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Relationship between long-term use of a typical antipsychotic medication by Chinese schizophrenia patients and the bone turnover markers serum osteocalcin and β-CrossLaps
Schizophrenia Research 176 (2016) 259–263
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Relationship between long-term use of a typical antipsychotic medication by Chinese schizophrenia patients and the bone turnover markers serum osteocalcin and β-CrossLaps Beibei Zhang a,d, Lu Deng a,d, Haishan Wu a,d, Xiaozi Lu b, Lihong Peng c, Renrong Wu a,d, Wenbin Guo a,d, Jindong Chen a,d,⁎, Lehua Li a,d, Jingping Zhao a,d a
Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China Qingdao Mental Health Center, Qingdao, Shandong, 266034, China c Metabolic Endocrinology Institute of the Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China d Mental Health Institute of the Second Xiangya Hospital, Central South University, Chinese National Clinical Research Center on Mental Disorders (xiangya), Chinese National Technology Institute on Mental Disorders, Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, Hunan, 410011, China b
a r t i c l e
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Article history: Received 25 September 2015 Received in revised form 27 June 2016 Accepted 27 June 2016 Available online 2 July 2016 Keywords: Schizophrenia Antipsychotics Bone turnover Osteoporosis Lipid Glucose
a b s t r a c t Background: Increasing evidence shows that schizophrenia patients with long-term exposure to antipsychotic medications have decreased bone mass, which suggests that they are at a high risk of osteoporosis. However, the mechanism underlying this remains unclear. In this study, we selected two bone turnover markers to explore whether atypical antipsychotics can affect bone metabolism and identified possible influencing factors. Methods: A total of 116 schizophrenia patients (18–40 years old) participated in the study. The subjects included 31 drug-naive first-episode patients and 85 patients who had undergone atypical antipsychotic monotherapy for at least 6 months. A total of 71 subjects were assigned as normal controls. Demographic and physical examination data were analyzed for all subjects. The positive and negative syndrome scale (PANSS) was used to assess psychopathology in schizophrenia patients. Levels of the bone turnover markers osteocalcin and β-CrossLaps were measured. Serum prolactin (PRL), lipid, sex hormone, glucose, insulin, and parathyroid hormone levels were also measured. Results: The serum β-CrossLaps levels of patients who had been treated with atypical antipsychotics were higher compared with those of drug-naive first-episode patients and normal subjects. Atypical antipsychotics, schizophrenia, age, gender, and body mass index, as well as serum levels of PRL, triglyceride, high-density lipoprotein cholesterol, glucose, and testosterone, were significantly associated with serum osteocalcin and β-CrossLaps levels. Serum insulin was only positively associated with serum osteocalcin, whereas estradiol was only negatively associated with serum β-CrossLaps. Conclusion: Patients who had been treated with atypical antipsychotics had accelerated bone resorption. Our findings uncover a link between atypical antipsychotics and bone metabolism, possibly through abnormalities in glucose and lipid metabolism and insulin resistance. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Osteoporosis is a metabolic bone disorder characterized by osteopenia per unit volume and bone microstructure degeneration. Osteoporosis can promote bone fragility, and the condition is a risk factor for serious bone fractures. According to the World Health Organization, osteoporosis is second to cardiovascular disorders among diseases that endanger human health. Long-term use of antipsychotics increases the risk of osteoporosis and/or reduced bone mineral density (BMD), thereby increasing the risk of fractures (Halbreich et al., 2003).
⁎ Corresponding author. E-mail address: [email protected] (J. Chen).
http://dx.doi.org/10.1016/j.schres.2016.06.034 0920-9964/© 2016 Elsevier B.V. All rights reserved.
Conventional (typical) antipsychotic agents are nonselective in blocking dopamine pathways, which is mainly achieved by the tubero-infundibular system and easily leads to hyperprolactinemia. Previous studies showed that hyperprolactinemia affects bone metabolism by inhibiting the hypothalamo–pituitary–gonadal axis (Kishimoto et al., 2008; O'Keane, 2008). Elevated prolactin (PRL) is caused by antipsychotic agents and leads to hypogonadism (mainly because of lower estradiol levels), which may be related to lower BMD. For the moment, antipsychotic-induced metabolic abnormalities, such as weight gain, glucose dysregulation, dyslipidemia, and increased risk of metabolic syndrome, have gained much attention (Young et al., 2014). However, discrepancies exist among studies investigating the relationship between antipsychotic treatment and bone metabolism in schizophrenia patients. A possible reason is that bone metabolism may not only be
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related to the cumulative effects of long-term antipsychotic treatment, but also abnormalities in glucose and lipid metabolism caused by such treatments. Bone turnover markers can reflect the degree of bone formation and resorption, and also clearly predict ongoing growth trends in the bone. Therefore, bone turnover markers may be useful risk predictors of bone fractures that are independent of BMD (Garnero et al., 2000). Compared with BMD, bone turnover markers have higher sensitivity and can be detected in peripheral blood. Hence, we hypothesized that bone turnover markers may be more suitable for monitoring changes in the bone metabolism of schizophrenia patients. In this study, we selected two types of bone turnover markers, namely, osteocalcin and β-CrossLaps to explore the effects of antipsychotics on bone metabolism. We explored possible influencing factors underlying these effects, and investigated whether glucose dysregulation and dyslipidemia are related to bone metabolism.
metabolism, including PRL, sex hormone, insulin, and parathyroid hormone (PTH) levels. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose levels were measured using an automatic biochemical analyzer (7170A, Japan). 2.3. Statistical analysis All statistical analyses were performed with SPSS 17. One-way ANOVA was performed to compare demographic parameters and laboratory data. Data are presented as mean values with standard deviation. Multiple linear regression analysis with dummy variables was used to evaluate whether group and age are independent factors associated with the bone turnover markers osteocalcin and β-CrossLaps. Multiple-stepwise regression analysis was performed to assess possible risk predictors for osteocalcin and β-CrossLaps, including PRL, sex hormone, glucose, lipid, insulin, PTH, and body mass index (BMI).
2. Patients and methods 3. Results 2.1. Patients This study was approved by the hospital ethics committee and involved 116 Chinese outpatients or inpatients with schizophrenia between the ages of 18 and 40. Thirty-one of them were drug-naive first-episode patients, with an average age of 25.6 years (standard deviation, SD = 5.1 years). Eighty-five schizophrenia patients had undergone atypical antipsychotic monotherapy (olanzapine, risperidone) for at least 6 months, and their average age was 29.7 years (SD = 7.1 years). Written informed consent was obtained from all subjects. All patients were diagnosed in accordance with the diagnostic criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV). Seventy-one healthy subjects served as normal control, and their average age was 30.2 years (SD = 5.0 years). The following criteria were used for exclusion of potential participants: (1) patients with physical diseases, such as cardiopathy, chronic liver disease, and chronic kidney disease; (2) patients with metabolic diseases known to affect bone metabolism, such as diabetes mellitus and hyperthyroidism; (3) patients taking a mood stabilizer, antidepressant, or anxiolytic that can affect BMD in addition to the antipsychotics within 3 months; (4) patients with a history of hypogonadism (in males, testosterone b 10 nmol/L or b 3 ng/mL; in females, b6 menstrual cycles per year); (5) pregnant or lactating women; and (6) patients with a history of fracture within a year. 2.2. Methods All subjects completed an interview conducted by the researcher. Demographic data were collected for all subjects and included the following: smoking and drinking history, dietary habit, disease duration, administration dosage of atypical antipsychotics, and family history of fractures. Information regarding physical activity was collected through a structured, detailed, retrospective interview by taking into consideration all physical activities that occurred in the period the patient underwent therapy. Using this information, an index of activity (intensity × minutes × number of sports) was calculated. Physical examination was performed to measure the height, weight, and blood pressure of each participant. Actual schizophrenic symptoms were assessed via the positive and negative syndrome scale (PANSS). Blood samples were obtained from all the subjects between 7 AM and 9 AM. The samples were allowed to stand for 20 min at room temperature. All blood samples were centrifuged for 5 min (3500 rpm) in a table-top high-speed centrifuge to obtain 2 mL of serum. The following parameters were measured with an automatic electrochemical luminescence immunity analyzer (Cobase 601, Germany): osteocalcin, which is a bone formation marker; β-CrossLaps, which is a bone resorption marker; and laboratory parameters that may affect bone
3.1. Comparison of demographic and clinical characteristics between patients and controls The three groups showed no significant differences in average activity intensity, smoking, drinking, and positive subscale and total PANSS scores (Table 1). The antipsychotic treatment group showed significantly higher BMI values than the drug-naive first-episode group and controls (F = 3.360, p = 0.031). Compared with the antipsychotic treatment group and controls, the drug-naive first-episode group had significantly lower ages (F = 6.793, p = 0.001). 3.2. Comparison of laboratory results between patients and controls The laboratory results of the patients and normal subjects are presented in Table 2. The subjects showed no significant differences in LDL-C and PTH levels. Significantly different β-CrossLaps (F = 30.320, P b 0.001) and osteocalcin (F = 27.086, P b 0.001) levels were detected among the three groups. The drug-naive first-episode group and the antipsychotic treatment group demonstrated no significant difference in osteocalcin level (P = 0.094), while the controls had significantly lower osteocalcin values than the two other groups (PAC b 0.001, PBC b 0.001). The antipsychotic treatment group had significantly higher β-CrossLaps levels than the drug-naive first-episode group (P = 0.002) and the controls (P b 0.001). Serum levels of PRL and testosterone were significantly higher in the patients than in the normal subjects. The antipsychotic-treated patients had significantly higher levels of TG, TC, and glucose compared with the drug naive first-episode patients and normal subjects. HDL-C and estradiol levels were significantly lower in the schizophrenia patients than in the normal subjects. The antipsychotic-treated patients had higher insulin levels than the drug-naive first-episode patients and normal subjects. 3.3. Predictors of osteocalcin and β-CrossLaps in all subjects We utilized multiple linear regression analysis to identify predictors of osteocalcin (Table 3) and β-CrossLaps (Table 4) levels. Compared with the normal controls, groups 1 (antipsychotic-treated patients) and 2 (drug-naive first-episode patients) were associated with serum osteocalcin and β-CrossLaps. Serum osteocalcin was negatively associated with age groups 1 (26–30 years old) and 2 (31–40 years old) compared with patients aged 18–25 years old, whereas serum β-CrossLaps was only associated with age group 2. Gender, BMI, serum TG, HDL-C, glucose, PRL, and testosterone were associated with serum osteocalcin and β-CrossLaps. By contrast, serum insulin was only positively associated with serum osteocalcin, whereas estradiol was only negatively associated with serum β-CrossLaps.
B. Zhang et al. / Schizophrenia Research 176 (2016) 259–263
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Table 1 Demographic parameters in the healthy controls, patients with schizophrenia treated with antipsychotic and drug-naïve patients with first- episode schizophrenia.a Characteristics
A first-episode drug naive (N = 31)
B antipsychotic treatment (N = 85)
C control (N = 71)
Statistic
p-value
Multiple comparisons
Age, mean (SD), y Women, no. (%) BMI, mean (SD) Index of activitya, mean (SD) Smoking, no. (%) Drinking, no. (%) PANNS score Positive subscale Negative subscale
25.6 (5.1) 16(51.6) 22.5(3.2) 15.3(5.0) 5 (16.1) 1(3.2) 87.6(12.5) 20.19(5.0) 22.5(5.2)
29.7 (7.1) 43(50) 23.8(3.4) 18.2 (4.9) 18 (21.2) 4(4.7) 84.7(22.0) 20.8(7.5) 19.5(7.7)
30.2 (5.0) 39(54.9) 22.8(1.7) 17.2(5.4) 12 (16.9) 5(7.0) – – –
F = 6.793 Chi = 0.383 F = 3.360 Chi = 1.476 Chi = 0.628 Chi = 0.748 F = 0.483 F = 0.253 F = 3.979
0.001 0.826 0.031 0.239 0.730 0.688 0.489 0.616 0.048
C,B N A – B N A,C – – – – – –
BMI = body mass index; PANSS = Positive and Negative Symptom Scale. a Index of activity = intensity × minutes × number of sports.
4. Discussion In the present study, the level of the bone resorption marker serum β-CrossLaps was significantly higher in antipsychotic-treated patients than in subjects from the two other groups (Table 2). Our results are in agreement with previous findings of Doknic et al. (2011), who found that C-terminal telopeptide of collagen type I (CTx) increases to the upper limit of the normal level in patients treated with injectable risperidone. Bishop et al. (2012) also reported that N-terminal telopeptide of collagen type I (NTx), another marker of bone resorption, changes during the acute phase of risperidone treatment. In the present study, we detected no difference in serum osteocalcin between the drug naive first-episode patients and the antipsychotic-treated patients. Compared with the normal controls, the patients that received or did not receive antipsychotic treatment had higher osteocalcin levels. However, a previous study (Doknic et al., 2011) showed that the osteocalcin level in patients treated with injectable risperidone was not obviously different compared with that in normal controls. By contrast, multiple stepwise regression analysis showed that antipsychotics and schizophrenia are related to serum osteocalcin. Therefore, we considered that schizophrenia and secondary metabolic disorders, which are caused by atypical antipsychotics, may be the influencing factors. Further longitudinal studies should be conducted to confirm this conclusion. The results of the present study showed that PRL level was higher in the drug-naive first-episode patients and antipsychotic-treated patients than in the normal controls (Fig. 2). PRL was positively associated with serum osteocalcin and β-CrossLaps. Abraham et al. (2003) reported a high rate of bone turnover in patients with high PRL levels but normal BMD. Fujimaki et al. (1994) also showed that bone formation and resorption are accelerated in 21 non-psychiatric women with hyperprolactinemia. Numerous reports have shown that hypogonadism, which is caused by elevated PRL, influences bone turnover in different sexes (Bruce et al., 2013). In the present study, serum osteocalcin for all subjects was only associated with testosterone,
whereas serum β-CrossLaps was associated with both E2 and testosterone. The use of antipsychotic medications is frequently associated with considerable increase in body weight (Meyer and Koro, 2004), which can lead to dyslipidemia. Consistent with this, a recent study has shown that schizophrenia patients may have a higher risk of developing dyslipidemia (Wu et al., 2013). Compared with healthy controls, drugnaive first-episode schizophrenia patients had lower TC and HDL-C. Our results showed that the antipsychotic-treated patients had higher TG and TC levels than the drug-naive first-episode schizophrenia patients; however, no difference in HDL-C level was observed between the two groups. To examine the predictors of bone metabolism, we found that TG and HDL-C were negatively associated with osteocalcin and β-CrossLaps. Zhou et al. (2009) found negative correlation between serum osteocalcin and HDL-C in men, but positive correlation between TG and osteocalcin in premenopausal women. Majima et al. (2008) studied 281 subjects (aged 18–89 years old) with untreated hypercholesterolemia and found that NTx is significantly negatively correlated with HDL-C. Jeong et al. (2014) showed that TC concentration positively correlates with serum CTX and osteocalcin in premenopausal women. Similarly, LDL-C can promote osteoclastic differentiation in vitro (Majima et al., 2008). However, we found no correlation among TC, LDL-C, osteocalcin and β-CrossLaps. Further longitudinal studies are required to determine whether TC and LDL-C are risk predictors for bone metabolism. Antipsychotics can elevate plasma glucose levels in schizophrenia patients, among whom the prevalence of type 2 diabetes mellitus is as high as 28% (Young et al., 2014). In the present study, the fasting glucose level was higher in the patients treated with antipsychotics than in the other patients. Elevated glucose levels can affect bone metabolism. A recent meta-analysis based on 22 studies has reported lower serum osteocalcin and CTX levels in both T1D and T2D compared with their controls (Starup-Linde et al., 2014). Henriksen et al. (2003) and Chailurkit et al. (2008) reported that the percentage of change in βCTX after oral glucose administration in healthy individuals was 50%.
Table 2 Laboratory date in the healthy controls, patients with schizophrenia treated with antipsychotic and drug-naïve patients with first- episode schizophrenia, mean (SD). Variables
A first-episode (N = 31)
B antipsychotic treatment (N = 85)
C control (N = 71)
Statistic
p-value
Multiple comparisons
Prolactin, ng/mL Triglyceride, mmol/L TC, mmol/L HDL-C, mmol/L LDL-C, mmol/L Estradiol, pg/ml Testosterone, nmol/l Glucose, mmol/L Insulin, μIU/mL PTH, pg/mL Osteocalcin, ng/ml β-CrossLaps, ng/ml
51.30(43.29) 1.05(0.65) 4.01(0.76) 1.19(0.33) 2.46(0.72) 47.61(40.26) 2.45(2.36) 4.67(0.47) 10.32(7.27) 34.65(15.68) 25.37(10.46) 0.52(0.28)
66.87(53.81) 1.89(1.69) 4.23(0.85) 1.10(0.33) 2.34(0.71) 60.46(45.78) 1.78(1.72) 5.09(0.91) 21.81(19.26) 41.26(19.38) 24.05(9.81) 0.69(0.24)
20.04(10.76) 0.92(0.42) 4.18(0.66) 1.41(0.30) 2.61(0.71) 128.75(90.1) 1.23(1.28) 4.61(0.48) 7.52(3.75) 34.12(14.59) 15.17(4.64) 0.32(0.12)
F = 15.09 F = 14.12 F = 4.919 F = 16.979 F = 2.655 F = 23.747 F = 5.611 F = 8.789 F = 16.534 F = 3.868 F = 27.086 F = 30.320
b0.001 b0.001 0.008 b0.001 0.919 b0.001 0.004 b0.001 b0.001 0.220 b0.001 b0.001
A,B N C B N A,C B N A,C C N A,B – C N A,B A,B N C B N A,C BNANC – A,B N C BNANC
TC = total cholesterol; HDL-C = high density lipoprotein cholesterol; LDL-C = low density lipoprotein cholesterol; PTH = parathyroid hormone.
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Table 3 Multiple linear regression analysis (stepwise) of independent predictive factors associated with osteocalcin in all subjects. Independent variables enter the model Osteocalcin Group1 Group2 Age 1 Age 2 Gender BMI Triglyceride HDL-C Glucose Insulin PRL Testosterone
β
Beta
t
P
7.472 7.983 −3.478 −4.866 −4.373 −0.536 −1.353 −5.567 −2.531 0.190 0.002 1.391
0.394 0.315 −0.161 −0.249 −0.229 −0.172 −0.184 −0.208 −0.198 0.348 0.214 0.341
5.766 4.570 −2.330 −3.549 −3.701 −2.609 −2.145 −2.705 −2.398 3.790 3.313 4.975
b0.001 b0.001 0.021 b0.001 b0.001 0.01 0.033 0.007 0.018 b0.001 0.001 b0.001
The present study also found that elevated fasting glucose was caused by antipsychotics and associated with decreased serum osteocalcin and β-CrossLaps. In addition to glucose, bone turnover markers can also be affected through insulin-based mechanisms. Insulin affects bone metabolism mainly through the insulin signaling pathway within osteoblasts (Pramojanee et al., 2014). Insulin can stimulate mitogen in osteoblasts to increase osteocalcin secretion, which is coupled with inhibition of apoptosis (Thrailkill et al., 2005), which promotes bone formation. In the present study, serum insulin level was significantly elevated in the antipsychotic-treated patients, and their insulin levels were positively correlated with osteocalcin levels. We speculate that insulin directly affects osteocalcin levels via osteoblasts. Approximately 56% of Chinese schizophrenia patients are overweight or obese (Guo et al., 2013). By contrast, a previous study showed that high BMI is a protective factor against future fractures (Laet et al., 2005) and that BMI higher than 25 kg/m2 reduces the risk of fractures. In the present study, osteocalcin and β-CrossLaps negatively correlated with increasing BMI. This result is consistent with those obtained by Thomas et al. (2011), who found that osteocalcin and β-CTX significantly decrease with increasing BMI in men and premenopausal women but BMI is unrelated to osteocalcin in postmenopausal women. 5. Limitations Bone is a dynamic structure with a continuous tissue renewal process called remodeling, which is driven by the coordinated activities of osteoclasts, osteoblasts and osteocytes. Maintenance of bone mass is determined by the coupling of bone resorption to bone formation. However, this process is prone to imbalance due to factors such as drugs and calcium deficiency, which can easily increase the risk of fracture (Okamoto et al., 2010; Kunchur et al., 2009). In the present study, the patients treated with atypical antipsychotics had significantly higher level of β-CrossLaps. Since there are many kinds of bone turnover Table 4 Multiple linear regression analysis (stepwise) of independent predictive factors associated with β-CrossLaps in all subjects. Independent variables enter the model β-CrossLaps Group1 Group2 Age 3 Gender BMI Triglyceride HDL-C Glucose PRL TESTO Estradiol
β
Beta
t
0.153 0.327 −0.103 −0.085 −0.016 −0.046 −0.224 −0.049 5.083 0.019 −0.001
0.290 0.463 −0.190 −0.161 −0.174 −0.226 −0.301 −0.138 0.198 0.167 −0.018
4.149 b0.001 6.588 b0.001 −2.645 0.009 −2.543 0.012 −2.698 0.008 −2.963 0.003 −3.944 b0.001 −2.086 0.038 3.091 0.002 2.387 0.018 −2.612 0.01
P
markers for different aspects of bone metabolism, the levels of bone turnover markers in this study could not be considered “pathological” or indicative of a “recovering” bone. Future studies should further investigate this question in terms of bone mineral density and the levels of other bone turnover markers. 6. Conclusion We conducted a comprehensive study of the factors that may affect bone metabolism in patients treated with atypical antipsychotics for the first time. The bone resorption marker β-CrossLaps was found to be elevated in schizophrenia patients treated with atypical antipsychotics. Consistent with previous reports, this study found that bone turnover markers are related to several factors, including atypical antipsychotics and serum levels of PRL, sex hormones, BMI, glucose, lipids and insulin in schizophrenia patients and normal subjects. Thus, our findings suggest that atypical antipsychotics and secondary metabolic abnormalities might be related to bone metabolism. Funding This study was subsidized by National Natural Science Foundation of China (approve number: 81501163). Contributors Dr. Renrong Wu, Dr. Lehua Li, Dr. Jingping Zhao, and Dr. Jindong Chen designed the study, undertook the statistical analysis. Dr. Beibei Zhang recruited the participants, undertook the statistical analysis, and wrote the draft of the manuscript. Dr. Lu Deng, Dr. Haishan Wu, Dr. Xiaozi Lu recruited the participants. Mrs. Lihong Peng measured all of the samples. Conflict in interest None. Acknowledgment The authors are most grateful to the contributions of all of the doctors, nurses, technicians, and subjects that participated in this study.
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Relationship between long-term use of a typical antipsychotic medication by Chinese schizophrenia patients and the bone turnover markers serum osteocalcin and β-CrossLaps Beibei Zhang a,d, Lu Deng a,d, Haishan Wu a,d, Xiaozi Lu b, Lihong Peng c, Renrong Wu a,d, Wenbin Guo a,d, Jindong Chen a,d,⁎, Lehua Li a,d, Jingping Zhao a,d a
Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China Qingdao Mental Health Center, Qingdao, Shandong, 266034, China c Metabolic Endocrinology Institute of the Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China d Mental Health Institute of the Second Xiangya Hospital, Central South University, Chinese National Clinical Research Center on Mental Disorders (xiangya), Chinese National Technology Institute on Mental Disorders, Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, Hunan, 410011, China b
a r t i c l e
i n f o
Article history: Received 25 September 2015 Received in revised form 27 June 2016 Accepted 27 June 2016 Available online 2 July 2016 Keywords: Schizophrenia Antipsychotics Bone turnover Osteoporosis Lipid Glucose
a b s t r a c t Background: Increasing evidence shows that schizophrenia patients with long-term exposure to antipsychotic medications have decreased bone mass, which suggests that they are at a high risk of osteoporosis. However, the mechanism underlying this remains unclear. In this study, we selected two bone turnover markers to explore whether atypical antipsychotics can affect bone metabolism and identified possible influencing factors. Methods: A total of 116 schizophrenia patients (18–40 years old) participated in the study. The subjects included 31 drug-naive first-episode patients and 85 patients who had undergone atypical antipsychotic monotherapy for at least 6 months. A total of 71 subjects were assigned as normal controls. Demographic and physical examination data were analyzed for all subjects. The positive and negative syndrome scale (PANSS) was used to assess psychopathology in schizophrenia patients. Levels of the bone turnover markers osteocalcin and β-CrossLaps were measured. Serum prolactin (PRL), lipid, sex hormone, glucose, insulin, and parathyroid hormone levels were also measured. Results: The serum β-CrossLaps levels of patients who had been treated with atypical antipsychotics were higher compared with those of drug-naive first-episode patients and normal subjects. Atypical antipsychotics, schizophrenia, age, gender, and body mass index, as well as serum levels of PRL, triglyceride, high-density lipoprotein cholesterol, glucose, and testosterone, were significantly associated with serum osteocalcin and β-CrossLaps levels. Serum insulin was only positively associated with serum osteocalcin, whereas estradiol was only negatively associated with serum β-CrossLaps. Conclusion: Patients who had been treated with atypical antipsychotics had accelerated bone resorption. Our findings uncover a link between atypical antipsychotics and bone metabolism, possibly through abnormalities in glucose and lipid metabolism and insulin resistance. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Osteoporosis is a metabolic bone disorder characterized by osteopenia per unit volume and bone microstructure degeneration. Osteoporosis can promote bone fragility, and the condition is a risk factor for serious bone fractures. According to the World Health Organization, osteoporosis is second to cardiovascular disorders among diseases that endanger human health. Long-term use of antipsychotics increases the risk of osteoporosis and/or reduced bone mineral density (BMD), thereby increasing the risk of fractures (Halbreich et al., 2003).
⁎ Corresponding author. E-mail address: [email protected] (J. Chen).
http://dx.doi.org/10.1016/j.schres.2016.06.034 0920-9964/© 2016 Elsevier B.V. All rights reserved.
Conventional (typical) antipsychotic agents are nonselective in blocking dopamine pathways, which is mainly achieved by the tubero-infundibular system and easily leads to hyperprolactinemia. Previous studies showed that hyperprolactinemia affects bone metabolism by inhibiting the hypothalamo–pituitary–gonadal axis (Kishimoto et al., 2008; O'Keane, 2008). Elevated prolactin (PRL) is caused by antipsychotic agents and leads to hypogonadism (mainly because of lower estradiol levels), which may be related to lower BMD. For the moment, antipsychotic-induced metabolic abnormalities, such as weight gain, glucose dysregulation, dyslipidemia, and increased risk of metabolic syndrome, have gained much attention (Young et al., 2014). However, discrepancies exist among studies investigating the relationship between antipsychotic treatment and bone metabolism in schizophrenia patients. A possible reason is that bone metabolism may not only be
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related to the cumulative effects of long-term antipsychotic treatment, but also abnormalities in glucose and lipid metabolism caused by such treatments. Bone turnover markers can reflect the degree of bone formation and resorption, and also clearly predict ongoing growth trends in the bone. Therefore, bone turnover markers may be useful risk predictors of bone fractures that are independent of BMD (Garnero et al., 2000). Compared with BMD, bone turnover markers have higher sensitivity and can be detected in peripheral blood. Hence, we hypothesized that bone turnover markers may be more suitable for monitoring changes in the bone metabolism of schizophrenia patients. In this study, we selected two types of bone turnover markers, namely, osteocalcin and β-CrossLaps to explore the effects of antipsychotics on bone metabolism. We explored possible influencing factors underlying these effects, and investigated whether glucose dysregulation and dyslipidemia are related to bone metabolism.
metabolism, including PRL, sex hormone, insulin, and parathyroid hormone (PTH) levels. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose levels were measured using an automatic biochemical analyzer (7170A, Japan). 2.3. Statistical analysis All statistical analyses were performed with SPSS 17. One-way ANOVA was performed to compare demographic parameters and laboratory data. Data are presented as mean values with standard deviation. Multiple linear regression analysis with dummy variables was used to evaluate whether group and age are independent factors associated with the bone turnover markers osteocalcin and β-CrossLaps. Multiple-stepwise regression analysis was performed to assess possible risk predictors for osteocalcin and β-CrossLaps, including PRL, sex hormone, glucose, lipid, insulin, PTH, and body mass index (BMI).
2. Patients and methods 3. Results 2.1. Patients This study was approved by the hospital ethics committee and involved 116 Chinese outpatients or inpatients with schizophrenia between the ages of 18 and 40. Thirty-one of them were drug-naive first-episode patients, with an average age of 25.6 years (standard deviation, SD = 5.1 years). Eighty-five schizophrenia patients had undergone atypical antipsychotic monotherapy (olanzapine, risperidone) for at least 6 months, and their average age was 29.7 years (SD = 7.1 years). Written informed consent was obtained from all subjects. All patients were diagnosed in accordance with the diagnostic criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV). Seventy-one healthy subjects served as normal control, and their average age was 30.2 years (SD = 5.0 years). The following criteria were used for exclusion of potential participants: (1) patients with physical diseases, such as cardiopathy, chronic liver disease, and chronic kidney disease; (2) patients with metabolic diseases known to affect bone metabolism, such as diabetes mellitus and hyperthyroidism; (3) patients taking a mood stabilizer, antidepressant, or anxiolytic that can affect BMD in addition to the antipsychotics within 3 months; (4) patients with a history of hypogonadism (in males, testosterone b 10 nmol/L or b 3 ng/mL; in females, b6 menstrual cycles per year); (5) pregnant or lactating women; and (6) patients with a history of fracture within a year. 2.2. Methods All subjects completed an interview conducted by the researcher. Demographic data were collected for all subjects and included the following: smoking and drinking history, dietary habit, disease duration, administration dosage of atypical antipsychotics, and family history of fractures. Information regarding physical activity was collected through a structured, detailed, retrospective interview by taking into consideration all physical activities that occurred in the period the patient underwent therapy. Using this information, an index of activity (intensity × minutes × number of sports) was calculated. Physical examination was performed to measure the height, weight, and blood pressure of each participant. Actual schizophrenic symptoms were assessed via the positive and negative syndrome scale (PANSS). Blood samples were obtained from all the subjects between 7 AM and 9 AM. The samples were allowed to stand for 20 min at room temperature. All blood samples were centrifuged for 5 min (3500 rpm) in a table-top high-speed centrifuge to obtain 2 mL of serum. The following parameters were measured with an automatic electrochemical luminescence immunity analyzer (Cobase 601, Germany): osteocalcin, which is a bone formation marker; β-CrossLaps, which is a bone resorption marker; and laboratory parameters that may affect bone
3.1. Comparison of demographic and clinical characteristics between patients and controls The three groups showed no significant differences in average activity intensity, smoking, drinking, and positive subscale and total PANSS scores (Table 1). The antipsychotic treatment group showed significantly higher BMI values than the drug-naive first-episode group and controls (F = 3.360, p = 0.031). Compared with the antipsychotic treatment group and controls, the drug-naive first-episode group had significantly lower ages (F = 6.793, p = 0.001). 3.2. Comparison of laboratory results between patients and controls The laboratory results of the patients and normal subjects are presented in Table 2. The subjects showed no significant differences in LDL-C and PTH levels. Significantly different β-CrossLaps (F = 30.320, P b 0.001) and osteocalcin (F = 27.086, P b 0.001) levels were detected among the three groups. The drug-naive first-episode group and the antipsychotic treatment group demonstrated no significant difference in osteocalcin level (P = 0.094), while the controls had significantly lower osteocalcin values than the two other groups (PAC b 0.001, PBC b 0.001). The antipsychotic treatment group had significantly higher β-CrossLaps levels than the drug-naive first-episode group (P = 0.002) and the controls (P b 0.001). Serum levels of PRL and testosterone were significantly higher in the patients than in the normal subjects. The antipsychotic-treated patients had significantly higher levels of TG, TC, and glucose compared with the drug naive first-episode patients and normal subjects. HDL-C and estradiol levels were significantly lower in the schizophrenia patients than in the normal subjects. The antipsychotic-treated patients had higher insulin levels than the drug-naive first-episode patients and normal subjects. 3.3. Predictors of osteocalcin and β-CrossLaps in all subjects We utilized multiple linear regression analysis to identify predictors of osteocalcin (Table 3) and β-CrossLaps (Table 4) levels. Compared with the normal controls, groups 1 (antipsychotic-treated patients) and 2 (drug-naive first-episode patients) were associated with serum osteocalcin and β-CrossLaps. Serum osteocalcin was negatively associated with age groups 1 (26–30 years old) and 2 (31–40 years old) compared with patients aged 18–25 years old, whereas serum β-CrossLaps was only associated with age group 2. Gender, BMI, serum TG, HDL-C, glucose, PRL, and testosterone were associated with serum osteocalcin and β-CrossLaps. By contrast, serum insulin was only positively associated with serum osteocalcin, whereas estradiol was only negatively associated with serum β-CrossLaps.
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Table 1 Demographic parameters in the healthy controls, patients with schizophrenia treated with antipsychotic and drug-naïve patients with first- episode schizophrenia.a Characteristics
A first-episode drug naive (N = 31)
B antipsychotic treatment (N = 85)
C control (N = 71)
Statistic
p-value
Multiple comparisons
Age, mean (SD), y Women, no. (%) BMI, mean (SD) Index of activitya, mean (SD) Smoking, no. (%) Drinking, no. (%) PANNS score Positive subscale Negative subscale
25.6 (5.1) 16(51.6) 22.5(3.2) 15.3(5.0) 5 (16.1) 1(3.2) 87.6(12.5) 20.19(5.0) 22.5(5.2)
29.7 (7.1) 43(50) 23.8(3.4) 18.2 (4.9) 18 (21.2) 4(4.7) 84.7(22.0) 20.8(7.5) 19.5(7.7)
30.2 (5.0) 39(54.9) 22.8(1.7) 17.2(5.4) 12 (16.9) 5(7.0) – – –
F = 6.793 Chi = 0.383 F = 3.360 Chi = 1.476 Chi = 0.628 Chi = 0.748 F = 0.483 F = 0.253 F = 3.979
0.001 0.826 0.031 0.239 0.730 0.688 0.489 0.616 0.048
C,B N A – B N A,C – – – – – –
BMI = body mass index; PANSS = Positive and Negative Symptom Scale. a Index of activity = intensity × minutes × number of sports.
4. Discussion In the present study, the level of the bone resorption marker serum β-CrossLaps was significantly higher in antipsychotic-treated patients than in subjects from the two other groups (Table 2). Our results are in agreement with previous findings of Doknic et al. (2011), who found that C-terminal telopeptide of collagen type I (CTx) increases to the upper limit of the normal level in patients treated with injectable risperidone. Bishop et al. (2012) also reported that N-terminal telopeptide of collagen type I (NTx), another marker of bone resorption, changes during the acute phase of risperidone treatment. In the present study, we detected no difference in serum osteocalcin between the drug naive first-episode patients and the antipsychotic-treated patients. Compared with the normal controls, the patients that received or did not receive antipsychotic treatment had higher osteocalcin levels. However, a previous study (Doknic et al., 2011) showed that the osteocalcin level in patients treated with injectable risperidone was not obviously different compared with that in normal controls. By contrast, multiple stepwise regression analysis showed that antipsychotics and schizophrenia are related to serum osteocalcin. Therefore, we considered that schizophrenia and secondary metabolic disorders, which are caused by atypical antipsychotics, may be the influencing factors. Further longitudinal studies should be conducted to confirm this conclusion. The results of the present study showed that PRL level was higher in the drug-naive first-episode patients and antipsychotic-treated patients than in the normal controls (Fig. 2). PRL was positively associated with serum osteocalcin and β-CrossLaps. Abraham et al. (2003) reported a high rate of bone turnover in patients with high PRL levels but normal BMD. Fujimaki et al. (1994) also showed that bone formation and resorption are accelerated in 21 non-psychiatric women with hyperprolactinemia. Numerous reports have shown that hypogonadism, which is caused by elevated PRL, influences bone turnover in different sexes (Bruce et al., 2013). In the present study, serum osteocalcin for all subjects was only associated with testosterone,
whereas serum β-CrossLaps was associated with both E2 and testosterone. The use of antipsychotic medications is frequently associated with considerable increase in body weight (Meyer and Koro, 2004), which can lead to dyslipidemia. Consistent with this, a recent study has shown that schizophrenia patients may have a higher risk of developing dyslipidemia (Wu et al., 2013). Compared with healthy controls, drugnaive first-episode schizophrenia patients had lower TC and HDL-C. Our results showed that the antipsychotic-treated patients had higher TG and TC levels than the drug-naive first-episode schizophrenia patients; however, no difference in HDL-C level was observed between the two groups. To examine the predictors of bone metabolism, we found that TG and HDL-C were negatively associated with osteocalcin and β-CrossLaps. Zhou et al. (2009) found negative correlation between serum osteocalcin and HDL-C in men, but positive correlation between TG and osteocalcin in premenopausal women. Majima et al. (2008) studied 281 subjects (aged 18–89 years old) with untreated hypercholesterolemia and found that NTx is significantly negatively correlated with HDL-C. Jeong et al. (2014) showed that TC concentration positively correlates with serum CTX and osteocalcin in premenopausal women. Similarly, LDL-C can promote osteoclastic differentiation in vitro (Majima et al., 2008). However, we found no correlation among TC, LDL-C, osteocalcin and β-CrossLaps. Further longitudinal studies are required to determine whether TC and LDL-C are risk predictors for bone metabolism. Antipsychotics can elevate plasma glucose levels in schizophrenia patients, among whom the prevalence of type 2 diabetes mellitus is as high as 28% (Young et al., 2014). In the present study, the fasting glucose level was higher in the patients treated with antipsychotics than in the other patients. Elevated glucose levels can affect bone metabolism. A recent meta-analysis based on 22 studies has reported lower serum osteocalcin and CTX levels in both T1D and T2D compared with their controls (Starup-Linde et al., 2014). Henriksen et al. (2003) and Chailurkit et al. (2008) reported that the percentage of change in βCTX after oral glucose administration in healthy individuals was 50%.
Table 2 Laboratory date in the healthy controls, patients with schizophrenia treated with antipsychotic and drug-naïve patients with first- episode schizophrenia, mean (SD). Variables
A first-episode (N = 31)
B antipsychotic treatment (N = 85)
C control (N = 71)
Statistic
p-value
Multiple comparisons
Prolactin, ng/mL Triglyceride, mmol/L TC, mmol/L HDL-C, mmol/L LDL-C, mmol/L Estradiol, pg/ml Testosterone, nmol/l Glucose, mmol/L Insulin, μIU/mL PTH, pg/mL Osteocalcin, ng/ml β-CrossLaps, ng/ml
51.30(43.29) 1.05(0.65) 4.01(0.76) 1.19(0.33) 2.46(0.72) 47.61(40.26) 2.45(2.36) 4.67(0.47) 10.32(7.27) 34.65(15.68) 25.37(10.46) 0.52(0.28)
66.87(53.81) 1.89(1.69) 4.23(0.85) 1.10(0.33) 2.34(0.71) 60.46(45.78) 1.78(1.72) 5.09(0.91) 21.81(19.26) 41.26(19.38) 24.05(9.81) 0.69(0.24)
20.04(10.76) 0.92(0.42) 4.18(0.66) 1.41(0.30) 2.61(0.71) 128.75(90.1) 1.23(1.28) 4.61(0.48) 7.52(3.75) 34.12(14.59) 15.17(4.64) 0.32(0.12)
F = 15.09 F = 14.12 F = 4.919 F = 16.979 F = 2.655 F = 23.747 F = 5.611 F = 8.789 F = 16.534 F = 3.868 F = 27.086 F = 30.320
b0.001 b0.001 0.008 b0.001 0.919 b0.001 0.004 b0.001 b0.001 0.220 b0.001 b0.001
A,B N C B N A,C B N A,C C N A,B – C N A,B A,B N C B N A,C BNANC – A,B N C BNANC
TC = total cholesterol; HDL-C = high density lipoprotein cholesterol; LDL-C = low density lipoprotein cholesterol; PTH = parathyroid hormone.
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Table 3 Multiple linear regression analysis (stepwise) of independent predictive factors associated with osteocalcin in all subjects. Independent variables enter the model Osteocalcin Group1 Group2 Age 1 Age 2 Gender BMI Triglyceride HDL-C Glucose Insulin PRL Testosterone
β
Beta
t
P
7.472 7.983 −3.478 −4.866 −4.373 −0.536 −1.353 −5.567 −2.531 0.190 0.002 1.391
0.394 0.315 −0.161 −0.249 −0.229 −0.172 −0.184 −0.208 −0.198 0.348 0.214 0.341
5.766 4.570 −2.330 −3.549 −3.701 −2.609 −2.145 −2.705 −2.398 3.790 3.313 4.975
b0.001 b0.001 0.021 b0.001 b0.001 0.01 0.033 0.007 0.018 b0.001 0.001 b0.001
The present study also found that elevated fasting glucose was caused by antipsychotics and associated with decreased serum osteocalcin and β-CrossLaps. In addition to glucose, bone turnover markers can also be affected through insulin-based mechanisms. Insulin affects bone metabolism mainly through the insulin signaling pathway within osteoblasts (Pramojanee et al., 2014). Insulin can stimulate mitogen in osteoblasts to increase osteocalcin secretion, which is coupled with inhibition of apoptosis (Thrailkill et al., 2005), which promotes bone formation. In the present study, serum insulin level was significantly elevated in the antipsychotic-treated patients, and their insulin levels were positively correlated with osteocalcin levels. We speculate that insulin directly affects osteocalcin levels via osteoblasts. Approximately 56% of Chinese schizophrenia patients are overweight or obese (Guo et al., 2013). By contrast, a previous study showed that high BMI is a protective factor against future fractures (Laet et al., 2005) and that BMI higher than 25 kg/m2 reduces the risk of fractures. In the present study, osteocalcin and β-CrossLaps negatively correlated with increasing BMI. This result is consistent with those obtained by Thomas et al. (2011), who found that osteocalcin and β-CTX significantly decrease with increasing BMI in men and premenopausal women but BMI is unrelated to osteocalcin in postmenopausal women. 5. Limitations Bone is a dynamic structure with a continuous tissue renewal process called remodeling, which is driven by the coordinated activities of osteoclasts, osteoblasts and osteocytes. Maintenance of bone mass is determined by the coupling of bone resorption to bone formation. However, this process is prone to imbalance due to factors such as drugs and calcium deficiency, which can easily increase the risk of fracture (Okamoto et al., 2010; Kunchur et al., 2009). In the present study, the patients treated with atypical antipsychotics had significantly higher level of β-CrossLaps. Since there are many kinds of bone turnover Table 4 Multiple linear regression analysis (stepwise) of independent predictive factors associated with β-CrossLaps in all subjects. Independent variables enter the model β-CrossLaps Group1 Group2 Age 3 Gender BMI Triglyceride HDL-C Glucose PRL TESTO Estradiol
β
Beta
t
0.153 0.327 −0.103 −0.085 −0.016 −0.046 −0.224 −0.049 5.083 0.019 −0.001
0.290 0.463 −0.190 −0.161 −0.174 −0.226 −0.301 −0.138 0.198 0.167 −0.018
4.149 b0.001 6.588 b0.001 −2.645 0.009 −2.543 0.012 −2.698 0.008 −2.963 0.003 −3.944 b0.001 −2.086 0.038 3.091 0.002 2.387 0.018 −2.612 0.01
P
markers for different aspects of bone metabolism, the levels of bone turnover markers in this study could not be considered “pathological” or indicative of a “recovering” bone. Future studies should further investigate this question in terms of bone mineral density and the levels of other bone turnover markers. 6. Conclusion We conducted a comprehensive study of the factors that may affect bone metabolism in patients treated with atypical antipsychotics for the first time. The bone resorption marker β-CrossLaps was found to be elevated in schizophrenia patients treated with atypical antipsychotics. Consistent with previous reports, this study found that bone turnover markers are related to several factors, including atypical antipsychotics and serum levels of PRL, sex hormones, BMI, glucose, lipids and insulin in schizophrenia patients and normal subjects. Thus, our findings suggest that atypical antipsychotics and secondary metabolic abnormalities might be related to bone metabolism. Funding This study was subsidized by National Natural Science Foundation of China (approve number: 81501163). Contributors Dr. Renrong Wu, Dr. Lehua Li, Dr. Jingping Zhao, and Dr. Jindong Chen designed the study, undertook the statistical analysis. Dr. Beibei Zhang recruited the participants, undertook the statistical analysis, and wrote the draft of the manuscript. Dr. Lu Deng, Dr. Haishan Wu, Dr. Xiaozi Lu recruited the participants. Mrs. Lihong Peng measured all of the samples. Conflict in interest None. Acknowledgment The authors are most grateful to the contributions of all of the doctors, nurses, technicians, and subjects that participated in this study.
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