Introduction
Osteoporosis is a progressive disease characterised by a marked loss as well as a change in the microstructure of bone tissue, resulting in a weakening of the skeletal structure [
1]. Its precursor, osteopenia, although not a disease category in itself, also carries an increased risk of fracture [
1]. Worldwide, 200 million people are estimated to have osteoporosis [
2]. The fragility fractures commonly resulting from this condition are associated with an increase in morbidity and mortality, as well as a decrease in overall quality of life [
3]. People with schizophrenia experience poorer general health outcomes than the general population, including an increased risk of osteoporosis [
4••]. The mechanism underlying reduced bone mineral density (BMD) in schizophrenia is not yet clear, and links have been made to lifestyle factors as well as the side-effects of antipsychotic medication [
5,
6]. Nonetheless, people with schizophrenia are at increased risk of fractures [
7] and in particular hip fractures [
8•], which are associated with considerable morbidity and mortality.
It has been suggested that antipsychotic-induced hyperprolactinaemia (defined as a serum PRL >24 ng/ml for females and a level >20 ng/ml for males) could play a role in the development of reduced BMD in people with schizophrenia [
9]. Other risk factors for osteoporosis such as smoking, excessive alcohol consumption, lack of physical activity, diabetes and vitamin D deficiency are also more prevalent in people suffering from psychotic illnesses [
10,
11•] and likely contribute to the development of osteoporosis in this patient group.
A recent meta-analysis demonstrated that over half (51.7 %) of people with schizophrenia have low BMD equating to an almost threefold increased risk versus healthy controls (odds ratio (OR) = 2.86, CI = 1.27–6.42,
p = 0.01 [
4••]). This increased prevalence of osteoporosis and osteopenia in patients with schizophrenia is of particular concern because of their increased risk of falls [
12] and fractures, which can have a serious negative impact on the patient’s mental state [
4••]. Patients with schizophrenia have a longer recovery time after hip fracture, spending on average 11 days more in hospital compared with those with no mental health conditions [
13••] and are at a greater risk of adverse events such as postoperative infection, deterioration of mental state and renal failure [
13••]. The time to full rehabilitation is also increased, with ambulatory rates below average after 1 year [
14]. A recent meta-analysis [
15] demonstrated that people with schizophrenia have reduced BMD, but the authors did not investigate skeletal site-specific differences in BMD and instead pooled all skeletal site results together. Given the particularly serious adverse events following hip fracture, understanding if site-specific differences in BMD exist is important and currently lacking in the literature.
Given the aforementioned gaps within the literature, we conducted a large-scale systematic review and meta-analysis to investigate differences between skeletal sites (e.g. hip, lumbar spine) affected by osteoporosis and osteopenia in people with schizophrenia versus healthy controls. In addition, we sought to identify potential moderators of reduced BMD at skeletal sites in schizophrenia, including gender, age, smoking, prolactin (PRL) levels and body mass index (BMI).
Discussion
To the authors’ knowledge, this is the first meta-analysis to investigate reduced bone mineral density in people with schizophrenia at different skeletal sites. Data from our meta-analysis found a significantly reduced BMD at both the lumbar spine and hip in patients with schizophrenia, with the lumbar spine showing the most marked decrease in BMD, with a large adjusted effect size. The lumbar spine shows reduced BMD in a younger patient cohort before the onset of osteopenia at other skeletal sites. This difference in BMD between skeletal sites may indicate that the lumbar spine is a better site at which to carry out screening for osteoporosis in patients with schizophrenia. Our meta-regression analysis suggests that hyperprolactinaemia and smoking are associated with reduced lumbar spine BMD in people with schizophrenia. In addition, increasing age was associated with greater hip BMD loss.
Fractures of the vertebrae are associated with pain and disability in addition to reduced quality of life and functioning in the general population [
48]. Our results demonstrate that people with schizophrenia may be particularly at risk of vertebral fractures, the principle symptom of which is pain [
49•]. People with schizophrenia have greatly reduced pain sensitivity [
50] meaning that in clinical practice, patients with a vertebral fracture may be less likely to report symptoms. Given this fact and the heightened risk of vertebral fractures, clinicians should be diligent in their assessment of back pain in people with schizophrenia and an observed thoracic kyphosis may be a possible indicator of fracture in this population [
51].
People with schizophrenia experience a higher mortality, longer hospital stays and poorer recovery of mobility following a hip fracture, as well as a negative impact on mental state caused by hospitalisation [
4••]. The presence of reduced BMD at the hip in patients with schizophrenia is of particular concern because of the more severe clinical implications of fracture for this patient group compared with patients without a history of mental illness. Considering the greatly increased risk of fracture for these patients [
7], it may be advisable to introduce a screening programme to monitor bone health and thus improve general health outcomes in this patient population.
Meta-regression analysis of moderators of low bone mass highlighted smoking as a risk factor for reduced BMD at the lumbar spine (Table
2). People with schizophrenia have high rates of smoking with higher cigarette consumption amongst those who smoke [
52,
53], factors which can contribute to the development of osteoporosis [
54,
55•]. The effects of smoking on BMD found in this study further indicate the need to develop effective interventions for smoking cessation amongst those with schizophrenia.
Antipsychotic medication was identified as a risk factor for osteoporosis in the narrative review, with PRL-raising antipsychotics having a larger impact on bone health than PRL-sparing medication. Of the four studies included in this review, investigating PRL alongside BMD, all found elevated levels of PRL in at least one patient group [
21,
22,
35,
39]. Two of the four studies [
21,
35] investigated patients on monotherapy with PRL-raising or PRL-sparing antipsychotics and found higher PRL levels in the PRL-raising group. However, it is important to note that these studies were not carried out in treatment-naïve patients and so previous treatment with a range of antipsychotics may have already had an impact on bone health.
Schizophrenia is usually diagnosed between the ages of 16 and 30, at which point peak bone mass has yet to be achieved [
56]. When administered to such a young patient group, PRL-raising medications may prevent an optimum peak bone mass from being achieved, thus reducing lifelong BMD and predisposing patients to osteoporosis. Our study findings should be viewed in relation to the recognition that sustained hyperprolactinaemia can have longer term adverse bone effects, including increasing the risk for osteoporotic fractures [
7]. This is in addition to other established risks to bone health such as low vitamin D, commonly seen in psychosis [
10,
11•]. Our findings that hyperprolactinaemia is associated with reduced BMD in schizophrenia provides additional support and impetus for the inclusion of regular PRL monitoring in guidelines for physical health monitoring in those with schizophrenia.
The mean age of the schizophrenia cohort in our study was 34 years, with only one study [
38] measuring BMD in a patient group older than 50. Osteoporosis is a disease of the older population, most commonly seen in postmenopausal women and men over 65 [
3]. The presence of reduced BMD in such a young population as identified in our study is concerning, particularly because of the scale of the BMD loss, which was above 50 %, even with the exclusion of the Jung et al. study [
38]. Current UK guidelines suggest assessment of fracture risk in men over 50 and postmenopausal women, and treatment only of high-risk groups above that age [
57]. Our study findings indicate that those with schizophrenia are at an increased risk of reduced BMD and suggest that a diagnosis of schizophrenia should be considered alongside other well-validated risk factors for reduced BMD, to improve fracture prognostication in this population, and prompting a lower threshold for the initiation of treatment in this population with increased fracture risk.
For patients younger than this age threshold, it is unlikely that medical intervention to prevent fractures would be considered. It may be necessary to adapt guidelines to manage the risk of osteoporosis in people with schizophrenia, perhaps by introducing a modified
T-score as a threshold for medical intervention regardless of age. Careful assessment for modifiable risk factors for the development of osteoporosis in schizophrenia such as smoking, hyperprolactinaemia, and vitamin D deficiency, and appropriate treatment interventions should be more fully incorporated into the care of schizophrenia patients. Advice on weight-bearing exercise, calcium and vitamin D intake and smoking cessation should be provided to patients. For individuals with hyperprolactinaemia, consideration of dose reduction or a switch to an antipsychotic with a lower risk of causing hyperprolactinaemia should be made, if clinically safe to do so. If the risk of psychotic relapse is high, then consideration for an addition of aripiprazole to the antipsychotic treatment could be made, as its use has been associated with attenuation of PRL levels [
58].
Limitations
It is necessary to acknowledge the limitations of both the primary data and our meta-analysis. Firstly, due to lack of information, we could not investigate the effects of specific antipsychotic medications on BMD. Few studies separated patients by type of antipsychotic and only two consistently reported the dose used. Although several studies separated subgroups into PRL-raising/PRL-sparing or FGA/SGA subgroups and some provided details of the antipsychotics used, these classifications can overlap in individual antipsychotic effect on PRL, and the potential effects on BMD could be unclear. Further, the lack of information on lifetime antipsychotic use is a major limitation in our ability to examine the enduring effects of antipsychotic use on BMD. Second, the mean age of this patient group was 34 years with little inclusion of older patients, which is not representative of the general patient population. Thirdly, all but one of the studies were cross-sectional in design, with only one [
33] investigating BMD in treatment-naïve people with schizophrenia. More studies of this kind may help identify risk factors without the confounding influence of antipsychotic medication. Finally, there was considerable heterogeneity and/or absence in reporting data for risk factors such as smoking, vitamin D, diet, ethnicity, medical comorbidities (e.g. diabetes) and exercise levels, such that although several studies did report this information, we were unable to pool some or all of the data for moderator analysis.
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