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

NCT07256769 | Recruiting

• 1 other identifier: RS 328/IRE/25
• Study Type: observational
• Target: 134
• Locations: 1 country
• Sites: 2

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®

Conditions

Osteoporosis Secondary; Breast Cancer Females

Keywords

Vitamin K; d-chiro-inositol; α-lactalbumin; calcium; cancer treatment induced bone loss; vitamin d; synostea

Outcome Measures

Primary Outcomes (1)

• Evaluation of differences in mean vitamin D levels after six months in patients treated with calcium carbonate + cholecalciferoland patients treated with calcium carbonate + cholecalciferol + vitamin K + α-lactalbumin + d-chiro-inositol

  Change in mean vitamin D levels in the two treatment groups after 6 months of therapy

  6 months

Secondary Outcomes (18)

• Evaluation of the differences in Hip Bone Mineral Density by D-XA between groups

  12 months

• Evaluation of the differences in lumbar fragility score by Radiofrequency Echographic Multi Spectrometry between groups

  12 months

• Evaluation of the differences in serum levels of total calcium betweeeng groups after 12 months

  12 months

• Evaluation of the differences in serum levels of parathyroid hormone betweeen groups after 12 months

  12 months

• Evaluation of the differences in serum levels of bone alkaline phosphatase betweeen groups after 12 months

  12 months

Study Arms (2)

Group 1

Standard therapy

Dietary Supplement: Group 1: calcium carbonate/cholecalciferol

Group 2

Synostea®

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

Interventions

Group 1: calcium carbonate/cholecalciferol DIETARY_SUPPLEMENT

Intake of calcium carbonate 500 mg + cholecalciferol 2000 IU

Group 1

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

Group 2

Eligibility Criteria

• Age: 35 Years - 70 Years
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Adult women (aged between 35 and 70) with breast cancer undergoing treatment with aromatase inhibitors or tamoxifen + GnRH analogues or aromatase inhibitors + GnRH analogues, and about to start treatment with oral bone resorption inhibitors (alendronate), and meeting the other criteria

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Regina Elena Cancer Institute: lead

Study Sites (2)

Santa Maria Goretti Hospital

Latina, Italy, 04100, Italy

NOT YET RECRUITING

Regina Elena National Cancer Institute

Roma, Italy, 00144, Italy

RECRUITING

Related Publications (11)

• 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.

  PMID: 39861434 BACKGROUND

• 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.

  PMID: 24646824 BACKGROUND

• 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.

  PMID: 32670820 BACKGROUND

• 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.

  PMID: 33090422 BACKGROUND

• 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.

  PMID: 36737996 BACKGROUND

• 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.

  PMID: 25927875 BACKGROUND

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

  PMID: 32825311 BACKGROUND

• 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.

  PMID: 18470667 BACKGROUND

• 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.

  PMID: 23846118 BACKGROUND

• 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.

  PMID: 39125301 BACKGROUND

• 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.

  PMID: 39680363 BACKGROUND

MeSH Terms

Interventions

Cholecalciferol; Calcium Carbonate

Intervention Hierarchy (Ancestors)

Cholestenes; Cholestanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Lipids; Calcium Compounds; Inorganic Chemicals; Carbonates; Carbonic Acid; Carbon Compounds, Inorganic; Minerals

Study Officials

• Marialuisa Appetecchia, MD

  Regina Elena National Cancer Insitute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Marialuisa Appetecchia, MD

CONTACT

0039 0652666026; marialuisa.appetecchia@ifo.it

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: November 18, 2025
• First Posted: December 1, 2025
• Study Start: September 29, 2025
• Primary Completion (Estimated): September 29, 2027
• Study Completion (Estimated): March 31, 2028
• Last Updated: December 1, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Time Frame: Data will be available after study publication
• Access Criteria: Data will be available for free

Locations

IT (2)