Prolactin elevation has been proposed as a risk factor for low bone density and potentially osteoporosis in patients on long-term treatment with prolactin-elevating antipsychotics. Our objective was to study the acute effects of prolactin elevation on serum markers of bone formation and resorption in patients treated with risperidone. Thirty participants meeting Diagnostic and Statistical Manual of Mental Disorders fourth edition criteria for schizophrenia, major depressive disorder with psychotic features, or bipolar disorder with psychosis were enrolled. At baseline, subjects were antipsychotic free. Subjects were evaluated before and after 4 weeks of risperidone treatment. Assessments included symptom ratings along with testosterone, estradiol, prolactin, osteocalcin (marker of bone formation), and n-telopeptide crosslinks (NTx marker of bone resorption). Primary analysis examined the impact of risperidone treatment on change in the bone markers and hormone levels from pre to post treatment. Prolactin levels significantly increased from 12.1 ± 1.9 ng/ml to 65.7 ± 12.2 ng/ml after treatment (p < 0.001). NTx markers of bone resorption significantly decreased from 18.31 ± 1.49 nM bone collagen equivalent (BCE) before treatment to 15.50 ± 1.22 nM BCE after treatment in the study sample as a whole (p < 0.05). A trend was observed indicating that NTx may increase in individuals who have the greatest increases in prolactin after treatment r = 0.33, p = 0.07). These findings suggest that prolactin elevation is associated with changes in bone physiology very early in the course of treatment with risperidone. Bone resorption decreased in many subjects but higher levels of bone resorption occurred in patients with the greatest increases in prolactin. This may have important implications for prolactin monitoring or the periodic assessment of osteoporosis-related outcomes in patients requiring extended treatment.
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This study describes changes in serum hormones and markers of bone turnover observed early in treatment with the antipsychotic risperidone in individuals with psychosis who had little or no prior antipsychotic exposure. To our knowledge, this is the first study to examine the acute effects of risperidone exposure on markers of bone turnover and relationships with prolactin, testosterone, and estradiol. Our results identify potentially important drug-related effects that may help to better elucidate the mechanisms of antipsychotic influences on bone homeostasis. Our a priori hypothesis was that risperidone-associated prolactin elevation would be related to changes in bone turnover as measured by osteocalcin or NTx. We anticipated identifying increases in NTx markers of bone resorption or decreases in osteocalcin markers of bone formation. In this study sample, NTx markers of bone resorption, but not osteocalcin markers of bone formation, changed during the acute phase of risperidone treatment. Increases in prolactin were observed as expected. Estradiol and testosterone did not change over the course of treatment. In this study sample, NTx markers of resorption on average decreased after treatment, and these decreases appear to occur in those with less robust increases in prolactin. Interestingly there was a trend indicative of a positive correlation between increases in prolactin and increases in NTx, suggesting that greater increases in prolactin were correlated with potentially deleterious increases in bone resorption. We did not observe a statistically significant relationship between risperidone dose and the outcomes described herein. Exposure to antipsychotics results in a number of physiometabolic changes. As a result, it has been difficult to determine exactly what pharmacological consequences of drug administration cause or influence changes in bone metabolism. In the absence of antipsychotic treatment or other causes of prolactin elevation, dopamine signaling through dopamine D2 receptors on the anterior pituitary modulates prolactin release. D2 antagonism from antipsychotic medications like risperidone disinhibits this negative feedback, resulting in prolactin elevation [ Fitzgerald and Dinan, 2008 ]. Extended periods of elevated prolactin suppress gonadotropin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and subsequently testosterone and estrogen [ Tresguerres et al . 1981 ; Bhasin and Serdloff, 1985 ; Bartke et al . 1987 ]. Data from hyperprolactinema studies in nonpsychiatric patient populations, largely in the context of prolactinomas, implicate related gonadal dysfunction as an underlying mechanism for bone loss in women and men [ Shibli-Rahhal and Schlechte, 2009 ]. In this context, the clinical relationship between prolactin elevation and changes in bone density appears to correlate with menstrual dysregulation in women. In studies of patients with prolactin elevation during chronic antipsychotic treatment, hypogonadism has also been observed [ Smith et al . 2002 ; Kinon et al . 2003 ; Huber et al . 2005 ; O’Keane and Meaney, 2005 ; Kishimoto et al . 2008 ]. Studies in rodents and nonhuman primates also illustrate that chronic treatment with risperidone lowers BMD by increasing bone resorption [ Kunimatsu et al . 2010 ; Sackett et al . 2010 ], and that this increase in resorption is related to prolactin elevation and reductions in estrogen. In addition to these indirect effects of hyperprolactinemia on bone physiology, accumulating evidence also suggests that prolactin may have direct effects on bone. Osteoblasts express prolactin receptors and in rodent models, the effects of increases in prolactin appear to be related to age [ Krishnamra and Seemoung, 1996 ; Seriwatanachai et al . 2009 ]. Elevating prolactin may reduce osteoblasts by slowing proliferation [ Seriwatanachai et al . 2009 ]. Furthermore, prolactin elevation in mature rats increases the rate of calcium release, resulting in bone loss [ Krishnamra and Seemoung, 1996 ]. Cell culture studies further clarify that exposing MG-63 osteoblast-like cells to prolactin decreases alkaline phosphatase and increases the ratios of receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) proteins [ Coss et al . 2000 ; Seriwatanachai et al . 2008 ]. Increasing the ratio of RANKL (which increases osteoclast differentiation) to OPG (which inhibits osteoclast differentiation) [ Manolagas, 2000 ] results in an overall increase in bone resorption. Taken together these findings indicate that the effects of hyperprolactinemia on bone homeostasis involve a complex interplay of direct and indirect effects. In the context of our short-term study, we observed decreases in bone resorption in patients with less robust increases in prolactin in the absence of any observable changes in estradiol or testosterone. Additionally we observed a trend suggesting that greater increases in prolactin may be associated with increases in bone resorption. It is likely that the extent and timeframe of prolactin elevation observed in our study was not sufficient to result in any indirect effects on bone metabolism from prolactin-associated hypogonadism, as evidenced by minimal changes in estrogen and testosterone after treatment. As previously indicated, longer-term exposure to antipsychotics may be required to suppress this axis, further influencing bone physiology [ O’Keane, 2008 ]. Perhaps increases in bone resorption observed in those with greater prolactin increases were the result of alterations in bone remodeling associated with the direct effects on osteoblasts or osteoclasts. However, we do not have information on other bone physiology markers to help us clarify these relationships. The reasons for the reduction in NTx at lower levels of prolactin change are unclear. We did not collect information on diet before or during the study period that would have been informative in assessing whether changes in nutrient intake influenced this measure. Until now, the early time course and dose relationships of antipsychotics with bone turnover have not been extensively studied and to our knowledge this is the first investigation to study the acute effects of risperidone on bone turnover in a group of first-episode patients with little prior antipsychotic exposure. In other longitudinal studies, Abraham and colleagues did not find a relationship between prolactin elevation and BMD in women over the course of 1 year of treatment with risperidone or olanzapine [ Abraham et al . 2003b ]. However, those with prolactin elevation did have higher rates of bone resorption over the course of the study, indicating that a longer timeframe was likely needed to observe the resulting effects on BMD. More recently, evidence was observed that in premenopausal women, treatment for 1 year with prolactin-raising antipsychotics such as risperidone, sulpride, amisulpride, or depot first-generation antipsychotics reduced lumbar BMD compared with patients treated with the prolactin-sparing agent olanzapine [ Meaney and O’Keane, 2007 ]. The findings presented herein need to be interpreted in the context of certain limitations of the study. The study sample examined here is too small to clearly delineate sex differences in relationships between hormone markers and bone turnover. Additionally, our lack of controls and small sample size increases the risk for type 1 and type 2 errors. The flexible dosing strategy employed, while representative of typical clinical practice, likely increased the variability observed in some of the outcomes, but similarly allowed us to gain insight into potentially important effects to examine in future studies. It is unknown whether any of the antipsychotic-associated changes observed here differ based on diagnosis. We were not powered to detect effects by diagnostic category. However, an exploratory post hoc analysis did not identify evidence for differences across diagnostic groups. Other modifying factors may also influence bone homeostasis in patients requiring treatment with antipsychotic agents. These include biological and environmental variables such as diet, smoking, and exercise [ Halbreich and Palter, 1996 ]. We did not examine diet or exercise in these participants but an examination of smoking status (data not shown) did not reveal evidence for associations with bone markers before or after treatment. Finally, this was an acute study examining short-term drug exposure on selected blood-based biomarkers related to bone homeostasis. There are also other biomarkers beyond NTx and osteocalcin not assessed in this study that may be informative for identifying drug-related effects on bone metabolism. It is unclear how these short-term effects translated into longer-term outcomes. In longer-term studies researchers often use DEXA scans as a gold standard for assessing bone density changes over extended periods of time and it will be informative to conduct subsequent studies examining the relationships between blood biomarkers of bone metabolism and bone density from imaging studies. Risperidone-associated prolactin elevation is common and is observed in most patients treated with this medication [ Haddad and Wieck, 2004 ]. All participants in our study showed an increase in prolactin after treatment. However, there is accumulating evidence that the extent of elevation is important. Our findings indicate that changes in bone metabolism are observed after 4 weeks of treatment and may be related to the extent of prolactin elevation experienced. In light of previous studies identifying relationships between long-term exposure to prolactin-elevating antipsychotics and bone density, this information provides a platform for subsequent investigations. Maximizing the likelihood of clinical response while minimizing side effects is an ongoing struggle, but increasing our knowledge about the mechanisms underlying insidious effects such as the disruption of bone homeostasis and other antipsychotic-associated side effects is an important part of refining and improving the ways we approach drug selection and dosing in patients with psychotic disorders. This work was supported by the National Institute of Mental Health (grant numbers K08MH083888 to Bishop and R01MH062134 to Sweeney), the American College of Clinical Pharmacy (to Bishop), the University of Illinois Campus Research Board (to Bishop), National Institute of Child Health and Human Development (grant number K12HD055892), and the National Institutes of Health Office of Research on Women’s Health (to Rubin). Dr Bishop has received research grant support from Ortho-McNeil Janssen. Dr Sweeney has received research grant support from Ortho-McNeil Janssen. Dr Pavuluri is on the Speaker’s Bureau for Bristol-Meyers Squibb. The other authors have nothing to disclose.