Osteoporosis is a significant cause of morbidity and mortality in the US and costs approximately $17 billion dollars annually 
. It results in over two million fractures annually in the US, 71% of which occur in women 
. Therefore, investigation and identification of risk factors are of great importance. There have been several studies with conflicting findings regarding the possible influence of depression on BMD 
; most of these studies were retrospective analyses conducted in post-menopausal women. In this study, we followed a group of premenopausal women with MDD and healthy controls prospectively and measured their BMD at regular intervals. Our finding that neither group exhibited a substantial change in BMD at any skeletal site over time may not be surprising since BMD has been reported to remain relatively stable in healthy premenopausal women 
. The observation that women with MDD maintained their BMD throughout the study is reassuring as it implies that little, if any, bone loss was associated with MDD in this age range and time span. It should be however noted that these subjects were aware that they were participating in a clinical experiment, thus we cannot exclude a non specific “Hawthorne effect”. In this particular case, regular encounters with the research team may have positively influenced their mood and induced improvements in life style conditions. Our observation allows for considering prophylactic treatment of these women to prevent osteoporosis after menopause, when their risk is magnified. Women reach peak bone mass by their third decade 
and BMD remains relatively stable until menopause where women begin to lose up to 1–2% of the BMD annually 
Alterations in the HPA axis are significant findings in biological psychiatry 
. Several studies have investigated the possible pathophysiology of osteoporosis in psychiatric patients and have hypothesized a link between depression and low BMD 
. Elevated ACTH and cortisol levels, and enhanced cortisol responsiveness have been demonstrated in depressed individuals 
. Similar to the bone loss observed in Cushing syndrome as a result of hypercortisolemia, women with depression could thus have decreased BMD, albeit not as pronounced as in Cushing syndrome. We found that ACTH levels and bone-specific alkaline phosphatase levels tended to be elevated in women with depression compared to controls. Serum and urinary free cortisol, osteocalcin, and urinary N-telopeptide levels were not different between participants with depression and controls throughout the study.
In an ancillary investigation, we reported that women with depression had a greater prevalence of Bcl1
polymorphism, which is associated with glucocorticoid hypersensitivity 
. Therefore, women with MDD may also have a greater HPA activity at tissue level. The cortisol plasma levels were not elevated in our study of women with MDD, but hyperactivity of the HPA axis is not always accompanied by hypercortisolism 
. Alterations in the HPA axis tend to occur during acute depressive states and normalize after treatment 
. Given that the majority of the subjects with depression were being pharmacologically treated throughout the duration of the study as previously reported 
, increases in cortisol levels may not have occurred, as these patients were likely to be in clinical remission. As we have recently reported in greater detail in a related manuscript 
, approximately half of the sample was comprised of women with melancholic depression, and the remaining subjects suffered either from undifferentiated or atypical depression. Women with atypical features of depression had higher ACTH levels during the night and women with undifferentiated depression had a significantly higher prevalence of low BMD at the femoral neck than controls. Thus, the clinical subtype of depression may influence bone and endocrine features, among other parameters.
In the women with MDD and moderate osteopenia or osteoporosis, weekly alendronate was effective in increasing BMD. This is the first pharmacotherapeutic study of osteoporosis in younger women with MDD and one of the few controlled studies of alendronate treatment in premenopausal women 
. Of note, in this arm the drop-out rate was only 10%, much smaller than in the overall cohort. In future research, it would be interesting to identify the predictors of drop-out rate in studies of women with depression. It is possible that the women participating in the randomized controlled arm of this trial may have been more motivated to remain in the study than the women with depression in the natural history arm and the normal controls, possibly because of the therapeutic advantages of the drug being received. As estrogens are not a treatment option in this population, our study supports the possible use of alendronate in this population. Recently the use of selective serotonin reuptake inhibitors has been linked to an increased risk of fractures and bone loss 
. As reported 
, in our study the use of selective serotonin reuptake inhibitors was not associated with low BMD.
Vitamin D levels were lower in women with MDD than controls. Consistent with decreased vitamin D levels, women with MDD had significantly higher iPTH and ionized calcium levels, highly suggestive of secondary hyperparathyroidism. PTH levels remained elevated in women with MDD compared to controls. While elevated PTH levels have been demonstrated in depressed elderly women and young men 
, to the best of our knowledge, this is the first time elevated PTH plasma levels are observed in premenopausal women with MDD. Future studies should be conducted to evaluate the pathogenetic role of secondary hyperparathyroidism in subjects with depression.
Study limitations and merits
The small sample size, together with a drop-out rate of approximately 30% in the first year, may have reduced our ability to detect some associations. Vitamin D levels were only measured at baseline. Furthermore, since there is little bone loss in this age range 
, the duration of the study and the age of the participants may have limited our ability to identify a subtle decrease in BMD. Our results may have failed to detect significant changes in biochemical markers and hormones in patients who were in remission since abnormalities in many of these parameters might only be apparent during acute disease states 
. Our sample was well characterized and homogeneous, and the length of follow-up was longer than most studies of this kind.
Premenopausal women with MDD had lower BMD than controls over a sustained period of time. Larger and longer studies are needed to confirm and extend these observations. The effects of antidepressants and other psychotropic medications on bone mass per se should be assessed. The reversibility of bone loss due to successful behavioral or pharmacologic interventions or to spontaneous resolution of depression should be considered. Lastly, studies examining the role of genetics leading to enhanced susceptibility to reductions in BMD need to be conducted.