Calcitriol-Dependent and -Independent Regulation of Intestinal Calcium Absorption, Osteoblast Function, and Skeletal Mineralization during Lactation and Recovery in Mice

Abstract

Recovery from lactation-induced bone loss appears to be calcitriol-independent, since mice lacking 1-alpha-hydroxylase or vitamin D receptor (VDR) exhibit full skeletal recovery. However, in those studies mice consumed a calcium-, phosphorus-, and lactose-enriched "rescue" diet. Here we assessed whether postweaning skeletal recovery of Vdr null mice required that rescue diet. Wild type (WT) and Vdr null mice were raised on the rescue diet and switched to a normal (1% calcium) diet at Day 21 of lactation until 28 days after weaning. Unmated mice received the same regimen. In WT mice, cortical thickness was significantly reduced by 25% at 21 days of lactation and was completely restored by 28 days after weaning. Three-point bending tests similarly showed a significant reduction during lactation and full recovery of ultimate load and energy absorbed. Although Vdr null mice exhibited a similar lactational reduction in cortical thickness and mechanical strength, neither was even partially restored after weaning. Unmated mice showed no significant changes. In microcomputed tomography scans, diaphyses of Vdr null femora at 28 days after weaning were highly porous and exhibited abundant lowdensity bone extending into the marrow space from the endocortical surface. To quantify, we segregated bone into low-, mid-, and high-density components. In WT diaphyses, high-density bone was lost during lactation and restored after weaning. Vdr null mice also lost high-density bone during lactation but did not replace it; instead, they demonstrated a threefold increase in low-density bone mass. Histology revealed that intracortical and endocortical surfaces of Vdr null bones after weaning contained very thick (up to 20 micron) osteoid seams, covered with multiple layers of osteoblasts and precursors. We conclude that during the postweaning period, osteoblasts are potently stimulated to produce osteoid despite lacking VDRs, and that either calcitriol or a calcium-enriched diet are needed for this immature bone to become mineralized.

Clinical effectiveness of calcitriol and calcium gluconate in treating older male patients with osteoporosis

“…Furthermore, calcitriol contributes to calcium salt replenishment, new bone formation, increased calcium and phosphorus reabsorption by renal tubular cells, and reduced urinary excretion [26]. A pivotal target of calcitriol is osteoblasts, in which it prompts the synthesis of matrix and proteins, playing a critical role in bone mineralization, function and metabolism [27][28][29]. Importantly, calcium supplementation alone is insufficient to address bone loss and treat OP.…”

Recent Insights into Pregnancy and Lactation-Associated Osteoporosis (PLO)

“…Recently, data obtained from mice have suggested that osteoblasts are potently stimulated to produce osteoid and that calcitriol and/or a calcium-enriched diet are needed for this immature bone to become mineralized. [13][14][15] Pregnancy and lactation are major challenging periods for maternal bone metabolism. However, the female skeleton is well prepared to face these periods successfully, and resistance does not seem to be affected in the long term.…”

The Impact of Withholding Cost-Effective Early Treatments, such as Vitamin D, on COVID-19: An Analysis Using an Innovative Logical ParadigmThe Impact of Withholding Cost-Effective Early Treatments, such as Vitamin D, on COVID-19: An Analysis Using an Inno

“…Locations for generating calcitriolintracellularly, in peripheral target cells-need to be considered regarding its mechanisms and efficacy for prevention and using vitamin D as an adjunctive therapy [41,42]. The circulating hormonal form of calcitriol generated in renal tubular cells is crucial for musculoskeletal activities and calcium/magnesium metabolism [43,44]. However, calcitriol circulates in the blood in picomolar concentration: it does not enter extra-renal target cells, like immune cells [45,46], to affect their biology and physiological functions [47,48].…”