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Psychoactive Treatments
Selective Serotonin Re-uptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs) are commonly used antidepressants that increase levels of 5-hydroxytryptamine (5-HT) (serotonin) by inhibiting the serotonin transporter and thereby preventing serotonin reuptake. Bone cells express 5-HT receptors, and activation of these receptors leads to either stimulatory or inhibitory effects depending upon the subtype of receptor. Animal studies of the effects of SSRIs on the skeleton are inconsistent, reporting both increases and decreases in bone mass. In patients, the results of observational studies on BMD have been variable with prospective cohort studies and cross-sectional studies in boys, women and older men finding higher rates of bone loss and lower BMD, but a prospective cohort study of middle-aged women initiating an SSRI and the Women's Health Initiative (WHI) observational study failing to find such an association. When adverse effects of SSRIs on BMD have been reported the magnitude of effect is small, of the order of 0·5%/year, and therefore of dubious clinical significance. Observational studies (that identified evidence of publication bias) have found an increased risk of fracture with SSRI use (pooled RR 1·7). As this increased risk was independent of BMD, it has been suggested that it may be due to an association between depression and increased fracture risk or may represent an effect of SSRIs to increase the risk of falls, rather than a direct effect on bone mass or strength. There is no consensus regarding management of bone health in these patients, although there have been recommendations that SSRI use be considered a secondary cause of osteoporosis. Although there is an absence of consistent data demonstrating adverse effects on bone mass, there may be an indirect effect to increase fracture risk; thus, in older adults (>60 years) receiving long-term SSRI therapy, an assessment of fracture risk could be performed and treatment considered in those at high fracture risk. In younger adults, whose baseline risk of fracture is low, it would seem reasonable for management to be as per the general population.
Antipsychotic Drugs
Antipsychotic drugs are used in the treatment of psychoses, as a result of their ability to block dopamine receptors. There are only a limited number of preclinical studies of antipsychotic drugs, which showing conflicting effects on bone. Cross-sectional studies generally show reduced BMD in patients taking antipsychotic drugs compared with normative data, but the magnitude of effect varies, as does the affected site(s). Bone turnover tends to be increased in association with hypogonadism induced by an increased prolactin level. There is evidence from cross-sectional studies that fracture rates are higher in patients taking antipsychotic drugs (OR 1·7–2·6). Proposed mechanisms by which antipsychotic agents cause reduced BMD are by inducing hyperprolactinaemia and thereby hypogonadism, by a direct effect on bone metabolism or by increasing the risk of falls. Studies have failed to consistently show a difference in BMD or fracture rate between people taking antipsychotic drugs that increase prolactin and those that do not. Studies of the effects of these drugs are confounded by other risk factors for low BMD in patients with schizophrenia, such as low body weight, reduced exercise, smoking and poor diet. A recent study found that schizophrenia was associated with reduced BMD, after controlling for medications and other risk factors for osteoporosis. It has been recommended that patients with psychosis who have osteopenia/osteoporosis or are at significant risk for reduced BMD be considered for treatment with prolactin-sparing antipsychotic medications. However, in the absence of consistent evidence of a causative relationship between antipsychotic drugs and low BMD and/or fracture, no specific screening or treatment measures outside those for the general population seem indicated.
Anti-epileptic Drugs
Anti-epileptic drugs (AED) are a diverse group of drugs used to treat or prevent epileptic seizures. Many of these drugs are also regularly used in the management of psychiatric conditions and neuropathic pain. The AEDs most commonly reported to affect BMD and bone metabolism are the inducers of the cytochrome P450 enzyme system (phenobarbital, phenytoin, carbamazepine and primidone) and sodium valproate, an enzyme inhibitor. It has been proposed that CYP450-inducing AEDs increase catabolism of 25(OH) vitamin D, leading to decreased calcium absorption and secondary hyperparathyroidism. In the past, institutionalized patients receiving AEDs were found to have osteomalacia and rickets caused by vitamin D deficiency. In recent studies of community dwelling adults and children, there is an increased incidence of vitamin D insufficiency (levels <20 ng/ml). Increased parathyroid hormone (PTH) levels have been reported in patients receiving AEDs. An increase in markers of bone turnover has been found in a number of small studies of patients receiving AEDs, and this may be associated with a decrease in BMD. Epidemiological studies link AED use to decreased bone mass in adults under 40 years and children, but prospective studies are lacking. In a single prospective study lasting up to 29 months, young male patients with epilepsy treated with a variety of AED (predominantly phenytoin and carbamazepine) experienced an annual 1·8% drop in femoral neck BMD. A recent meta-analysis of observational studies reported a significant increase in fracture risk amongst users of AEDs; however, patients receiving AEDs often have other risk factors for fracture, and the increase in risk may not relate to use of the drugs. In the absence of any evidence-based screening or treatment guidelines for managing bone health in patients receiving AEDs, most authors recommend treatment and surveillance as per the general population, with additional measurement of 25(OH) vitamin D levels.
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