Increased PTHrP and Decreased Estrogens Alter Bone Turnover but Do Not Reproduce the Full Effects of Lactation on the Skeleton

Abstract

During lactation, calcium is mobilized from the maternal skeleton to supply the breast for milk production. This results in rapid but fully reversible bone loss. Prior studies have suggested that PTHrP, secreted from the breast, and estrogen deficiency, due to suckling-induced central hypogonadism, combine to trigger bone resorption. To determine whether this combination was sufficient to explain bone loss during lactation, we raised PTHrP levels and decreased levels of estrogens in nulliparous mice. PTHrP was infused via osmotic minipumps and estrogens were decreased either by using leuprolide, a long-acting GnRH agonist, or by surgical ovariectomy (OVX). Bone mineral density declined by 23.2 ± 1.3% in the spine and 16.8 ± 1.9% in the femur over 10 d of lactation. This was accompanied by changes in trabecular architecture and an increase in both osteoblast and osteoclast numbers. OVX and PTHrP infusion both induced a modest decline in bone mineral density over 10 d, but leuprolide treatment did not. The combination of OVX and PTHrP was more effective than either treatment alone, but there was no interaction between PTHrP and leuprolide. None of the treatments reproduced the same degree of bone loss caused by lactation. However, both forms of estrogen deficiency led to an increase in osteoclasts, whereas infusion of PTHrP increased both osteoblasts and osteoclasts. Therefore, although the combination of PTHrP and estrogen deficiency contributes to bone loss, it is insufficient to reproduce the full response of the skeleton to lactation, suggesting that other factors also regulate bone metabolism during this period.

Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation

“…We have previously observed that infusion of PTHrP (1–36) into virgin mice for 11 days caused a modest degree of bone loss both at the spine (5.2±1.2%) and at the femur (4.5±1.8%) (13) . BSEM showed osteocyte lacunar area was significantly increased in vertebral trabecular bone (34.1±2.3*, μm 2 ) from PTHrP-treated mice as compared to placebo-treated mice (30.7±1.9) *p<0.05 (n=5).…”

“…PTHrP-treated mice received a continuous infusion of PTHrP (1–36) subcutaneously using Alzet mini-osmotic pumps (model 2002) at a rate of 10pmol/hr until sacrifice on day 12, as described in our previous publications (13) .…”

Selective laser sintering scaffold with hierarchical architecture and gradient composition for osteochondral repair in rabbits

“…bone volume, trabecular thickness). The threshold was set at 375 mg HA/cm 3 to distinguish mature bone from the residual scaffold and soft tissue [37]. …”

Osteocytic osteolysis: time for a second look?

“…This process of rapid bone loss is associated with increased bone turnover and increased numbers of surface osteoclasts and bone resorption. Furthermore, this process is triggered in part by the secretion of PTHrP from the breast 535455. PTHrP interacts with the same type 1 PTH/PTHrP receptor (PTHR1) in bone as does PTH.…”