To our knowledge, this is the first study to investigate the impact of antipsychotic-induced hyperprolactinemia on BMD at the radius in children and adolescents, finding a negative association. This effect appears more specific to trabecular bone. In further analyses, we also found a prominent effect of SSRI treatment on BMD at the lumbar spine and the ultradistal radius. This, to our knowledge, has also never been reported in youths.
A unique feature of this study is the use of pQCT. The strengths of this technique, as opposed to the traditional DXA, include isolating trabecular from cortical bone and measuring volumetric, rather than areal, BMD 14, 15
. These two characteristics are important since hormonal abnormalities, such as hyperprolactinemia, initially affect trabecular bone and since volumetric measurements are less susceptible to body size compared to those generated by projectional methods like DXA 8, 14, 15
. The limitations of DXA, in this context, perhaps underlie the inconsistent findings from studies investigating the consequences of antipsychotic-induced hyperprolactinemia on BMD in adults 31, 32
. It is possible that pQCT is more sensitive than DXA to detect early differences in trabecular vBMD and that, over a more extended duration of hyperprolactinemia, DXA-based measurements will be similarly affected.
As hypothesized, pQCT-generated trabecular vBMD was more sensitive to the negative effect of prolactin on bone mineral accrual, even after taking into account significant confounders. Since total vBMD combines trabecular and cortical vBMD, it is not surprising that it was somewhat less markedly affected by prolactin. In fact, we failed to consistently find a statistically significant association between prolactin and total vBMD, after controlling for relevant covariates, though the trend remained in the negative direction. This might reflect a heterogeneity related to the racial/ethnic diversity, albeit small, in our sample since, when the analyses were restricted to non-Hispanic Caucasians, the findings were more prominent. However, while race and ethnicity are well known to influence BMD 28
, to our knowledge, there is no evidence that they also differentially moderate the effect of prolactin on BMD.
In females with prolactin-secreting tumors, hypogonadism mediates the impact of hyperprolactinemia on BMD 7, 8, 33
. This was not the case in our sample where we found no association between prolactin and total testosterone. Similar results have been reported in males with prolactinomas, the majority of whom progressed through puberty normally, yet had low BMD 34
. This is also consistent with most, but not all, studies in antipsychotic-treated adults with schizophrenia where no correlation was found between prolactin and sex hormones 9, 12, 35, 36
. Moreover, BMD does not necessarily recover following the normalization of gonadal status 33, 34
. These findings, combined, suggest that mechanisms other than hypogonadism might be implicated. In fact, a direct effect of hyperprolactinemia on bone turnover in males has been postulated 34
. In addition, recent animal work has not only identified prolactin receptors in osteoblasts, it has also shown that hyperprolactinemia activates the phosphoinositide 3-kinase pathway, through these receptors, to suppress alkaline phosphatase activity 37
. Prolactin also disturbs the expression ratio of receptor activator of nuclear factor kB ligand (RANKL) and osteoprotegerin, which play a critical role in the regulation of bone resorption 38, 39
. Such a mechanism would also be in agreement with findings in males with prolactin-secreting tumors of negative correlations between aBMD and osteocalcin on the one hand and prolactin on the other, but not with testosterone 40
. Another potential mechanism involves parathyroid hormone-related peptide, a bone-resorptive agent, which is elevated in lactating women and in patients with prolactin-producing tumors and is negatively associated with lumbar aBMD 41, 42
Like others 9, 35
, we could not find an independent effect of duration of risperidone treatment on BMD. It is possible that this variable does not accurately reflect the duration of hyperprolactinemia due to differences in individual susceptibility to this dose-related side effect, the changes in the dose of risperidone during the course of the treatment, as well as the potential for spontaneous resolution of hyperprolactinemia 43
. On the other hand, it is possible that the duration of hyperprolactinemia is not a critical determinant of bone loss just as the duration of amenorrhea in patients with prolactin-secreting tumors has not been consistently found to influence the degree of bone loss 42, 44
. Others have found a negative association between BMD in adults and the duration of illness or treatment 10, 36, 45
. However, these analyses did not control for age which is usually positively associated with duration of illness and treatment and negatively associated with BMD.
Equally significant was our finding that SSRI treatment was associated with reduced BMD both at the ultra-distal radius site and in the lumbar spine. SSRIs may increase prolactin, thereby hindering bone mineralization 46
. However, two findings from our work suggest that this might not be the case. First, after controlling for development, and the dose of risperidone and psychostimulants, we found no independent effect of SSRIs on prolactin concentration 16
. In addition, the negative association between SSRIs and BMD emerged after adjusting for several covariates, including prolactin. Rather, it is likely that SSRIs act directly on the serotonin transporter or, indirectly, on any of the other functional serotoninergic receptors that have been identified in osteoblasts, osteoclasts, and osteocytes 29, 47, 48
. In fact, the serotonin system appears to be implicated in bone metabolism with in vitro studies revealing that serotonin regulates osteoclast differentiation and activity, promotes preostoblasts proliferation, and modulates the interaction between osteoblasts and osteoclasts by regulating the release of RANKL and osteoprotegerin 47, 49
. Moreover, controlled experiments in mice have associated the use of SSRIs with reduced BMD, altered bone architecture, and inferior mechanical properties 30
. This effect involved both cortical and trabecular bone, although the latter was impacted to a larger extent, and appears to be secondary to reduced bone formation rather than accentuated resorption 30, 50, 51
By design, all our participants received risperidone, which itself interacts with serotonin receptors 52
. Therefore, we could not rule out the possibility of an interaction between SSRIs and risperidone, resulting in reduced BMD. In light of the widespread prescribing of SSRIs to children and adolescents 53
, the need for their prolonged use 54, 55
, and the epidemiological evidence associating SSRI treatment in adults with reduced BMD and increased fracture risk 18–20
, it is necessary to investigate the impact of SSRIs on BMD in youths without the confounding effect of antipsychotic treatment. With the medium effect size that we found, the clinical implications of such research can be significant because this effect would substantially increase the risk for osteoporotic fractures 5
. In addition, a thorough psychiatric assessment would be pivotal to avoid the pitfalls of confounding by indication. This refers to the fact that mood disorders, for which SSRIs are often prescribed, can themselves interfere with BMD and, consequently, confound the association between SSRIs and BMD 56, 57
. In our study, we did not start administering psychiatric measures until the majority of our participants had been recruited. Nevertheless, in order to address the possibility that participants receiving SSRIs had a lower BMD due to the effect of an underlying depressive disorder (i.e., confounding by indication), we controlled, in the regression models, for the clinical diagnosis of a mood disorder. The results remained virtually unchanged with the depression diagnosis not significantly contributing to the model (p>0.6).
Our findings should be interpreted in light of several important limitations. The temporal stability of hyperprolactinemia cannot be verified due to our cross-sectional design. Thus, the results should be viewed as preliminary, rather than reflecting irreversibly low BMD. In fact, longitudinal studies have revealed that risperidone-induced hyperprolactinemia resolves in many patients during extended treatment 43
. Since BMD continues to accrue during adolescence, it is possible that once prolactin concentration normalizes, either spontaneously or following the discontinuation of risperidone, its effect on bone mineralization will subside. The impact of hyperprolactinemia and SSRIs on BMD will be clinically relevant only if it leads to increased bone fragility and fractures. It is reassuring that we did not find any history of fractures in our subjects with hyperprolactinemia; however, longer-term investigations with much larger samples are necessary to thoroughly investigate this outcome. In order to address these shortcomings, our group is currently conducting a follow up assessment to prospectively monitor the change in BMD and the incidence of fractures. This will better establish the role that long-term hyperprolactinemia and SSRI treatment may play in hindering bone mineral accrual. In addition, we are seeking additional funding support to investigate the effect of hyperprolactinemia on bone turnover markers, though these can be highly variable in puberty 58
. It is premature, at this point, to make any definitive conclusions regarding the effect of psychotropics on bone mineralization based on a single measurement using one research modality (i.e., pQCT or DXA). Measuring bone turnover markers would potentially complement our findings, especially that they reflect the dynamic aspect of bone metabolism across the entire skeleton in contrast to radiological techniques which measure BMD at selected sites 59
. In fact, our findings cannot be extended to other bone structures, such as the hip, since we did not collect BMD measurements at those sites. However, measuring BMD at the hip in growing children is of questionable reliability due to limited reproducibility 60
. We focused our study on risperidone since it is most consistently associated with hyperprolactinemia. However, other psychotropics can alter prolactin secretion or directly affect bone metabolism and deserve investigation 30, 46
. Finally, we did not correct for multiple comparisons since our primary analysis was hypothesis-driven. Nevertheless, it is necessary to replicate this finding in a larger and more ethnically/racially diverse sample that would also include females and a comparative control group.