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Donald S. Robinson, MD

Primary Psychiatry. 2008;15(10):32-34
 

Dr. Robinson is a consultant with Worldwide Drug Development in Burlington, Vermont.

Disclosure: Dr. Robinson has served as a consultant to Bristol-Myers Squibb, Epix, Johnson and Johnson, PGxHealth, Pfizer, QRx Pharma, and Schering.


Osteoporosis is a common medical condition among older aged adults in the United States. It is estimated that 50% of women and 20% of men >50 years of age of Caucasian descent are afflicted, and as a result, they carry higher risk for osteoporotic fractures during their lifetime.1 Osteoporosis represents a major public health concern, with an estimated annual cost of $17 billion in the US alone.2,3 Numerous widely prescribed medications may have heightened risk for osteoporotic fractures. A recent example is linkage between popular drugs prescribed for heartburn and acid reflux, the proton pump inhibitors (eg, omeprazole), and hip fracture.4 While the mechanism of this increased risk is unclear, it is speculated that inhibiting stomach acid by proton pump-inhibiting drugs speeds up bone demineralization.

Several psychotropic medications are implicated in increased risk of osteoporotic fracture.5-7 Selective serotonin reuptake inhibitors (SSRIs), in particular, are linked to greater susceptibility to bone fractures. This raises concerns because of the likelihood of long-term exposure to SSRIs at both ends of the age spectrum, ie, children and adolescents as well as older adults. These age groups appear to be more susceptible to potential adverse effects of certain psychotropic agents on skeletal health. A recent large epidemiologic study of residents enrolled in the provincial healthcare system of the Province of Manitoba, Canada implicates psychotropic medications as a cause of bone fragility fractures in older adults.8

Role of Neurotransmitter Systems in Bone Metabolism

There are convincing data that the nervous system exerts a significant physiologic influence on bone and periosteum tissue. These structures have sympathetic nerve fiber and sensory innervation. Studies show that nerve terminals innervating bone contain several neuropeptides, including calcitonin gene-related peptide, vasoactive intestinal peptide, substance P, and neuropeptide Y.9 Current investigations suggest that neurotransmitters play a role in regulating bone metabolism. Studies in rodents with genetically deleted transporter for the neurotransmitter dopamine find reduced cancellous bone mass of vertebrae and tibia and decreased femur length and thickness.10 Impairment of the dopamine transporter appears to affect skeletal structure and integrity during growth periods.

Serotonin (5-HT) receptors have been isolated from osteoblastic cells, the major cell type involved in bone production. The 5-HT transporter (5-HTT) appears to be an important modulator of bone cell activity.10,11 Rodents with genetically deleted 5-HTT transporter have significantly less bone mineral content. Bone mineral content is diminished in normal animals treated chronically with fluoxetine.11 This fluoxetine effect was most prominent at weight-bearing sites of skeletal bone.

Several 5-HT receptor subtypes have been identified in osteoblasts, osteoclasts, and periosteal fibroblasts, including 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptors.11,12 Osteoblasts appear to contain a functional 5-HT receptor system intracellularly as well as an intrinsic 5-HT uptake mechanism to modulate the effects of this neurotransmitter on bone metabolism. Abnormalities ascribed to chronic fluoxetine administration are of concern because SSRIs are often prescribed to children and adolescents as well as older adults who are at greater risk for age-related osteoporosis.

Population Studies of SSRI Use and Fragility Fractures

Several prior studies show that SSRI treatment is associated with lower bone mineral density13,14 and increased fracture risk.8,15-18 Utilizing healthcare administrative data, studies15-18 find that SSRI use correlates with incidence of fragility fractures. However, these investigations all suffer the drawback that they failed to adequately control for potential confounding factors, including concomitant medications, lifestyle differences, and health conditions that might affect bone density.

In a recent large population study,7 investigators involved in the Canadian Multicentre Osteoporosis Study examined SSRI use and fracture risk due to bone fragility. They conducted a population-based, randomly selected, prospective cohort study of >5,000 community-dwelling adults ≥50 years of age. Clinical fragility fractures were defined as those due to minimal trauma and documented by radiography. The subjects were participants in a long-term osteoporosis study living near seven regional urban centers in Canada. As part of the osteoporosis study, subjects underwent an in-depth health status interview at entry, and again 5 years later. Data on medication use, dosage, type of drug, and frequency of use were collected. Only data on SSRIs available for prescription at the time of the initial interview were analyzed. Bone-mineral density of the lumbar spine and hip was measured by radiography. Fragility fractures were categorized as those due to minimal trauma, eg, falling from bed, chair, or upright standing position.

The study enrolled 6,005 subjects ≥50 years of age; 997 subjects were excluded for incomplete or missing data. Of the remaining 5,008 subjects, 609 (12.2%) reported depressive symptoms, and 137 (2.7%) were found to be chronic SSRI users. This prevalence of SSRI use was similar to that reported by Canadian and US general populations.7 After adjusting for potential confounding factors documented by the in-depth interview, the findings clearly showed that daily SSRI use is correlated with heightened risk of fragility fracture (hazard ratio, 2.0; 95% confidence interval 1.3–3.1). Anatomic location of fractures sustained by SSRI users were: forearm (40%), foot and ankle (21%), hip (13%), rib (13%), femur (9%), and back (4%). Chronic SSRI use was associated with reduced bone mineral density of the hip and lumbar spine.

Case-Controlled Study of Fracture Risk and Use of Psychotropic Medications

University of Manitoba investigators utilizing provincial healthcare data recently reported the largest, most definitive study to date of psychotropic drug use and osteoporotic fractures.8 This case-controlled study accessed patient population data from the Manitoba Department of Health to assess health status and concurrent medication use of patients with recorded bone fractures. Manitoba Health provides comprehensive coverage for essentially all residents of the province of Manitoba, and claims data and pharmacy records are relatively complete for the provincial population. Patients ≥50 years of age with diagnosis of vertebral, wrist, or hip fractures were selected for study. Each patient was randomly matched to three controls based on year of birth, sex, ethnicity, and comorbidity index calculated from diagnostic codes. Only subjects with continuous coverage for health services from the Manitoba government between the years 1988 and 2004 were included. Exclusions were for incomplete medication data, long-term care facility residency, and exposure to drugs that might affect osteoporosis, eg, parathyroid hormones, estrogens, or biphosphanates.

Of 15,797 fracture cases, 99.5% of cases were successfully matched to three control subjects. There were three categories of medication usage, namely, none, past use, and current use within 3 months preceding bone fracture. Potential confounders adjusted for in the statistical analysis were diagnostic codes recorded during the 3-year pre-fracture period for diabetes, heart disease, epilepsy, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), dementia, schizophrenia, and home health care (as a proxy for fragility). Multivariate statistical analyses were employed to control for demographic variables, including income and place of residence, and confounding medical diagnoses and medication usage.

Osteoporotic Fractures and Psychotropic Drug Use

Analysis of demographic variables showed that fractures were more common among urban dwellers and those with the lowest incomes.8 Fractures were more prevalent in subjects with diagnoses of diabetes; epilepsy; arthritis; COPD; and psychiatric diagnoses for depression, substance abuse, schizophrenia, and dementia. Antidepressant and benzodiazepine usage was significantly higher among the fracture cases (Table).

 

 

Depression, dementia, schizophrenia, and substance abuse disorders all correlated with higher fracture risk. Among psychotropic agents, SSRIs were the medication most strongly associated with fractures, even after adjusting for medical and psychiatric diagnoses and concurrent medications. The odds ratio of 1.45 with chronic SSRI usage observed in this study falls within the range reported previously and provides compelling evidence that SSRIs are a significant risk factor for fragility fractures in older adults. This multivariate statistical analysis found that the dosage of both SSRIs and benzodiazepines correlated with fracture risk, unlike other antidepressants, antipsychotics, and lithium.

Conclusion

Population studies show a relationship between psychotropic drug usage and risk of fractures resulting from bone fragility. The mechanism of this heightened susceptibility to bone fracture is unclear. Bone-mineral metabolism appears to be controlled, in part, by serotonin-modulated systems, which could account for the susceptibility of older individuals taking SSRIs to osteoporotic fractures. Unresolved is the issue of how SSRIs might impact bone-mineral accrual in the growing skeleton during phases of growth and development in younger subjects. PP

References

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9.    Hill EL, Elde R. Distribution of CGRP-, VIP-, DβH-, SP-, and NPY-immunorecative nerves in the periosteum of the rat. Cell Tissue Res. 1991;264(3):469-480.
10.    Bliziotes MM, Eshleman AJ, Zhang XW, Wiren KM. Neurotransmitter action in osteoblasts: expression of a functional system for serotonin receptor activation and reuptake. Bone. 2001;29:477-486.
11.    Warden SJ, Robling AG, Sanders MS, Bliziotes MM, Turner CH. Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology. 2005;146(2):685-693.
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