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

November 25, 2025 updated by: Marialuisa Appetecchia, Regina Elena Cancer Institute

Synergic Role of Vitamin k, D-chiro Inositol and α-lactalbumin in Bone Homeostasis in Breast Cancer Patients Treated With Aromatase Inhibitors

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®

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Estimated)

134

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
    • Italy
      • Latina, Italy, Italy, 04100
        • Not yet recruiting
        • Santa Maria Goretti Hospital
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Camilla Virili, MD
        • Sub-Investigator:
          • Maria Flavia Bagaglini, MD
      • Roma, Italy, Italy, 00144
        • Recruiting
        • Regina Elena National Cancer Institute
        • Sub-Investigator:
          • Giulia Puliani, MD
        • Contact:
        • Sub-Investigator:
          • Maria Flavia Bagaglini, MD
        • Contact:
        • Principal Investigator:
          • Marialuisa Appetecchia, MD
        • Sub-Investigator:
          • Marta Bianchini, MD
        • Sub-Investigator:
          • Marilda Mormando, MD
        • Sub-Investigator:
          • Rosa Lauretta, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

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

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Group 1
Standard therapy
Dietary supplement: Group 1: calcium carbonate/cholecalciferol
Intake of calcium carbonate 500 mg + cholecalciferol 2000 IU
Group 2
Synostea®
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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Time Frame: 6 months
Change in mean vitamin D levels in the two treatment groups after 6 months of therapy
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluation of the differences in Hip Bone Mineral Density by D-XA between groups
Time Frame: 12 months
To evaluate difference in the change from baseline in hip BMD (Bone Mineral Density) by dual x ray absorptiometry after 12 months between the 2 groups (standard vitamin d and calcium supplementation vs Synostea®)
12 months
Evaluation of the differences in lumbar fragility score by Radiofrequency Echographic Multi Spectrometry between groups
Time Frame: 12 months
To evaluate difference in the change from baseline in lumbar fragility score by Radiofrequency Echographic Multi Spectrometry after 12 months between the 2 groups (standard vitamin d and calcium supplementation vs Synostea®)
12 months
Evaluation of the differences in serum levels of total calcium betweeeng groups after 12 months
Time Frame: 12 months
To compare the changes in serum levels of total calcium after 12 months of treatment in the two groups (standard supplementationm with calcium and vitamin d vs Synostea®)
12 months
Evaluation of the differences in serum levels of parathyroid hormone betweeen groups after 12 months
Time Frame: 12 months
To compare the changes in serum levels of total calcium after 12 months of treatment in the two groups (standard supplementation with calcium and vitamin d vs Synostea®)
12 months
Evaluation of the differences in serum levels of bone alkaline phosphatase betweeen groups after 12 months
Time Frame: 12 months
To compare the changes in serum levels of bone alkaline phosphatase after 12 months of treatment in the two groups (standard supplementation with calcium and vitamin d vs Synostea®)
12 months
Evaluation of the differences in serum levels of C-terminal telopeptide of type I collagen betweeen groups after 12 months
Time Frame: 12 months
To compare the changes in serum levels of C-terminal telopeptide of type I collagen (CTX) after 12 months of treatment in the two groups (standard supplementation with calcium and vitamin d vs Synostea®)
12 months
Evaluation of the differences in 24-hour calciuria levels betweeen groups after 12 months
Time Frame: 12 months
To compare the changes in 24-hour calciuria levels after 12 months of treatment in the two groups (standard supplementation with calcium and vitamin d vs Synostea®)
12 months
Evaluation of the differences in serum levels of total calcium betweeen groups after 6 months
Time Frame: 6 months
To compare the changes in serum levels of total calcium after 6 months of treatment in the two groups (standard supplementation with calcium and vitamin d vs Synostea®)
6 months
Evaluation of the differences in serum levels of parathyroid hormone betweeen groups after 6 months
Time Frame: 6 months
To compare the changes in serum levels of parathyroid hormone after 6 months of treatment in the two groups (standard supplementation with calcium and vitamin d vs Synostea®)
6 months
Evaluation of the differences in serum levels of bone alkaline phosphatase betweeen groups after 6 months
Time Frame: 6 months
To compare the changes in serum levels of bone alkaline phosphatase after 6 months of treatment in the two groups (standard supplementation with calcium and vitamin d vs Synostea®)
6 months
Evaluation of the differences in serum levels of C-terminal telopeptide of type I collagen betweeen groups after 6 months
Time Frame: 6 months
To compare the changes in serum levels of C-terminal telopeptide of type I collagen (CTX) after 6 months of treatment in the two groups (standard supplementation with calcium and vitamin d vs Synostea®)
6 months
Evaluation of the differences in 24-hour calciuria levels betweeen groups after 6 months
Time Frame: 6 months
To compare the changes in 24-hour calciuria levels after 6 months of treatment in the two groups (standard supplementation with calcium and vitamin d vs Synostea®)
6 months
Evaluation of the differences in Lumbar Bone Mineral Density by D-XA between groups
Time Frame: 12 months
To evaluate difference in the change from baseline in lumbar BMD (Bone Mineral Density) by dual x ray absorptiometry after 12 months between the 2 groups (standard vitamin d and calcium supplementation vs Synostea®)
12 months
Evaluation of the differences in hip fragility score by Radiofrequency Echographic Multi Spectrometry between groups
Time Frame: 12 months
To evaluate difference in the change from baseline in hip fragility score by Radiofrequency Echographic Multi Spectrometry after 12 months between the 2 groups (standard vitamin d and calcium supplementation vs Synostea®)
12 months
Evaluation of the differences in serum levels of total alkaline phosphatase betweeen groups after 6 months
Time Frame: 6 months
To compare the changes in serum levels of total alkaline phosphatase after 6 months of treatment in the two groups (standard supplementation with calcium and vitamin d vs Synostea®)
6 months
Evaluation of the differences in serum levels of total alkaline phosphatase betweeen groups after 12 months
Time Frame: 12 months
To compare the changes in serum levels of total alkaline phosphatase after 12 months of treatment in the two groups (standard supplementation with calcium and vitamin d vs Synostea®)
12 months
Evaluation of the differences in treatment adherence betweeen groups after 12 months
Time Frame: 12 months
To assess the difference in treatment adherence between the two groups (standard supplementation with calcium and vitamin d vs Synostea®), evaluated using questionnaires created specifically for the study after 12 months.
12 months
Evaluation of the differences in treatment adherence betweeen groups after 6 months
Time Frame: 6 months
To assess the difference in treatment adherence between the two groups (standard supplementation with calcium and vitamin d vs Synostea®), evaluated using questionnaires created specifically for the study after 6 months.
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Regina Elena Cancer Institute

Investigators

  • Principal Investigator: Marialuisa Appetecchia, MD, Regina Elena National Cancer Insitute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 29, 2025

Primary Completion (Estimated)

September 29, 2027

Study Completion (Estimated)

March 31, 2028

Study Registration Dates

First Submitted

November 18, 2025

First Submitted That Met QC Criteria

November 25, 2025

First Posted (Actual)

December 1, 2025

Study Record Updates

Last Update Posted (Actual)

December 1, 2025

Last Update Submitted That Met QC Criteria

November 25, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RS 328/IRE/25

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

IPD will be published in GARRbox

IPD Sharing Time Frame

Data will be available after study publication

IPD Sharing Access Criteria

Data will be available for free

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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