Vitamin k, D-chiro Inositol and α-lactalbumin in Bone Homeostasis

Overview

In women with breast cancer undergoing adjuvant hormone therapy, the marked tissue hypoestrogenism induced by therapy with aromatase inhibitors and/or tamoxifen ± GnRH analogues causes a significant acceleration in bone mass loss, with a consequent increased risk of fracture from the first year of therapy. It is therefore essential to start treatment with antiresorptive drugs and calcium and vitamin D supplementation. It has been hypothesized that vitamin K and α-lactalbumin have an effect in improving the absorption of calcium and vitamin D. In addition, vitamin K promotes gamma-carboxylation of osteocalcin, causing its activation and leading to increased incorporation of hydroxyapatite into the bone, resulting in increased calcium uptake from the blood and other tissues. Studies have reported that a combination of alendronate and vitamin K2 can lead to a decrease in the ratio of uncarboxylated osteocalcin to carboxylated osteocalcin, contributing to an increase in BMD, especially in the femoral neck. α-lactalbumin is able to increase the bioaccessibility of calcium due to its ability to prevent its precipitation at the neutral pH present in the absorptive tracts of the small intestine. Furthermore, α- lactalbumin has a binding site for vitamin D3, and the complexes formed by monomers of this protein and vitamin D have shown good stability in the presence of high vitamin concentrations. Inositol is a carbohydrate structurally similar to glucose which, in its isomeric form D-chiro-inositol, acts on bone remodeling by blocking the activation of osteoclasts through inhibition of the binding of RANK-L to its receptor present on pre-osteoclasts. Our hypothesis is that the use of the combination of vitamin K, α- lactalbumin, and D-chiro-inositol should improve the intestinal absorption of calcium and vitamin D, increasing the percentage of patients able to normalize serum levels of vitamin D and urinary calcium excretion (as a parameter of adequate calcium intake). This aspect, together with the direct effect of these components on bone remodeling, could enhance the anti-resorptive effect of standard therapy with bisphosphonates, improving the quantitative and qualitative parameters of bone. Therefore, we design a prospective randomized pilot study to assess efficacy of the combination of vitamin K, α-lactalbumin, and D-chiro-inositol, comparing patients with standard therapy and patients treated with Synostea®

Recommendations regarding the ideal daily intake of calcium and vitamin D vary based on the anthropometric characteristics and comorbidities of patients. An adequate level of these two nutrients is recommended especially in patients undergoing treatment with anti-resorptive drugs used for both preventive and therapeutic purposes in osteoporosis. This occurs in women with breast cancer, in whom the marked tissue hypoestrogenism induced by adjuvant therapy (aromatase inhibitors and/or tamoxifen ± GnRH analogues) causes a significant acceleration in bone loss (CTIBL-Cancer Treatment-Induced Bone Loss), with a consequent increased risk of fracture from the first year of therapy. It is therefore essential to start treatment with antiresorptive drugs and calcium and vitamin D supplementation in order to safeguard bone health and prevent secondary osteoporosis. Optimal serum concentrations of calcium and vitamin D play a central role in bone health, but insufficient intake can depend on numerous factors, including diet and the presence of other nutrients, as well as the body's ability to absorb them effectively. It has been hypothesized that vitamin K and α-lactalbumin improve the absorption of calcium and vitamin D. Vitamin K is a fat-soluble vitamin that comes in various forms, including vitamin K2 (menaquinone), which is involved in bone remodeling. It promotes gamma-carboxylation of osteocalcin, causing its activation and leading to increased incorporation of hydroxyapatite into bone, resulting in increased uptake of calcium from the blood and other tissues. High levels of the uncarboxylated form of osteocalcin, which is found in cases of vitamin K deficiency, have been associated with an increased risk of fractures despite adequate therapy with oral bisphosphonates. Studies have reported that a combination of alendronate and vitamin K2 can lead to a decrease in the ratio of uncarboxylated osteocalcin to carboxylated osteocalcin, contributing to an increase in BMD, especially in the femoral neck, thus reducing the risk of fragility fractures. α-Lactalbumin is a small acidic protein that has a binding site with high affinity for Ca++. The bioaccessibility of Ca++, i.e., the amount of micronutrient potentially available for absorption in the human body, depends on the amount of soluble calcium released from food processing during digestion. It has been hypothesized that binding to peptides such as α-lactalbumin may increase bioaccessibility due to its ability to prevent precipitation at the neutral pH present in the absorptive tracts of the small intestine. In addition, α-lactalbumin has a binding site for vitamin D3, and complexes consisting of monomers of this protein and vitamin D have shown good stability in the presence of high vitamin concentrations. It is also known from in vitro studies that α-lactalbumin can improve the intestinal absorption of D-chiro-inositol by as much as 10 times compared to the absence of this protein in the intestine. The combination of vitamin K, α-lactalbumin, and D-chiro-inositol should improve the intestinal absorption of calcium and vitamin D, increasing the percentage of patients able to achieve normalization of serum vitamin D levels and urinary calcium excretion (understood as a parameter of adequate calcium intake). This aspect, together with the direct effect of these components on bone remodeling, could enhance the antiresorptive effect of standard bisphosphonate therapy, improving the quantitative and qualitative parameters of bone. Inositol is a carbohydrate structurally similar to glucose which, in its D-chiro-inositol isomeric form, acts on bone remodeling by blocking the activation of osteoclasts through inhibition of the binding of RANK-L to its receptor present on pre-osteoclasts. Therefore, we design a prospective randomized pilot study aims to evaluate the effect of synergistic effect of vitamin K, α-lactalbumin and D-chiro-inositol supplementation compared to standard therapy with calcium carbonate and vitamin D alone on calcium-phosphorus metabolism parameters and bone mineral density in patients with breast cancer treated with alendronate for the prevention of bone damage from hormone therapy.