Beaumont Hospital, Dublin, Ireland
The Maudsley Hospital, London
Anatomy Department, Trinity College, Dublin, Ireland
Division of Psychological Medicine, Institute of Psychiatry, London
Division of Psychological Medicine, Institute of Psychiatry, London
Correspondence: Veronica OKeane, Division of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK. Tel: +44 (0)207 8480212; fax: +44 (0)207 8376982; e-mail: v.o'keane{at}iop.kcl.ac.uk
Declaration of interest Work supported by an unrestricted educational research grant from Eli-Lilly, Ireland.
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ABSTRACT |
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Aims To examine bone mineral density in relation to relevant endocrine variables in patients with schizophrenia taking prolactin-raising antipsychotics.
Method Fifty-five patients who had been receiving prolactin-raising antipsychotic medication for >10 years underwent dual-energy X-ray absorptiometry of their lumbar and hip bones. Among the endocrine variables assessed were plasma prolactin and sex hormones.
Results Age-related reduced bone mineral density measures were found in 17 (57%) of the male and 8 (32%) of the female patients. Higher doses of the female patients. Higher doses of medication were associated with increased rates of both hyperprolactinaemia and bone mineral density loss. Bone loss for the whole group was correlated with medication dose, and for men was inversely correlated with testosterone values.
Conclusions These results suggest that patients with schizophrenia on long-term prolactin-raising antipsychotic medication are at high risk of developing reduced bone mineral density as a consequence of hyperprolactinaemia-induced hypogonadism.
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INTRODUCTION |
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METHOD |
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Clinical assessment
Clinical assessment included a semi-structured clinical interview with
resultant DSMIV diagnoses (American
Psychiatric Association, 1994). Illness severity was measured
using the Brief Psychiatric Rating Scale (BPRS;
Overall & Gorham, 1962) and the Schedule for Assessment of Negative Symptoms (SANS;
Andreason, 1983). A medical
history was obtained detailing relevant information, such as a history of
fractures or polydipsia. Each participant had a full physical examination,
including body mass index evaluation.
A detailed drug history was recorded. In order to have a comparable value for each patient, medication was converted to chlorpromazine equivalents (Taylor et al, 2001). The atypical antipsychotics olanzapine and risperidone were converted according to the best pharmacological match for dopamine 2 receptor blockade to typicals: clozapine and haloperidol, respectively (Seeman, 1992). A modified version of an osteoporosis questionnaire was completed for each participant. This questionnaire examines information relevant to bone mineral density, such as family history, parity, dietary and weight-bearing exercise habits.
Endocrine assessment
A blood sample was drawn from each patient to measure oestradiol,
progesterone, testosterone, follicle-stimulating hormone, luteinising hormone
and sex hormone binding globulin (a marker of gonadal hormone concentrations).
Plasma prolactin, cortisol, thyroid-stimulating hormone, thyroxine and
triiodothyronine were also measured in each patient. Samples were collected at
random times during the day (09.0018.00 h), spun within 1 hour and the
frozen serum/plasma was batch analysed. Blood sampling was not related to the
timing of meals.
Prolactin, oestradiol, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and thyroxine levels were measured using time-resolved fluoroimmunoassays methods with commercial kits (AutoDELFIA, PerkinElmer, Inc.: human hormone references supplied by Wallac Oy, Turku, Finland). Progesterone, testosterone and sex-hormone-binding globulin were measured using radioimmunoassay kits (17x-Hydroxyprogesterone 125I RIA Kit, Testosterone 125I RIA and Sex Binding Globulin 125I Immunoradiometric Assay Kit supplied by ICN Pharmaceuticals).
Bone mineral density assessment
Osteoporosis is defined by the World Health Organization as a bone mineral
density of more than 2.5 standard deviations below the mean value for peak
bone mass in young adults when measured by dual-energy X-ray absorptiometry
(DEXA) (World Health Organization Study
Group, 1994). The bone mineral density was determined in lumbar
vertebrae L1L4 and in the femoral neck, trochanteric and
intertrochanteric regions of the left hip using a DEXA scan, which is
currently the most precise and widely used method of assessing bone mineral
density. Bone density is measured in relation to two sets of values generated
by the DEXA scanner: t scores compare the patients results
with standardised peak bone mass of females/males 2030 years old; and
Z scores compare the bone mineral density with the average for
her/his age group. Only Z scores are reported in this paper.
Statistical analysis
The SPSS for Windows (1999 version) was used to analyse the data. Results
were analysed both for the whole group and separately for each gender.
Independent t-tests (two-tailed) were used to identify differences
between groups, and cross-tabulations were performed using 2
analyses when appropriate. Multiple regression analyses were performed to
examine associations between the multiple variables hypothesised to be
correlated with bone mineral density. Results are expressed as means and
standard deviations.
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RESULTS |
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Clinical data
No associations were found between bone mineral density values and clinical
measures of psychiatric illness (BPRS or SANS), or the presence of polydipsia.
Among the lifestyle variables, only cigarette smoking was significantly
correlated with reduced Z scores in L4 for the combined group
(r=-0.27, P=0.04).
Endocrine data (see Table 2)
Both gender groups had a mean prolactin level of approximately three times
the upper limit of normal, with no gender or ethnicity differences in mean
values between groups. Hyperprolactinaemia was present in 62% of the overall
group (18 (60%) of males and 16 (64%) of females) and the mean dose of
medication was higher in those who were hyperprolactinaemic (602 (s.d.=477)
mg/day) compared with those who were normoprolactinae normoprolactinaemic (267
(s.d.=336) mg/day: t=2.8, d.f.=53, P<0.01).
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Medication (see Table 3)
Within the total group, 17 (31%) were receiving more than one antipsychotic
agent. All patients taking the prolactin-sparing antipsychotic olanzapine were
also on a conventional depot antipsychotic drug. Participants were divided
into two groups: those receiving more than the upper limit of the British
National Formulary range for usual maintenance dose of
chlorpromazine (300 mg/day) and those receiving less than this. There were no
significant differences between these groups in terms of age, gender,
treatment duration, lifestyle variables or scores on clinical rating
scales.
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Significantly more patients had hyperprolactinaemia and bone loss in the
high-compared with the low-dose group: 20 (81%) v. 11 (45%) for
hyperprolactinaemia (2=7.505, d.f.=1, P<0.01) and
15 (62%) v. 7 (27%) for bone loss (
2=6.42, d.f.=1,
P=0.01), respectively. Similarly, patients in the high-compared with
the low-dose group had significantly more severely reduced bone mineral
density scores (<2 s.d. below normative data): 9 (35%) and 3 (11.5%),
respectively (
2=4.73, P=0.03).
Bone mass density measures
Overall, 17 (57%) of the men and 8 (32%) of the women had reduced bone
mineral density values on at least one bone measure.
Correlational measures
Hormone levels and bone mineral density
The free testosterone index (testosterone/sex-hormone-binding globulin) was
correlated with the bone mineral density Z summary lumbar score (see
Fig. 1). The summary lumbar
score is a DEXA-generated calculation of bone mineral density scores from L1
to L4 for each individual, and thus reflects the total bone density in the
lumbar spine. This correlation was not found in the hip region. There was no
statistical relationship between prolactin, follicle-stimulating hormone,
luteinising hormone, oestradiol, progesterone or thyroid hormones and bone
mineral density values.
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Chlorpromazine equivalents and bone mineral density (see Table 4 and Fig. 2)
There was a significant correlation between chlorpromazine equivalence
scores and both lumbar-weighted scores (r=0.4, P=0.002) and
combined lumbar- and hip-weighted scores (r=0.35,
P=0.009).
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Multivariate regression analysis
In a multivariate regression analysis for both genders combined examining
clinical, endocrine and lifestyle variables, only the chlorpromazine
equivalence scores were statistically predictive of reduced bone mineral
density scores at L1L4 (P<0.0001). When genders were
analysed separately, no further factors were predictive of bone mineral
density loss in females. In the male group the free testosterone index was
also predictive of low bone mineral density in L1L4 (P=0.03);
and sex-hormone-binding globulin almost reached significance as a predictive
value (P=0.06).
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DISCUSSION |
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The findings of associations between chlorpromazine equivalents scores and both prolactin levels and low bone mineral density values is novel. Antipsychotic medication blocks the type 2 dopamine (D2) receptors on the lactotrophs of the anterior pituitary, thus releasing these cells from dopamine inhibition and consequently suppression of prolactin secretion (Dickson et al, 2000). One positron emission tomography study has demonstrated that hyperprolactinaemia is likely to occur when central D2 receptor occupancy exceeds 72% (Kapur et al, 2000). This physiological process may underlie the strong statistical relationship between chlorpromazine equivalence scores and prolactin levels. Any potent D2-blocking antipsychotic, whether typical or atypical, is likely to cause prolactin secretion and thus all patients in this study taking the antipsychotic risperidone had hyperprolactinaemia, in keeping with the established prolactin-raising profile of this drug (Kinon et al, 2003).
Bone strength is largely determined by calcium content and rate of bone loss, which in turn is determined by genetic factors, weight, ethnicity, diet, exercise, hormone status and gender (Hobson & Ealston, 2001). Although the physiological processes mediating bone loss are complicated, the most common cause of bone loss is sex hormone deficiency (Schlecter et al, 1983; Davies et al, 1995). The bone loss associated with hyperprolactinaemic states, whether prolactin is elevated pathologically or physiologically, is probably mediated by secondary hypogonadism, although other mechanisms have been proposed (see Wieck & Haddad, 2003). Prolactin interferes with the pulsatile secretion of gonadotrophin-releasing hormone from the hypothalamus and may also have a peripheral effect at the level of the gonads, inhibiting some luteinising hormone- and follicle-stimulating hormone-mediated effects.
The association of low free testosterone index with osteoporosis in this study supports hyperprolactinaemic-induced hypogonadism as being the relevant pathological process in the male patients because the association was present in males only in the gender-specific multivariate regression analysis. Free testosterone index values represent the biologically active, or unbound, part of the circulating testosterone. Bone loss was associated with the free testosterone index in the lumbar spine region only, and not the hip joint. The absence of bone loss in the hip joint in this relatively young male sample is in keeping with the fact that bone loss typically first occurs in the spine region (in 92% of individuals).
The female group was post-menopausal and thus uniformly hypogonadal, preventing an a priori hypothesis of an association between gonadal status and bone measures to be tested. A previous study by our group found that 75% (n=15) of a group of premenopausal females with a diagnosis of schizophrenia on prolactin-raising antipsychotics were hyperprolactinaemic and high prolactin levels were negatively correlated with both oestradiol and progesterone levels (Smith et al, 2002). A recently published study has also reported associations between high prolactin levels and low key reproductive hormone levels in males and females on antipsychotic medication (Kinon et al, 2003).
Osteoporosis and schizophrenia
Decreased bone mineral density in psychiatric patients has been recognised
for some time but only recently investigated. Cases of osteoporosis have been
reported in women and men with anorexia nervosa, chronic alcoholism,
depression and schizophrenia (Delva et
al, 1989; Abraham et
al, 1995; Halbreich et
al, 1995). Halbreich et al
(1995) reported that patients,
particularly males with major depressive disorder, schizophrenia,
schizoaffective disorders, mania and adjustment disorders, had significantly
decreased bone mineral density. Original reports of osteoporosis in people
with schizophrenia suggested an association with polydipsia
(Delva et al, 1989)
but we found no correlation between polydipsia and reduced bone mineral
density. Bilici et al
(2002) reported increased rates
of reduced lumbar spine bone mineral density scores in a group of patients
with schizophrenia taking classical antipsychotic medication
compared with a group on atypical antipsychotics and a healthy control group.
That study did not examine relative prolactin levels in the groups but all the
patients in the classical antipsychotic group were on
prolactin-raising agents, whereas 38% in the atypical group (n=15)
were on prolactin-sparing agents. Previous studies have not specifically
addressed a possible association between osteoporosis and
antipsychotic-induced hyperprolactinaemia, but more recent reviews have
focused on the possibility of such a relationship
(Naidoo et al, 2003;
Wieck & Haddad, 2003).
Other established risk factors, such as high alcohol intake and cigarette smoking, could possibly account for the high rates of osteopenia/osteoporosis found in this sample with schizophrenia. We did find a correlation between bone mineral density scores in the lumbar spine and smoking, but this significance was lost in the multivariate analysis, suggesting that the medication-related risk factors were more significant. There was no association between alcohol intake and any of the bone measures. Immobility is an unlikely cause of reduced bone mineral density even in individuals with negative symptoms of schizophrenia because activity levels involved in routine daily living are sufficient to retard bone mineral density loss in weight-bearing bones. It is unknown to what degree decreased exposure to sunshine and dietary deficiency contribute to reduced bone mineral density in patients with chronic mental illnesses, but all participants in our study indicated on the osteoporosis questionnaire that they had adequate intake of calcium in their diet. Low body mass index is another established risk factor for bone mineral loss, but all participants in this study were overweight with a mean body mass index bordering on obese.
It is conceivable that bone loss found in these people may be related to a metabolic disorder that is part of the syndrome of schizophrenia rather than the endocrine consequences of antipsychotic medication. This is unlikely, given the findings of significant associations between bone loss measures and medication and endocrine variables, and the absence of associations between clinical symptom scores and bone mineral density measures.
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Osteoporosis: morbidity and mortality |
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The absence of evidence associating prolactin-raising antipsychotic drug use with bone loss may explain why drugs such as glucocorticoids, lithium, anticonvulsants, thyroxine and gonadotrophin-releasing hormone antagonists are listed by the World Health Organization and the Royal College of Physicians as being associated with the development of osteoporosis but antipsychotic drugs are not (World Health Organization Study Group, 1994).
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Limitations of this study |
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A potential limitation of the study was the collection of blood samples at random times during working hours, given that the secretion of prolactin is subject to a diurnal rhythm. This is not important, however, in the context of either low- or high-grade hyperprolactinaemia because the diurnal rhythm is largely obliterated in both states (Veldman et al, 2001). In states of normal prolactin secretion, the nocturnal surge accounts for the diurnal variation and levels between 09.00 h and 24.00 h are generally stable.
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Clinical Implications and Limitations |
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LIMITATIONS
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REFERENCES |
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American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM - IV) . Washington, DC: APA.
Andreason, N. (1983) Scale for Assessment of Negative Symptoms (SANS). Iowa City, IA: University of Iowa.
Bilici, M., Cakirbay, H., Guler, M., et al (2002) Classical and atypical neuroleptics, and bone mineral density, in patients with schizophrenia. International Journal of Neuroscience, 112, 817 -828.[CrossRef][Medline]
Davies, M. C., Gulekli, B. & Jacobs, H. S. (1995) Osteoporosis in Turners syndrome and other forms of primary amenorrhoea. Clinical Endocrinology (Oxford), 43, 741 -745.[Medline]
Delva, N., Crammer, J. L., Jarzylo, S. V., et al (1989) Osteopenia, pathological fractures, and increased calcium excretion in schizophrenic patients with polydipsia. Biological Psychiatry, 26, 781 -793.[CrossRef][Medline]
Dickson, R., Seeman, M. & Corenblum, B. (2000) Hormonal side effects in women: typical versus atypical antipsychotic treatment. Journal of Clinical Psychiatry, 61 (suppl. 3), 10 -15.[Medline]
Halbreich, U., Rojansky, N., Palter, S., et al (1995) Decreased bone mineral density in medicated psychiatric patients. Psychosomatic Medicine, 57, 485 -491.[Abstract]
Hobson, E. E. & Ealston, S. H. (2001) Role of genetic factors in the pathophysiology and management of osteoporosis. Clinical Endocrinology (Oxford), 54, 1-9.[CrossRef][Medline]
Kapur, S., Zipursky, R., Jones, C., et al
(2000) Relationship between dopamine D(2) occupancy, clinical
response, and side effects: a double-blind PET study of first-episode
schizophrenia. American Journal of Psychiatry,
157, 514
-520.
Kinon, B. J., Gilmore, J. A., Liu, H., et al (2003) Prevalence of hyperprolactinaemia in schizophrenic patients treated with conventional antipsychotic medication or risperidone. Psychoneuroendocrinology, 28, 55-68.
Naidoo, U., Goff, D. C. & Klibanski, A. (2003) Hyperprolactinemia and bone mineral density: the potential impact of antipsychotic agents. Psychoneuroendocrinology, 28 (suppl. 2), 97 -108.[CrossRef][Medline]
Overall, J. E. & Gorham, D. R. (1962) The Brief Psychiatric Rating Scale. Psychological Reports, 10, 799 -812.
Schlecter, J. A., Sherman, B. & Martin, R. (1983) Bone density in amenorrheic women with and without hyperprolactinaemia. Journal of Clinical Endocrinology and Metabolism, 56, 1120 -1123.[Abstract]
Seeman, P. (1992) Dopamine receptor sequences: therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology, 7, 261-284.[Medline]
Smith, S., Wheeler, M., Murray, R., et al (2002) The effects of anti-psychotic induced hyperprolactinaemia on the hypothalamic-pituitary-gonadal axis. Journal of Clinical Psychopharmacology, 22, 109 -114.[CrossRef][Medline]
Taylor, D., McConnell, H., McConnell, D., et al (2001) The Maudsley 2001 Prescribing Guidelines (6th edn). London: Martin Dunitz.
Veldman, R. G., Frolich, M., Pincus, S. M., et al
(2001) Basal, pulsatile, entropic and 24-hour features of
secondary hyperprolactinaemia due to functional pituitary stalk disconnection
mimic tumoral (primary) hyperprolactinaemia. Journal of Clinical
Endocrinology and Metabolism, 86, 1562
-1567.
Wieck, A. & Haddad, P. M. (2003)
Antipsychotic-induced hyperprolactinaemia in women: pathophysiology, severity
and consequences. Selective literature review. British Journal of
Psychiatry, 182, 199
-204.
World Health Organization Study Group (1994) Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis. Report of a WHO Study Group. WHO Technical Report Series no. 843, pp. 1-12. Geneva: WHO.
Received for publication September 10, 2003. Revision received January 19, 2004. Accepted for publication February 1, 2004.
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