Study selection
Figures 1 and 2 depict the results of the search strategy separately for each search, including the eligible and excluded studies at each stage of assessment. Overall, the e-search yielded 3102 articles, from which Covidence identified and removed 653 duplicates. A total of 2449 articles remained for title and abstract screening, with 2158 excluded. Following this, 291 full-text articles were assessed, of which 263 articles were excluded with reasons (96 had ineligible study design, 69 were grey literature, 25 wrong patient group, 30 wrong setting, 19 wrong outcome, and 24 further duplicates). The remaining 28 articles were considered for data extraction and quality assessment. A further article was found by hand-searching the reference lists of related systematic reviews. Thus, 29 articles were eligible for inclusion in this review.
Methodological quality of included studies
The overall mean methodological quality score was 56.4% (range 23.3–83.3%), see Tables 1–4.
Narrative synthesis
The characteristics of the included studies and summary of findings according to each outcome are presented in Tables 1–4 and described in the following sections, respectively.
Schizophrenia and BMD
Study characteristics
There were 17 studies published between 1997 and 2021 that examined associations between schizophrenia and BMD [49, 50, 60,61,62,63,64,65,66,67,68,69,70,71,72,73,74]. The sample sizes ranged between 14 [70] to 229 [67] adults with schizophrenia. Of the 17 studies, 12 were conducted in Asia (70.6%; with 29.4% in China), three in Europe (17.6%) and two in North America (11.7%).
Only one study was conducted within a population-based setting (Manitoba Bone Density Program database) [61], with all other studies conducted within clinical settings. Among these studies, 15 [49, 50, 60, 62,63,64,65,66,67,68, 70,71,72,73,74] compared BMD between people with schizophrenia and a control group, one study [69] used reference data for age- and race-matched healthy males, while another study [61] compared the percentage of schizophrenia among people with low BMD and normal BMD. Seven studies [60, 61, 64, 68, 69, 71, 73] used an age- and sex-matched control group and other studies used only an age-matched [72] or sex-matched [49, 65] control group. The remaining studies used an aged- and sex-similar [70, 74] or unmatched control group [50, 62, 63, 66, 67].
Two prospective studies [72, 73] measured BMD before and after treatment with antipsychotic medication, of which we only included the baseline data (pre-treatment). Eight studies [62,63,64, 66,67,68, 70, 74] investigating BMD were cross-sectional, reporting a single measurement of BMD. Eleven studies [50, 62,63,64, 66, 67, 70,71,72,73,74] included both sexes, while three studies [65, 68, 69] included men only and the remaining [49, 60, 61] women only. Three studies [49, 50, 60] out of 17 included premenopausal women, and two studies [61, 67] examined postmenopausal women, while the menstruation status was not reported for the remaining studies.
Of the 17 included studies, 12 used DSM-IV/5 alone or combined with other diagnostic criteria for identifying people with schizophrenia [49, 60, 62, 64,65,66,67, 69,70,71,72, 74], two used ICD [61, 73], one used the SCID [63] and two studies recruited patients with an existing diagnosis of schizophrenia [50, 68].
Most of the included studies that examined BMD used DXA as the ascertainment method; two studies used QUS [63, 74] and another QCT [65]. Two studies [63, 74] reported that QUS values were transformed to ascertain BMD, according to a previously published method (see Colling et al. [75]). BMD sites varied across studies including: the lumbar spine (n = 14) [49, 50, 60,61,62, 64,65,66,67,68, 70,71,72,73], femoral neck (n = 9) [49, 60, 61, 64, 66,67,68, 70, 71], trochanter (n = 5) [61, 66,67,68, 71], Ward’s triangle (n = 3) [67, 68, 71], total hip (n = 2) [61, 71] and distal radius (n = 1) [69]. Two studies used QUS and subsequently reported bone density of the right heel [63, 74]. The highest number of sites assessed was reported by Liang et al. [71], measuring multiple sites, including lumbar spine: L1, L2, L3, L4, and L1-4, hip: femoral neck, trochanter, Ward’s triangle, total hip, and radius: one-third distal, ultra-distal, middle distal, and total radius ulna [71]. Thirteen studies [49, 50, 60, 62, 64,65,66,67,68,69, 71, 73, 74] reported BMD in g/cm2, while ten studies [49, 60,61,62,63, 66, 67, 69, 70, 72] reported T-scores and Z-scores were reported by five studies [50, 62, 64, 69, 72].
Findings
Among the 16 studies using a control group (including one study [69] using reference data as a comparator), 12 (75.0%) found significantly lower BMD in the schizophrenia group compared with a control group in at least one region or at least one patient subgroup [49, 50, 63, 65,66,67,68,69,70,71,72, 74]. Furthermore, in the only case-control study which investigated the prevalence of schizophrenia among adults with low BMD, Bolton et al. reported a schizophrenia diagnosis was associated with increased odds of osteoporotic BMD [adjusted odds ratio (AOR) 1.98, 95% CI 1.0, 3.77] [61]. In addition, sex differences were observed in several studies [50, 66, 67]. In a polish study assessing BMD at L2-L4, the association between schizophrenia and low BMD was observed among women only [50]. Similarly, Jung et al. [66] reported lower BMD at the lumbar spine, femoral neck, Ward’s triangle and trochanter for the total group and females; however, no relationship was detected among the males at any BMD sites. In 2011, Jung et al. reported significantly lower BMD at the lumbar spine, femoral neck, and trochanter for women with schizophrenia; in the male group, significantly lower BMD was recorded at the femoral neck, trochanter and Ward’s triangle compared to controls [67].
Differential results were observed according to specific sites; Keely et al. [68] measured BMD in male samples and observed significantly lower BMD at the lumbar spine, Ward’s triangle and trochanter in the group with schizophrenia, while no association was observed at the femoral neck. Liang et al. [71] measured BMD in 13 sites and documented a significant difference between people with schizophrenia and controls at L3, femoral neck, trochanter, ultra-distal, middle distal, and total radius ulna.
Only one study stratified the sample of patients with schizophrenia by age [69]; males with schizophrenia (age range=31–78 years) who were categorised into five-year age bands were found to have significantly lower BMD at the distal radius in all ages except 30–34, 35–39, 50-54 age groups, compared to the reference data.
In contrast, four [60, 62, 64, 73] studies did not detect any significant differences in BMD between patients with schizophrenia and controls. Bergemann et al. [60] included 72 females with schizophrenia and compared them with 71 age- and sex-matched controls [60] observing no significant differences in mean BMD T-score at the femoral neck and lumbar spine [60]. Doknic et al. [64] conducted a cross-sectional study comparing the lumbar spine and femoral neck BMD of 26 patients with schizophrenia with 35 age-, sex-, body mass index (BMI)-, and education-matched healthy controls [64], and reported a trend for reduced BMD at the lumbar spine for patients with schizophrenia. However, no difference was observed for femoral neck BMD between patients and controls [64]. A prospective cohort study compared L1-L4 BMD of 163 patients with schizophrenia to 90 matched controls (age-, sex-, BMI-, marital status-, and years of education-matched) and observed no significant differences in baseline BMD between controls and patients (all p > 0.05) [73]. A recent cross-sectional study conducted in Taiwan explored L2-L4 BMD in 47 patients with schizophrenia and 39 controls and found BMD was similar in the two groups [62].
Overall, a total of 110 analyses were extracted from 17 studies; from which, 98 analyses measured BMD. Of 98 analyses, 65.3% indicated significantly lower BMD in people with schizophrenia, while 34.7% did not observe significant results for an association between schizophrenia and BMD. In addition, out of 64 analyses reported significant association, 53.1% reported significant lower BMD in both sexes, with 31.3% in women and 15.6% in men. Taken together, these results suggest that people with schizophrenia have significantly lower BMD than controls.
Schizophrenia and fracture
Study characteristics
Published between 2004 and 2022, there were eight studies that investigated fracture risk in individuals with schizophrenia compared to controls without schizophrenia [27, 67, 76,77,78,79,80,81]. Sample sizes ranged from 46 [79] to 30,335 [27] adults with schizophrenia. Three studies were conducted in the USA (37.5%), two in Europe (25.0%) and three in Asia (37.5%).
Six studies used population-based data [27, 76,77,78, 80, 81]; all population-based studies except one [78] had age- and sex-matched controls and/or adjusted for age and sex. Among the population-based studies, two studies [76, 77] used a case-control design, including 32,133 cases with a fracture and 77,178 controls without a fracture [76, 77]. The two remaining studies used clinical data [67, 79], and matched for age and sex. All included studies comprised both sexes in their study population, except for one study [79] that focused on women only.
Six studies [27, 76, 78,79,80,81] used ICD and two studies [67, 77] used DSM to identify people with schizophrenia. Across the studies investigating fracture, six studies used ICD diagnostic criteria to identify fractures [27, 76,77,78, 80, 81], one used confirmed radiograph reports to identify fractures [67], and the other recorded bone fractures [79]. Hip fracture was the most commonly investigated fracture in people with schizophrenia [27, 76,77,78, 80, 81], with femoral neck fractures the second most investigated site [76]. In addition, two cohort studies from Canada and Taiwan examined the association between schizophrenia and major osteoporotic fracture (MOF), including hip, spine (clinical), wrist, humerus and forearm [27, 78].
Findings
Four studies reported a relationship between schizophrenia and fracture [67, 77, 79, 81]. In a retrospective study, Bishop et al. [79] noted the rate of fracture in 46 women with schizophrenia was significantly higher than that in the 46 age- and sex-matched controls [12/46 (26.1%) vs. 1/46 (2.2%), p < 0.001] [79]. In a cross-sectional study conducted by Jung et al. [67], 229 inpatients with schizophrenia reported a significantly higher lifetime prevalence of fracture compared to 125 healthy controls [55/229 (24.0%) vs. 7/125 (5.6%), p = 0.001] [67]. Furthermore, among those with schizophrenia, 16 out of 229 (6.9%) experienced two or more fractures; however, no controls had more than one fracture [67]. A Canadian population-based study, using an administrative database consisting of 15,792 persons with osteoporotic fractures and 47,289 controls (matched for age, sex, ethnicity, and comorbidity), reported that a diagnosis of schizophrenia was more prevalent among the fracture group, compared to the non-fracture group (OR 2.17, 95% CI 1.75, 2.69; p < 0.05) [77]. In a multivariable model, simultaneously adjusted for antipsychotics, a diagnosis of schizophrenia was still significantly associated with increased odds of fracture (adjusted OR 1.61, 95% CI 1.27, 2.04; p < 0.01) [77]. In a recent nationwide population-based cohort study conducted in Taiwan, including 2028 people with schizophrenia and 8112 controls, a higher incidence of new fracture [89 out of 2028 (4.4%) vs. 257 out of 8112 (3.2%) p < 0.01], hip fracture [25 out of 2028 (1.2%) vs. 54 out of 8112 (0.7%) p = 0.01], and vertebral fracture [53 out of 2028 (2.6%) vs. 142 out of 8112 (1.7%) p = 0.01], in the schizophrenia group was reported. However, the incidence of wrist fracture was similar between schizophrenia and control groups.
However, similar findings were not observed in the remaining studies [27, 76, 78, 80], with the authors suggesting that the relationships between schizophrenia and fracture could be explained by antipsychotic medication use in these studies. For example, in a population-based case-control study conducted in the UK, 16,341 cases with fracture and 29,889 adults without fracture as controls [76] were included in a univariate analysis—reporting that hip fracture was associated with schizophrenia (OR 1.73, 95% CI 1.32, 2.28). However, this association was explained by the addition of antipsychotic medication to the model as a potential confounder (OR 1.01, 95% CI 0.72, 1.40; p = 0.971) [76]. A Danish population-based study consisting of 15,431 people with schizophrenia and 3,807,597 individuals from the general population without a diagnosis of schizophrenia reported similar findings [80]. For example, schizophrenia was associated with a significantly higher incidence rate ratio (IRR) of hip fracture (IRR 1.19 95% CI 1.08, 1.13) after adjustment for all covariates except antipsychotic use; after adding antipsychotic use to the model, the association between schizophrenia and hip fracture was no longer significant (IRR 1.00, 95% CI 0.90, 1.11) [80]. In a retrospective population-based cohort conducted in Taiwan using data from 30,335 people with schizophrenia and 121,340 age- and sex-matched controls without a diagnosis of schizophrenia, a higher incidence of MOF was observed in patients with schizophrenia, compared to controls [n = 1,667 (5.5%) vs. 4,257 (3.5%) p < 0.0001]; but there was no significant difference detected in non-MOFs between groups [n = 1,228 (4.1%) vs. 4,886 (4.0%) p = 0.8652] [27]. However, after adjustment for the psychiatric proportion of days covered (PDC), the relationship between schizophrenia and the risk of major osteoporosis fracture was not significant, and the authors suggested that the observed association may be caused by psychotropic medication, not schizophrenia disorder per se [27]. In a Canadian population-based cohort using 68,730 individuals’ data, schizophrenia was significantly associated with MOF [adjusted hazard ratio (aHR) 1.82, 95% CI 1.6, 2.85; p < 0.05] and with hip fracture (aHR 2.34, 95% CI 1.05, 5.21; p < 0.05) [78]. Nevertheless, when medications were analysed with mental disorders in the same model, the association between schizophrenia and MOF (aHR 1.21, 95% CI 0.75, 1.97) and hip fracture (aHR 1.12, 95% CI 0.48, 2.63) were no longer significant [78].
Overall, of eight studies, 50% reported a significant association between schizophrenia and fracture in the first analyses (univariate models or multivariate models without antipsychotics); however, after including antipsychotics in the analyses, the association between schizophrenia and fracture was not sustained. Thus, there is a possibility that the association between schizophrenia and fracture could be due to related medications, with antipsychotics being a recognised and important risk factor for fracture [27, 76, 78, 80].
Schizophrenia and bone quality
Study characteristics
Three studies examined bone quality in patients with schizophrenia (n = 1086) and controls without schizophrenia (n = 6578) [34, 82, 83], published between 2009 and 2010. The sample size ranged from 48 [34] to 965 [83] adults with schizophrenia. Two studies were conducted in Europe (66.6%) and one in Asia (33.3%).
Two studies used DSM-IV alone or in combination with other diagnostic criteria for selecting samples. One used the Research Version of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID-I) [34]. All included studies examined bone quality by QUS. In two of the studies, skeletal status was indexed by amplitude-dependant speed of sound (Ad-SoS) [82] and BUA [83], while in the third study, skeletal status was expressed by two values of bone quality, BUA and SOS (Z-score) [34].
One of these three included studies had a population-based setting and utilised data from the Health 2000 Survey database [34] with the other two studies being conducted in a clinical setting [82, 83]. Each of the included studies consisted of participants of both sexes. Partti et al. [34] used age- and sex-matched controls for comparing groups [34], while Rey-Sánchez et al. (2010) matched controls by age, sex, height and gonadal status [82].
Findings
All included studies found significantly poorer bone quality in the schizophrenia group compared with a control group in at least one value (BUA/SOS) or at least one patient subgroup (male/female). Results of the three studies vary based on confounders such as age [83] and sex [34, 82]. In a study examining Ad-SoS in 73 patients with schizophrenia (34.2% female) and 73 matched controls (34.2% female), women with schizophrenia had significantly lower Ad-SoS (p < 0.05), while men with schizophrenia had significantly higher Ad-SoS (p < 0.05), compared to controls [82]. In a cross-sectional study that recruited 965 patients with schizophrenia aged over 20 years, and 405 community members, it was observed that younger males aged ≤60 years and females aged ≤50 years with schizophrenia had lower BUA compared to controls, respectively [83]. Nevertheless, the same association was not observed in men older than 60 and women older than 50 years, and these groups had higher BUA compared to the control group [83]. In a population-based study using 6241 individuals’ data, Partti et al. reported that people with schizophrenia (n = 48) had significantly lower age- and sex-standardised BUA and SOS compared to the rest of the population [34]. After controlling for the common confounders for osteoporosis, including antipsychotic use, mood stabilising medications and vitamin D, the only significant determinant of low standardised BUA and SOS in women was schizophrenia (Z-BUA = -0.54 95% CI –0.90, –0.19; p = 0.002; Z-SOS = –0.55 95% CI –0.95, –0.15; p = 0.007) [34].
Schizophrenia and bone turnover markers
Study characteristics
Published between 2008 and 2020, nine studies investigated bone turnover markers in people with schizophrenia (n = 721) and controls without schizophrenia (n = 489) [49, 60, 62, 64, 65, 72, 82, 84, 85]. The sample sizes ranged from 26 [64] to 167 [84] adults with schizophrenia. Six studies were conducted in Asia (66.6%; with two in China 22.2%) and three studies in Europe (33.3%).
All the included studies used DSM-IV/5 alone or combined with other diagnostic criteria for identifying schizophrenia. The examined bone turnover markers varied across the included studies. The bone turnover markers investigated the most frequently in patients with schizophrenia was ALP [49, 62, 72, 82] and OC [60, 62, 64, 85], followed by TRACP-5b [65, 84]. BALP [65], CTx [64], TRAP [82], B-CTX [85], PYD [60] and DPD [60].
All studies were conducted in a clinical setting. Six studies [62, 64, 72, 82, 84, 85] included both sexes, with two studies stratifying the sample by sex in the analyses [82, 84]. Two studies focused only on women [49, 60] and one study only on men [65]. Controls were matched by age [60, 64, 72, 82], sex [60, 64], BMI, education [64], weight [82], height [82], and gonadal status [82].
Findings
A total of 19 analyses were conducted across the nine included studies [49, 60, 62, 64, 65, 72, 82, 84, 85]. All of the analyses [60, 62, 64, 65, 72, 82, 85], but two [49, 84] reported at least one higher bone turnover markers in people with schizophrenia compared to controls. Chiang et al. conducted a study with 47 people with schizophrenia and 39 healthy controls and reported significantly higher ALK-P in adults with schizophrenia (p = 0.035) [62]. Similarly, Lin et al., in a study of 111 patients with schizophrenia and 44 healthy controls, observed higher ALP in the schizophrenia group (p < 0.001) [72]. A study in Serbia compared bone turnover markers in 26 people with schizophrenia, and 35 age-, sex-, BMI-, and education-matched controls, and reported higher CTX in patients with schizophrenia (p = 0.023) [64]. In addition, Zhang et al. compared OC and B-CTX in 116 Chinese adults with schizophrenia and compared them with 71 healthy participants—OC and B-CTX were higher in the patient group (p < 0.001) [85].
Moreover, in a study comparing 72 females with schizophrenia with 71 age- and sex-matched controls, significantly higher PYD, DPD, and OC was reported in the patient group (p < 0.001) [60]. For males, one Chinese study observed a significantly increased TRAC-5b in 70 men with schizophrenia compared to 56 healthy controls (p = 0.002) [65]. Sex differences were observed in two studies that examined associations between schizophrenia and bone turnover markers, thus they were stratified by sex. First, in a study of 73 patients with schizophrenia and 73 controls, higher ALPH and TRAP were observed in women with schizophrenia (p < 0.0001), while the same was not observed for men [82]. Second, in a paper by Okita et al., 167 men and women with schizophrenia were compared with 60 controls—lower TRACP-5b was observed in females with schizophrenia (p < 0.01), but not men [84].
Separately, seven of the 19 analyses (36.8%) recorded no significant difference between people with schizophrenia and controls on bone turnover markers. For example, two studies reported no significant difference in OC between the schizophrenia group and the control group [62, 64]. A Turkish study investigated ALP in 30 premenopausal females with schizophrenia and 40 healthy controls and observed no significant difference in ALP between the groups [49]. A study conducted in China with 70 males with schizophrenia and 56 controls reported no significant difference in BAP [65]. The remaining three analyses stratified by sex reported no significant difference in TRACP-5b [84], ALPH and TRAP [82] for men with schizophrenia compared with controls.
In summary, of 19 analyses, 63.2% indicated a significant relationship between schizophrenia and bone turnover markers compared to controls, while 36.8% did not observe any significant association. From 12 significant studies, 50% reported this association in women, 41.7% in both sexes and 8.3% in men. These results suggest that people with schizophrenia have significantly higher bone turnover markers (resorption and formation markers) compared to the healthy controls.
Meta-analyses
BMD
Of 17 studies examining associations between schizophrenia and BMD that were considered for meta-analyses, seven studies were removed due to information deficiency or heterogeneity. Four studies [49, 60, 61, 69] did not report mean BMD for people with schizophrenia or control groups. In addition, three studies used methods other than DXA to ascertain BMD [63, 65, 74] thus, they were excluded. One study [73] reported BMD at the lumbar spine for L1-L4 range, and we considered L4 for this analysis consistent with the previously published systematic reviews [40, 41]. Thus, ten analyses were included in the meta-analyses to examine associations between schizophrenia and BMD.
Pooled results for lumbar spine BMD
The pooled lumbar spine BMD for females was calculated from nine [50, 62, 64, 66, 67, 70,71,72,73] studies, including 680 participants.
Women with schizophrenia had lower BMD (SMD –0.50, 95% CI –1.05, –0.05) compared to controls, with evidence of heterogeneity (I2 = 90.79%, H2 = 10.86). The pooled lumbar spine BMD for males that was calculated from ten studies [50, 62, 64, 66,67,68, 70,71,72,73] including 733 participants, and showed that men with schizophrenia have lower BMD (SMD –1.00, 95% CI –1.99, –0.01) compared to controls, but with high heterogeneity (I2 = 97.02%, H2 = 33.59).
The overall pooled lumbar spine BMD from 19 analyses of included studies [50, 62, 64, 66,67,68, 70,71,72,73] (N = 1413) showed that adults with schizophrenia have lower BMD (SMD –0.74, 95% CI –1.27, –0.20). The overall effect size test (Z = –2.71, p = 0.01) showed that there is a significant association between schizophrenia and lumbar BMD.
The test of group differences by sex was not significant (Q = 0.75, p = 0.39); heterogeneity was observed (I2 = 95.09%, H2 = 20.36).
Publication bias was assessed using Egger’s bias tests (Z = –6.40, p ≤ 0.001) and Begg-Mazumdar: Kendall’s s (Z = –2.52, p = 0.014) and rejected the symmetry of the funnel plot (Fig. 3). Thus, sensitivity analyses were performed to explore the potential sources of the heterogeneity. Subgroup analyses were conducted for publication year and participant size (including samples and controls). Lower heterogeneity was observed when studies [64, 68, 70] with less than 40 in each analysis were removed for women (I2 = 54.81%), men (I2 = 0.00%) and overall (I2 = 37.77%). Meta trim-and-fill reported three hypothetical studies were estimated to be missing. After imputing for those studies, overall bias-adjusted SMD was –0.28 (95% CI –1.07, 0.52) in comparison to the earlier observed SMD –0.74 (95% CI –1.27, –0.20). The bias-adjusted SMD was not significant, indicating that the impact of publication bias was high; in that imputing the missing studies changed the overall result (Fig. 4).
SMD < 0 suggests that people with schizophrenia have lower BMD as compared to people without schizophrenia. SMD > 0 suggests that people with schizophrenia have higher BMD as compared to people without schizophrenia. SMD = 0 suggests that BMD is the same for both groups.
Publication bias assessment plot with trim and fill for lumbar spine in schizophrenia versus controls.
Pooled results for femoral neck BMD
The pooled female femoral neck BMD was calculated from five studies [64, 66, 67, 70, 71] with 379 participants. Women with schizophrenia had lower femoral neck BMD (SMD –0.72, 95% CI –1.00, –0.45), with low evidence of heterogeneity (I2 = 26.57%, H2 = 1.36). The pooled male femoral neck BMD was calculated using six studies [64, 66,67,68, 70, 71], including 440 participants. Men with schizophrenia had lower femoral neck BMD (SMD –0.89, 95% CI –1.42, –0.36), with evidence of heterogeneity (I2 = 80.71%, H2 = 5.19). The overall pooled femoral neck BMD using 11 studies [64, 66,67,68, 70, 71] (n = 819), showed that people with schizophrenia have lower BMD (SMD −0.78, 95% CI −1.03, −0.53).
The overall effect size test showed a significant association between schizophrenia and femoral neck BMD (Z = –6.18, p = <0.001). The test of group differences by sex was not significant (Q = 0.30, p = 0.58). However, we observed evidence of heterogeneity (I2 = 55.92%, H2 = 2.27). Publication bias was assessed using Egger’s bias tests (Z = –2.38, p = 0.017) and Begg-Mazumdar: Kendall’s s (Z = –1.56, p = 0.16) and rejected the symmetry of the funnel plot (Fig. 5). Sensitivity analyses were performed to determine sources of heterogeneity. As per the previous analyses, subgroup analyses were conducted for the publication’s year and participant size (including samples and controls). Lower heterogeneity was observed when one study [68] with a publication year prior to 2000 was removed (I2 = 28.25%, 0.00%, 0.00% for female, male and overall, respectively). Meta trim-and-fill reported three hypothetical studies were estimated to be missing. After imputing for those studies, overall bias-adjusted SMD was –0.63 (95% CI –0.97, –0.29) in comparison to the earlier observed SMD -0.78 (95% CI -1.03, -0.54). There is only a slight difference between original and bias-adjusted OR; thus, the impact of publication bias is negligible (Fig. 6).
SMD < 0 suggests that people with schizophrenia have lower BMD as compared to people without schizophrenia. SMD > 0 suggests that people with schizophrenia have higher BMD as compared to people without schizophrenia. SMD = 0 suggests that BMD is the same for both groups.
Publication bias assessment plot with trim and fill for femoral neck in schizophrenia versus controls.
Fracture
Six out of the seven studies were considered for the meta-analyses to examine associations between schizophrenia and fracture. Since two studies [77, 78] were drawn from data from different time points of the same data source (i.e., Manitoba Bone Density Program), it was decided to include the most recent study by Bolton et al. [78].
Pooled results for fracture
The pooled odds ratio for fracture among females was calculated from seven studies [27, 67, 76, 78,79,80,81] with 2,284,378 participants. Women with schizophrenia had a 1.45-fold higher odds of fracture (OR 1.45, 95% CI 1.22, 1.73), with evidence of heterogeneity (I2 = 84.71%, H2 = 6.54). The pooled odds ratio for fracture among males was calculated from six studies [27, 67, 76, 78, 80, 81] including 1,676,514 participants. Men with schizophrenia had a 1.41-fold higher risk of fracture (OR 1.41, 95% CI 1.19, 1.67), with high heterogeneity (I2 = 86.05%, H2 = 7.17). The overall pooled odds ratio for fracture, including 3,960,892 participants, showed that people with schizophrenia had a 1.43-fold higher odds of fracture (OR 1.43, 95% CI 1.27, 1.61), with an overall effect size test (Z = 5.88, p = 0.00). The test of group differences by sex did not observe any significant associations (Q = 0.05, p = 0.82). Evidence of heterogeneity was observed (I2 = 87.26%, H2 = 7.85); thus, sensitivity analyses were conducted to find a source of heterogeneity (Fig. 7). Subgroup analysis for publication year and participant size (including samples and controls), fracture site and methodological quality were conducted, but heterogeneity did not change the results.
OR > 1 suggests that people with schizophrenia have higher odds of fracture as compared to people without schizophrenia. OR < 1 suggests that people with schizophrenia have lower odds of fracture as compared to people without schizophrenia. OR = 1 suggest that the odds of fracture are the same for both groups.
Publication bias was assessed using Egger’s bias tests (Z = 2.95, p = 0.0031) and Begg-Mazumdar: Kendall’s s (Z = 0.48, p = 0.6293) rejected the symmetry of the funnel plot. Meta trim-and-fill reported five hypothetical studies were estimated to be missing. After imputing for those studies, the overall bias-adjusted odds of fracture was 1.32 (95% CI 1.28, 1.35) in comparison to the earlier observed OR 1.43 (95% CI 1.27, 1.61). There is only a slight difference between the original and bias-adjusted OR, with the narrowing of the CIs and likely due to the inclusion of more studies (Fig. 8).
Publication bias assessment plot with trim and fill for fracture in schizophrenia versus controls. *There is overlap between some studies.
