Dairy cows experiencing negative energy balance (NEB) are prone to metabolic and inflammatory disorders, including ketosis, fatty liver, mastitis, endometritis, and hypocalcemia, which impair productive and reproductive performance. NEB elevates non-esterified fatty acids (NEFA) and β-hydroxybutyrate (BHBA), leading to disrupted lipid metabolism characterized by increased fatty acid synthesis (via SREBP-1c, ACC, FASN), impaired lipid export (downregulated MTTP, ApoB100, ACAT2), and reduced oxidation (suppressed SIRT1–PPARα–CPT1A/2 pathway), resulting in triacylglycerol (TAG) accumulation and ketosis. Excess reactive oxygen species (ROS) trigger oxidative and endoplasmic reticulum (ER) stress and apoptosis through JNK, p53/Nrf2, and PERK–eIF2α signaling, while HIF-2α–mediated hypoxia aggravates hepatic damage. Elevated NEFA/BHBA impair polymorphonuclear neutrophil (PMN) chemotaxis and phagocytosis, promoting mastitis and endometritis, and hypocalcemia further weakens immune defense. Rumen-protected choline (RPC) improves lipid metabolism by enhancing VLDL assembly and TAG export (upregulating MTTP, ApoB100, ATG3; inhibiting SREBF1, DGAT2), stimulating fatty acid oxidation (activating AMPK–PPARα–CPT1α), and reducing oxidative stress (suppressing ROS–ERN1). Moreover, RPC decreases IL-6 and TNF-α levels and enhances antioxidant capacity and PMN function. Overall, RPC alleviates NEB-induced metabolic and inflammatory diseases, supporting its inclusion in periparturient management to mitigate NEB and associated disorders.

This study compared the regulatory effects of dietary supplementation with natural clinoptilolite (CLN) versus a dietary cation-anion difference (DCAD) regimen on calcium homeostasis in dairy cows during the last 21 days prepartum. Results showed that cows in the DCAD group exhibited significantly higher blood ionized calcium (iCa) and parathyroid hormone (PTH) concentrations than those in the CLN group (p < 0.05). Serum PTH concentrations displayed a declining trend in both groups prepartum, which deviates from the classical theory of compensatory PTH secretion, suggesting that alternative compensatory pathways may be involved in the regulation of calcium homeostasis during the periparturient period in dairy cows. Monitoring of calcium homeostasis and related metabolic parameters following postpartum oral calcium bolus administration revealed that the incidence of subclinical hypocalcemia in the DCAD group was 26%, lower than the 62% observed in the CLN group. However, blood iCa concentrations returned to normal levels more rapidly in the CLN group. Additionally, CLN supplementation was associated with more stable blood pH and lower prepartum serum potassium concentrations (p < 0.05) that remained within the physiological range, which may contribute to improved tissue sensitivity to PTH.

Some dairy cows develop postpartum hypocalcemia because they cannot adapt to the drastic loss of blood calcium during the periparturient period. Parathyroid hormone (PTH) maintains calcium homeostasis by regulating bone calcium mobilization, gastric and intestinal calcium absorption, and renal calcium reabsorption. Traditionally, dysregulation of PTH has been considered the main cause of this disorder. Recent studies have confirmed that parathyroid hormone-related protein (PTHrP) secreted by the mammary gland is also involved in calcium homeostasis by promoting bone resorption. Based on existing research evidence and cross-species comparisons, this paper analyzes the effects of differences in mammary calcium output and compensatory mechanisms among various mammals on the risk of postpartum hypocalcemia, with a particular focus on processes related to bone resorption and bone formation. It further explains the pathogenesis of postpartum hypocalcemia in dairy cows by examining the roles of the mammary–brain–bone axis, PTH, and PTHrP in bone resorption and bone formation in these animals.