Site-specific changes in bone microarchitecture, mineralization, and stiffness during lactation and after weaning in mice

Abstract

Despite the dramatic bone loss that occurs during lactation, bone mineral density rapidly recovers after offspring are weaned and milk production stops. The goal of this study is to quantify site-specific changes in bone quantity and quality during and after lactation in a mouse model. We used micro computed tomography (mCT), individual trabecula segmentation (ITS), digital topological analysis (DTA)-based tissue mineral density (TMD) analysis, and micro finite element analysis (mFEA) to quantify the effects of lactation and weaning on bone microarchitecture, mineralization, and stiffness at the spine, tibia, and femur. We found a significant decrease in trabecular plate microarchitecture, tissue mineralization of the trabecular surface, trabecular central skeleton, and intervening envelopes, and whole bone stiffness in lactating versus nulliparous mice at all three sites. In recovered mice, all these different aspects of bone quality were comparable to nulliparous mice at the spine. In contrast, trabecular plate microarchitecture and whole bone stiffness at the tibia and femur in recovered mice were lower than nulliparous mice, as were central trabecular tissue mineralization and cortical structure at the femur. These findings are consistent with clinical observations of partial recovery of femoral bone mineral density BMD after lactation in humans. The observed differences in trabecular surface tissue mineralization in nulliparous, lactating, and recovered mice are consistent with prior observations that maternal bone turnover shifts from resorption to formation at the time of pup weaning. The significant differences in trabecular central tissue mineralization during these three states suggest that osteocytes may contribute to the reversible loss of mineral during and after lactation. Future studies are necessary to determine whether differing functions of various bone cells at individual skeletal sites cause site-specific skeletal changes during and after lactation. ß

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

“…The tibiae and femora show similar changes in trabecular bone, while cortical bone displays reductions in cortical thickness, cross-sectional area, and tissue mineral density, and an increase in cortical porosity and endosteal perimeter (35, 101,566,580). However, another microCT study from the same investigators found no significant change in cortical parameters in the femora except for an increase in tissue density (34), while a peripheral QCT (pQCT) study found that lactation increased tibial mid-shaft cortical width, area, periosteal circumference, and cross-sectional moment of inertia in frontal, sagittal, and torsional planes (772).…”

Irreversible Deterioration of Cortical and Trabecular Microstructure Associated With Breastfeeding

“…(10) Studies in rodent species variously report reversibility, partial or no reversibility after weaning. (13)(14)(15)(16)(17)(18) While trabecular bone is remodeled in rodents, rodents continue to grow throughout life and do not remodel cortical bone, or do so to a limited degree late in life. The synthesis of new trabeculae during continued growth may explain why the loss of trabecular bone is reversible.…”

“…Studies in rodent and other animal models demonstrate that trabeculae perforate, their numbers decrease, and cortical porosity increases. (10)(11)(12)(13)(14)(15)(16)(17)(18) This structural deterioration has been reported to be reversible in some animal models. (7,17,18) Bone loss during breastfeeding in humans is reported, but whether the microstructural deterioration is reversible after cessation of breastfeeding in human subjects is uncertain.…”

“…(10)(11)(12)(13)(14)(15)(16)(17)(18) This structural deterioration has been reported to be reversible in some animal models. (7,17,18) Bone loss during breastfeeding in humans is reported, but whether the microstructural deterioration is reversible after cessation of breastfeeding in human subjects is uncertain. (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) As trabecular bone loss, trabecular thinning, and perforation proceed rapidly after estrogen deficiency, the resulting bone fragility is attributed to deterioration in trabecular bone.…”

MicroRNA 874-3p Exerts Skeletal Anabolic Effects Epigenetically during Weaning by Suppressing Hdac1 Expression

“…This loss is reversed completely after weaning. For this reason, the weaning phase is considered the most anabolic phase in the reproductive cycle of a rodent and provides a vital window for the identification of new anabolic targets (7)(8)(9). For example, elevated levels of the neurohypophyseal hormone oxytocin during lactation and weaning led us to examine its action on bone (10,11).…”