# Changes in bone characteristics precede serum mineral deterioration in a mouse model of early stage chronic kidney disease

## TL;DR

In a mouse model of early chronic kidney disease, bone changes occur before serum mineral levels are affected, showing early signs of bone deterioration.

## Contribution

This study reveals that bone formation declines and bone marrow adiposity increases before serum calcium levels change in early CKD.

## Key findings

- Bone mass decreases in trabecular and later cortical bone in Col4a3−/− mice.
- Osteoblast number and activity are reduced, while osteoclast numbers remain unchanged.
- Increased bone marrow adiposity is associated with reduced bone formation in early CKD.

## Abstract

Calcium metabolism is tightly regulated and involves hormonal communication between the intestine, kidney, and bone. Renal failure leads to impaired calcium homeostasis, but how each of the calcium-handling tissues adapts during the initial phases of the disease, remains to be explored. To this end, we used Col4a3−/− mice in which CKD develops progressively, as shown by the gradually decreased glomerular filtration rate and increased uremia. Mineral homeostasis was disturbed with increased serum levels of phosphaturic hormones, FGF23, and PTH and decreased 1,25(OH)2D3 levels. These hormonal adaptations in Col4a3−/− mice preserved normal serum calcium levels and maintained intestinal calcium absorption and renal fractional clearance of calcium. However, bone mass was already affected, starting with a decrease in trabecular bone mass and later evolving to additional cortical bone loss. Histomorphometric analysis of Col4a3−/− mice revealed a reduced osteoblast number and activity, whereas osteoclast numbers were not different. Interestingly, the decrease in bone formation was associated with an increase in BM adiposity. Taken together, we show that the renal impairment in Col4a3−/− mice leads to the typical hormonal alterations of CKD that preserve normal serum calcium levels at the early stage, but the renal dysfunction already negatively affects bone formation and increases BM adiposity.

Graphical Abstract