons aged 50 years and older in Manitoba between 1996 and 2004. Persons with osteoporotic fractures (vertebral, wrist, or hip [n = 15,792]) were compared with controls (3 controls for each case matched for age, sex, ethnicity, and comorbidity [n = 47,289]). Medications examined included antidepressants (SSRIs vs other monoamines), antipsychotics, lithium, and benzodiazepines.
Selective serotonin reuptake inhibitors were associated with the highest adjusted odds of osteoporotic fractures (odds ratio [OR] = 1.45; 95% confidence interval [CI], 1.32-1.59). Other monoamine antidepressants (OR = 1.15; 95% CI, 1.07-1.24) and benzodiazepines (OR = 1.10; 95% CI, 1.04-1.16) were also associated with greater fracture risk, although the relationship was weaker. Lithium was associated with lower fracture risk (OR = 0.63; 95% CI, 0.43-0.93), whereas the relationship with antipsychotics was not significant in the models that adjusted for diagnoses. A dose-effect relationship was seen with SSRIs and benzodiazepines.
This study provides novel insight into the relationship between fractures and psychotropic medications in the elderly. Selective serotonin reuptake inhibitors seem to have a greater risk than other psychotropic classes, and higher doses may further increase that risk. Lithium seems to be protective against fractures.
Available from: Victoria Abbing
- "Concomitant use of antidepressants and benzodiazepines is proven to be effective to treat the acute phase of depression  and hence are often co-prescribed in routine clinical practice . The use of antidepressants        and benzodiazepines       have both been associated with an increased risk of fractures. The hazard patterns for fracture have been reported to be different for these two classes of medications. "
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ABSTRACT: Background: Antidepressants and benzodiazepines are often co-prescribed and both associated with an increased fracture risk, albeit with distinctive hazard patterns. Timing of initiation of one with respect to the other and duration of use may influence the combined fracture hazard. The objective of our study was to describe patterns of concomitant use of benzodiazepine and antidepressants in terms of timing of initiation and duration and to illustrate the potential impact of various scenarios of timing of co-use on hip fracture hazard. Methods: Patients initiating antidepressant therapy (2002-2009) were identified from the Netherlands Primary Care Research Database. Concomitant benzodiazepine use was assessed according to the start time of benzodiazepine with respect to antidepressant therapy start. Duration of concomitant use was estimated relative to the length of antidepressant treatment episode. Results: Among 16,087 incident antidepressant users, 39.0% used benzodiazepines concomitantly during their first antidepressant treatment episode. The time of initiation of benzodiazepine use was variable (64.4% starting before, 13.7% simultaneous and 21.9% after antidepressants). Duration of concomitant use in the three groups varied. Conclusion: Co-prescribed medications with a common adverse event, may not only require accounting for concomitant use, but also the timing of start and duration of use as the overall hazard may vary accordingly.
Available from: PubMed Central
- "SSRIs hinder the 5-HT transporter from taking up
5-HT from the synaptic space, thus increasing extracellular levels of 5-HT. It has been
reported that patients taking the SSRI fluoxetine appear to have an elevated risk of
fracture (9-16). Consistent with this finding, serum 5-HT was reported to be inversely
correlated with femoral neck total and trabecular volumetric bone mineral density (7). "
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ABSTRACT: The monoamine serotonin (5-hydroxytryptamine, 5-HT), a well-known neurotransmitter, also has important functions outside the central nervous system. The objective of this study was to investigate the role of 5-HT in the proliferation, differentiation, and function of osteoblasts in vitro. We treated rat primary calvarial osteoblasts with various concentrations of 5-HT (1 nM to 10 µM) and assessed the rate of osteoblast proliferation, expression levels of osteoblast-specific proteins and genes, and the ability to form mineralized nodules. Next, we detected which 5-HT receptor subtypes were expressed in rat osteoblasts at different stages of osteoblast differentiation. We found that 5-HT could inhibit osteoblast proliferation, differentiation, and mineralization at low concentrations, but this inhibitory effect was mitigated at relatively high concentrations. Six of the 5-HT receptor subtypes (5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, and 5-HT2C) were found to exist in rat osteoblasts. Of these, 5-HT2A and 5-HT1B receptors had the highest expression levels, at both early and late stages of differentiation. Our results indicated that 5-HT can regulate osteoblast proliferation and function in vitro.
Available from: Sarah Blott
- "ZNF804A has been reported to have a variant associated with schizophrenia in humans [20,21], and regulates expression of genes such as the catechol O-methyl transferase gene (COMT)  which has been associated with increased fracture risk in males . An elevated risk of fracture has been noted in schizophrenics , but no genes directly associated with fracture risk in schizophrenics have previously been reported. "
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ABSTRACT: Thoroughbred racehorses are subject to non-traumatic distal limb bone fractures that occur during racing and exercise. Susceptibility to fracture may be due to underlying disturbances in bone metabolism which have a genetic cause. Fracture risk has been shown to be heritable in several species but this study is the first genetic analysis of fracture risk in the horse.
Fracture cases (n = 269) were horses that sustained catastrophic distal limb fractures while racing on UK racecourses, necessitating euthanasia. Control horses (n = 253) were over 4 years of age, were racing during the same time period as the cases, and had no history of fracture at the time the study was carried out. The horses sampled were bred for both flat and National Hunt (NH) jump racing. 43,417 SNPs were employed to perform a genome-wide association analysis and to estimate the proportion of genetic variance attributable to the SNPs on each chromosome using restricted maximum likelihood (REML). Significant genetic variation associated with fracture risk was found on chromosomes 9, 18, 22 and 31. Three SNPs on chromosome 18 (62.05 Mb - 62.15 Mb) and one SNP on chromosome 1 (14.17 Mb) reached genome-wide significance (p < 0.05) in a genome-wide association study (GWAS). Two of the SNPs on ECA 18 were located in a haplotype block containing the gene zinc finger protein 804A (ZNF804A). One haplotype within this block has a protective effect (controls at 1.95 times less risk of fracture than cases, p = 1 x 10-4), while a second haplotype increases fracture risk (cases at 3.39 times higher risk of fracture than controls, p = 0.042).
Fracture risk in the Thoroughbred horse is a complex condition with an underlying genetic basis. Multiple genomic regions contribute to susceptibility to fracture risk. This suggests there is the potential to develop SNP-based estimators for genetic risk of fracture in the Thoroughbred racehorse, using methods pioneered in livestock genetics such as genomic selection. This information would be useful to racehorse breeders and owners, enabling them to reduce the risk of injury in their horses.
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