Clinical studies provide evidence that treatment with drugs for depression increases the risk of fracture in humans. Some of these drugs have been previously reported to reduce bone density in experimental studies, but their effect on bone biomarkers was not clear.
The group of researchers at Jamia Hamdard, New Delhi, under the Pharmaceutical Medicine program of Department of Pharmacology, evaluated the effect of two widely-prescribed antidepressant drugs, fluoxetine and escitalopram, on bone biomarkers after treatment with 40 days in male Wistar rats. The researchers also looked into how these drugs affect the microarchitecture of bones in these rats.
The biomarkers for bone are useful for the early detection of osteoporosis, a disease in which bones become brittle or fragile. The bone biomarkers are produced from the bone remodelling process which involves bone formation and bone resorption. The reference standard markers approved by International Osteoporosis Foundation for bone formation and resorption are serum procollagen type I amino-terminal propeptide (PINP) and carboxy- terminal cross-linking telopeptide of type I collagen (β-CTX) respectively. We, therefore, measured the blood levels of these biomarkers after treatment with the two antidepressant drugs studied in our laboratory.
Differential effects of two antidepressant drugs on bone
We found that fluoxetine administered rats showed significantly lowered serum levels of P1NP, while escitalopram treated rats were devoid of this effect. This shows that fluoxetine treatment results in reduced bone formation. Previously, a study reported fluoxetine to directly inhibit the growth of bone-forming cells (osteoblasts) during fracture healing. Our results further suggested that these drugs do not affect bone resorption as they did not change serum β-CTX levels. We confirmed these findings in a micro CT-scan of bones to report a deteriorated bone architecture in fluoxetine treated rats while no such deterioration in escitalopram treated rats. Thus, our study found these biomarkers to be useful for early diagnosis of these adverse effects of drugs.
Why the differential effects on bone?
The question arises as to why the two drugs for depression which belong to the same category and act by similar mechanism as antidepressants behave so differently on bone. Both fluoxetine and escitalopram belongs to a class of antidepressants termed selective serotonin reuptake inhibitors. They inhibit the reuptake of a chemical transmitter called serotonin and increase its availability in the brain. We searched the available literature and found that both gut and brain serotonin have opposite effects on bone. Thus, fluoxetine, by increasing gut serotonin, can act on bone formation cells to reduce their growth by reducing the addition of phosphate groups to a transcription factor called cAMP response element binding protein (CREB). To confirm this, we also looked at pCREB levels and we observed that fluoxetine caused a highly significant reduction of pCREB thus confirming this hypothesis. Escitalopram, on the other hand, only caused a minor reduction of pCREB.
The brain-derived serotonin, however, reduces the synthesis of epinephrine, and this is relayed in osteoblasts which via cyclin D1 gene which led to an increase bone formation and a decrease in resorption. However, we did not observe any of these effects, likely because 95% of serotonin is produced by the gut and only 5% is brain-derived. This could be the reason why there was no change in the marker for bone resorption in our study.
Can we translate the findings to humans?
Our study has translational significance for patients suffering from depression co-morbid with osteoporosis or in patients prone to bone loss. In such patients, escitalopram appears to be a safer option as compared to fluoxetine. Further, we advise monitoring of bones while the patient is on chronic treatment with fluoxetine. Our future plan is to translate these findings to humans by evaluating bone biomarkers and pCREB in adult patients undergoing treatment with these two drugs for depression.
The findings of the animal study are described in detail in our paper entitled Differential effects of serotonin reuptake inhibitors fluoxetine and escitalopram on bone markers and microarchitecture in Wistar rats, recently published in the European Journal of Pharmacology. This work was conducted by Manoj Kumar, Ravisha Wadhwa, Priyanka Kothari, Ritu Trivedi, and Divya Vohora from Jamia Hamdard, New Delhi and CSIR-CDRI, Lucknow.