Can High-Dose Folic Acid During Lactation Reverse SSRI-Induced Bone Resorption?

High doses of folic acid appeared to mitigate the effects of bone loss.

Use of selective serotonin reuptake inhibitors (SSRIs) during lactation was associated with bone resorption in mice, according to the results of a study presented at the Endocrinology Society’s Annual Meeting.  The authors further found that folic acid administered at high doses increased the expression of the bone-building gene osteocalcin by modulating the effects of SSRIs on the mouse mammary gland. 

“In a study where we were loading mice with folic acid and they were also receiving the SSRI fluoxetine, we saw an increase in [osteocalcin] ,” said Laura L. Hernandez, PhD, associate professor of dairy science at the University of Wisconsin-Madison.  “Potentially, this folic acid could reverse some of the bone effects we’re seeing.” 

Dr Hernandez added that the data suggest that SSRI use during pregnancy and lactation increases serotonin reuptake by the mammary gland, stimulating downstream signaling cascades responsible for bone resorption.

To test the hypothesis that that the use of SSRIs during lactation could lead to excessive bone resorption, Dr Hernandez and her colleagues administered 20 mg/kg of fluoxetine hydrochloride (Prozac) or saline daily to mice beginning on day 13 of pregnancy through day 10 of lactation.

Beginning 2 weeks before breeding, mice were also exposed to either a breeder diet or a diet supplemented with 20 mg/kg folic acid. Mice were separated into 4 groups: breeder diet/fluoxetine (BF), breeder diet/saline (BS), folic acid/fluoxetine (FF), and folic acid/saline (FS).

On day 1 of lactation, mice in the BS had higher serum serotonin levels than BF mice (7795 ± 1530 ng/mL vs 743 ± 80 ng/mL) and FS mice had elevated serotonin compared with FF mice (13 835 ± 4135 ng/mL vs 1378 ± 870 ng/mL). The researchers observed a similar pattern on the day 10 of lactation.

“On day 1 of lactation, we had a significant increase in calcium concentrations in the mom,” Dr Hernandez said of mice in the BF group.

Dr Hernandez and her colleges then administered fluoxetine from the date of pregnancy through 21 days of lactation. They examined the animals’ femurs 3 months after weaning and found a decrease in bone volume.

“We also saw a decrease in trabecular thickness,” she said. “This tells us that there is an effect of the SSRI after weaning even after taking the animals off the drug after lactation.”

The mRNA expression of the serotonin transporter SERT in mammary glands and bone-building osteocalcin in femurs was higher in the BS and FS groups compared with the BF and FF groups (P<0.05), and expression of bone breakdown M-CSF in femurs was increased in BF and FF groups compared with BS and FS mice (P<0.05).

Summary and Clinical Applicability

In a murine experimental model, SSRI use during pregnancy and lactation was associated with increased bone resorption, possibly due to the effects of SSRIs on the serotinergic-calcium axis.  

“SSRIs are the most widely prescribed class of antidepressants, particularly during pregnancy and breast-feeding,” Dr Hernandez said. “Therefore, it is of paramount importance that we explore the possibility that SSRIs may have detrimental effects on long-term maternal bone health.”

Limitations and Disclosures

These results will have to be studied in humans to confirm that the same downstream signaling cascades are affected to the same degree as in mice. This includes long-term studies following women into menopause, a period in which decreases in bone mineral density accelerates.  Additionally, equivalent dose adjustments of folic acid per kilogram would have to be determined. 

These findings were presented in abstract form during the Annual Endocrine Society meeting and have yet to undergo full peer review prior to journal publication.

The authors reported no conflicts of interest on disclosure forms.


Weaver S, Hernandez LL, Vezina C. Abstract OR09-6: Use of selective serotonin reuptake inhibitors promotes bone resorption during lactation. Presented at the 2016 Annual Meeting of the Endocrine Society; April 1-4, 2016; Boston, MA.

This article originally appeared on Endocrinology Advisor