Selective Serotonin Reuptake Inhibitors During Lactation Tied to Bone Loss in Mice

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

BOSTON — Use of selective serotonin reuptake inhibitors (SSRIs) during lactation was associated with excessive, irreversible bone resorption in mice, according to the results of a new study.

Laura L. Hernandez, PhD, associate professor of dairy science and an expert in lactation biology and milk synthesis at the University of Wisconsin-Madison, also noted that high doses of folic acid appeared to reduce bone loss by limiting serotonin’s action on the mammary gland.

She discussed the findings at ENDO 2016.

“In a study where we were loading mice with folic acid and they were also receiving the (SSRI) fluoxetine, we saw an increase in a bone-building gene,” said Dr Hernandez. “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, marketed as 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.”

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).


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