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

NCT ID: NCT07256769

Last Updated: 2025-12-01

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 134 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2025-09-29
• Study Completion Date: 2028-03-31

Brief Summary

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®

Detailed Description

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.

Conditions

Osteoporosis Secondary; Breast Cancer Females

Study Design

• Observational Model Type: OTHER
• Study Time Perspective: PROSPECTIVE

Study Groups

Group 1

Standard therapy

Group 1: calcium carbonate/cholecalciferol

Intervention Type: DIETARY_SUPPLEMENT

Intake of calcium carbonate 500 mg + cholecalciferol 2000 IU

Group 2

Synostea®

Group 2: Synostea® (calcium carbonate/cholecalciferol/vitamin K/α-lactalbumin/ d-chiro-inositol)

Intervention Type: DIETARY_SUPPLEMENT

Intake of Synostea® : calcium carbonate 400 mg + cholecalciferol 2000 IU + vitamin K (menaquinone 50 μg) + α-lactalbumin (30 mg) + d-chiro-inositol (150 mg)

Interventions

Group 1: calcium carbonate/cholecalciferol

Intake of calcium carbonate 500 mg + cholecalciferol 2000 IU

Intervention Type: DIETARY_SUPPLEMENT

Group 2: Synostea® (calcium carbonate/cholecalciferol/vitamin K/α-lactalbumin/ d-chiro-inositol)

Intake of Synostea® : calcium carbonate 400 mg + cholecalciferol 2000 IU + vitamin K (menaquinone 50 μg) + α-lactalbumin (30 mg) + d-chiro-inositol (150 mg)

Intervention Type: DIETARY_SUPPLEMENT

Eligibility Criteria

Inclusion Criteria

• caucasian women aged between 35 and 70;
• diagnosed with breast cancer undergoing treatment with aromatase inhibitors or tamoxifen + GnRH analogues or aromatase inhibitors + GnRH analogues not started more than 12 months ago, about to start treatment with oral bone resorption inhibitors (alendronate);
• vitamin D levels below 30 ng/ml (test carried out no more than 6 months prior to the baseline/T0 visit)
• patients able to comply with the procedures and/or requirements of the study
• informed consent to participate in the study and data processing, written personally and/or through a witness, before any study-specific procedure is carried out

Exclusion Criteria

• uncontrolled diabetes mellitus (HbA1c 8%), severe CRF (eGFR<30 ml/min);
• patients with primary or secondary hyperparathyroidism due to CRF;
• baseline vitamin D levels greater than 30 ng/ml;
• patients already being treated with anti-resorptive drugs;
• patients undergoing steroid therapy;
• patients undergoing treatment with other forms of vitamin D (calcifediol, calcitriol) or who require high doses of calcium (hypoparathyroidism);
• patients undergoing treatment with drugs that can affect calcium excretion (diuretics);
• inability to comply with the procedures required by the study.

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Regina Elena Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Marialuisa Appetecchia

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Marialuisa Appetecchia, MD

Role: PRINCIPAL_INVESTIGATOR

Regina Elena National Cancer Insitute

Locations

Santa Maria Goretti Hospital

Latina, Italy, Italy

Site Status: NOT_YET_RECRUITING

Regina Elena National Cancer Institute

Roma, Italy, Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Marialuisa Appetecchia, MD

Role: CONTACT

marialuisa.appetecchia@ifo.it

0039 0652666026

Facility Contacts

Marco Centanni, MD

Role: primary

marco.centanni@uniroma1.it

07736556225

Camilla Virili, MD

Role: backup

camilla.virili@uniroma1.it

Marialuisa Appetecchia, MD

Role: primary

marialuisa.appetecchia@ifo.it

0039 0652666026

Giulia Puliani, MD

Role: backup

giulia.puliani@ifo.it

0039 065266034

References

Atieh O, Daher J, Durieux JC, Abboud M, Labbato D, Baissary J, Koberssy Z, Ailstock K, Cummings M, Funderburg NT, McComsey GA. Vitamins K2 and D3 Improve Long COVID, Fungal Translocation, and Inflammation: Randomized Controlled Trial. Nutrients. 2025 Jan 16;17(2):304. doi: 10.3390/nu17020304.

Reference Type: BACKGROUND

PMID: 39861434 (View on PubMed)

Weaver CM. How sound is the science behind the dietary recommendations for dairy? Am J Clin Nutr. 2014 May;99(5 Suppl):1217S-22S. doi: 10.3945/ajcn.113.073007. Epub 2014 Mar 19.

Reference Type: BACKGROUND

PMID: 24646824 (View on PubMed)

Caputo M, Bona E, Leone I, Sama MT, Nuzzo A, Ferrero A, Aimaretti G, Marzullo P, Prodam F. Inositols and metabolic disorders: From farm to bedside. J Tradit Complement Med. 2020 Mar 24;10(3):252-259. doi: 10.1016/j.jtcme.2020.03.005. eCollection 2020 May.

Reference Type: BACKGROUND

PMID: 32670820 (View on PubMed)

Ranaldi G, Ferruzza S, Natella F, Unfer V, Sambuy Y, Monastra G. Enhancement of D-chiro-inositol transport across intestinal cells by alpha-Lactalbumin peptides. Eur Rev Med Pharmacol Sci. 2020 Oct;24(19):10143-10154. doi: 10.26355/eurrev_202010_23234.

Reference Type: BACKGROUND

PMID: 33090422 (View on PubMed)

Wang J, Aalaei K, Skibsted LH, Ahrne LM. Calcium bioaccessibility increased during gastrointestinal digestion of alpha-lactalbumin and beta-lactoglobulin. Food Res Int. 2023 Feb;164:112415. doi: 10.1016/j.foodres.2022.112415. Epub 2022 Dec 27.

Reference Type: BACKGROUND

PMID: 36737996 (View on PubMed)

Perego S, Del Favero E, De Luca P, Dal Piaz F, Fiorilli A, Cantu' L, Ferraretto A. Calcium bioaccessibility and uptake by human intestinal like cells following in vitro digestion of casein phosphopeptide-calcium aggregates. Food Funct. 2015 Jun;6(6):1796-807. doi: 10.1039/c4fo00672k.

Reference Type: BACKGROUND

PMID: 25927875 (View on PubMed)

Permyakov EA. alpha-Lactalbumin, Amazing Calcium-Binding Protein. Biomolecules. 2020 Aug 20;10(9):1210. doi: 10.3390/biom10091210.

Reference Type: BACKGROUND

PMID: 32825311 (View on PubMed)

Hirao M, Hashimoto J, Ando W, Ono T, Yoshikawa H. Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K2 in postmenopausal women. J Bone Miner Metab. 2008;26(3):260-4. doi: 10.1007/s00774-007-0823-3. Epub 2008 May 11.

Reference Type: BACKGROUND

PMID: 18470667 (View on PubMed)

Kasukawa Y, Miyakoshi N, Ebina T, Aizawa T, Hongo M, Nozaka K, Ishikawa Y, Saito H, Chida S, Shimada Y. Effects of risedronate alone or combined with vitamin K2 on serum undercarboxylated osteocalcin and osteocalcin levels in postmenopausal osteoporosis. J Bone Miner Metab. 2014 May;32(3):290-7. doi: 10.1007/s00774-013-0490-5. Epub 2013 Jul 12.

Reference Type: BACKGROUND

PMID: 23846118 (View on PubMed)

Aaseth JO, Finnes TE, Askim M, Alexander J. The Importance of Vitamin K and the Combination of Vitamins K and D for Calcium Metabolism and Bone Health: A Review. Nutrients. 2024 Jul 25;16(15):2420. doi: 10.3390/nu16152420.

Reference Type: BACKGROUND

PMID: 39125301 (View on PubMed)

Defeudis G, Cardinali L, Eftekhariranjbar S, Massari MC, Migliaccio S. Male osteoporosis: the impact of lifestyle, from nutrition to physical activity. J Endocrinol Invest. 2025 May;48(5):1075-1083. doi: 10.1007/s40618-024-02517-w. Epub 2024 Dec 16.

Reference Type: BACKGROUND

PMID: 39680363 (View on PubMed)

Other Identifiers

RS 328/IRE/25

Identifier Type: -

Identifier Source: org_study_id