The lactating mammary gland elegantly coordinates maternal homeostasis to provide calcium for milk. During lactation, the monoamine serotonin regulates the synthesis and release of various mammary gland-derived factors, such as parathyroid hormone-related protein (PTHrP), to stimulate bone resorption. Recent evidence suggests that bone mineral lost during prolonged lactation is not fully recovered following weaning, possibly putting women at increased risk of fracture or osteoporosis. Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants have also been associated with reduced bone mineral density and increased fracture risk. Therefore, SSRI exposure while breastfeeding may exacerbate lactational bone loss, compromising long-term bone health. Through an examination of serotonin and calcium homeostasis during lactation, lactational bone turnover and post-weaning recovery of bone mineral, and the effect of peripartum depression and SSRI on the mammary gland and bone, this review will discuss the hypothesis that peripartum SSRI exposure causes persistent reductions in bone mineral density through mammary-derived PTHrP signaling with bone.