Osteoporosis SecondarySynosteaNCT07256769
Vitamin k, D-chiro Inositol and α-lactalbumin in Bone Homeostasis
An observational study of Osteoporosis Secondary and Breast Cancer Females, run by Regina Elena Cancer Institute at 2 sites in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 35 to 70 years, women only
- Conditions the study is for
- Osteoporosis Secondary, Breast Cancer Females
- What is being tested?
- Group 1: calcium carbonate/cholecalciferol and Group 2: Synostea® (calcium carbonate/cholecalciferol/vitamin K/α-lactalbumin/ d-chiro-inositol)
- How many people
- 134 participants
- Where
- 2 sitesItaly
- Study dates
- 29 Sep 2025to 31 Mar 2028
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 70 years
- Women only
- No healthy volunteers
- Adult, Older adult
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
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Italy2 sites, 2 recruiting
- Not yet recruiting
Santa Maria Goretti Hospital
Latina, Italy, 04100
Marco Centanni, MD, 07736556225, marco.centanni@uniroma1.it
Camilla Virili, MD, camilla.virili@uniroma1.it
- Recruiting
Regina Elena National Cancer Institute
Roma, Italy, 00144
Marialuisa Appetecchia, MD, 0039 0652666026, marialuisa.appetecchia@ifo.it
Giulia Puliani, MD, 0039 065266034, giulia.puliani@ifo.it
About this study
Official title: 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®
Read the 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
- Being tested
- Group 1: calcium carbonate/cholecalciferol, Group 2: Synostea® (calcium carbonate/cholecalciferol/vitamin K/α-lactalbumin/ d-chiro-inositol)
- Keywords
- Vitamin K, d-chiro-inositol, α-lactalbumin, calcium, cancer treatment induced bone loss, vitamin d, synostea
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Group 1: calcium carbonate/cholecalciferolDietary supplement
Intake of calcium carbonate 500 mg + cholecalciferol 2000 IU
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)
| Study group | Role | What they receive |
|---|---|---|
| Group 1 | Standard therapy Receives: Dietary Supplement: Group 1: calcium carbonate/cholecalciferol | |
| Group 2 | Synostea® Receives: Dietary Supplement: Group 2: Synostea® (calcium carbonate/cholecalciferol/vitamin K/α-lactalbumin/ d-chiro-inositol) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 6 months
Secondary outcomes (18)
Evaluation of the differences in Hip Bone Mineral Density by D-XA between groups
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®)
Measured: 12 months
Evaluation of the differences in lumbar fragility score by Radiofrequency Echographic Multi Spectrometry between groups
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®)
Measured: 12 months
Evaluation of the differences in serum levels of total calcium betweeeng groups after 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®)
Measured: 12 months
Evaluation of the differences in serum levels of parathyroid hormone betweeen groups after 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®)
Measured: 12 months
Evaluation of the differences in serum levels of bone alkaline phosphatase betweeen groups after 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®)
Measured: 12 months
Evaluation of the differences in serum levels of C-terminal telopeptide of type I collagen betweeen groups after 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®)
Measured: 12 months
Evaluation of the differences in 24-hour calciuria levels betweeen groups after 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®)
Measured: 12 months
Evaluation of the differences in serum levels of total calcium betweeen groups after 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®)
Measured: 6 months
Evaluation of the differences in serum levels of parathyroid hormone betweeen groups after 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®)
Measured: 6 months
Evaluation of the differences in serum levels of bone alkaline phosphatase betweeen groups after 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®)
Measured: 6 months
Evaluation of the differences in serum levels of C-terminal telopeptide of type I collagen betweeen groups after 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®)
Measured: 6 months
Evaluation of the differences in 24-hour calciuria levels betweeen groups after 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®)
Measured: 6 months
Evaluation of the differences in Lumbar Bone Mineral Density by D-XA between groups
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®)
Measured: 12 months
Evaluation of the differences in hip fragility score by Radiofrequency Echographic Multi Spectrometry between groups
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®)
Measured: 12 months
Evaluation of the differences in serum levels of total alkaline phosphatase betweeen groups after 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®)
Measured: 6 months
Evaluation of the differences in serum levels of total alkaline phosphatase betweeen groups after 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®)
Measured: 12 months
Evaluation of the differences in treatment adherence betweeen groups after 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.
Measured: 12 months
Evaluation of the differences in treatment adherence betweeen groups after 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.
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Dec 2025
- Study start29 Sep 2025
- Primary completion29 Sep 2027 (estimated)
- Study completion31 Mar 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Osteoporosis SecondaryStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Prospective
- Enrolment
- 134 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Regina Elena Cancer Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Marialuisa Appetecchia, Regina Elena Cancer Institute
- Investigators
- Marialuisa Appetecchia, MD, Principal investigator, Regina Elena National Cancer Insitute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07256769
- Sponsor's protocol ID
- RS 328/IRE/25
- Acronym
- Synostea
- Status last verified
- Nov 2025
- First submitted
- 18 Nov 2025
- Last updated
- 1 Dec 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: IPD will be published in GARRbox
Publications
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.
PubMed 39861434Weaver 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.
PubMed 24646824Caputo 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.
PubMed 32670820Ranaldi 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.
PubMed 33090422Wang 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.
PubMed 36737996Perego 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.
PubMed 25927875Permyakov EA. alpha-Lactalbumin, Amazing Calcium-Binding Protein. Biomolecules. 2020 Aug 20;10(9):1210. doi: 10.3390/biom10091210.
PubMed 32825311Hirao 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.
PubMed 18470667Kasukawa 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.
PubMed 23846118Aaseth 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.
PubMed 39125301Defeudis 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.
PubMed 39680363
Study at a glance
From the registry record, last updated by the sponsor on 1 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Synergic Role of Vitamin k, D-chiro Inositol and α-lactalbumin in Bone Homeostasis in Breast Cancer Patients Treated With Aromatase Inhibitors
- ClinicalTrials.gov ID
- NCT07256769
- Acronym / sponsor ID
- Synostea / RS 328/IRE/25
- Conditions
- Osteoporosis Secondary, Breast Cancer Females
- Keywords
- Vitamin K, d-chiro-inositol, α-lactalbumin, calcium, cancer treatment induced bone loss, vitamin d, synostea
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 134 participants (estimated)
- Lead sponsor
- Regina Elena Cancer InstituteUniversity, hospital or other
- Study start
- 29 Sep 2025 (actual)
- Primary completion
- 29 Sep 2027 (estimated)
- Study completion
- 31 Mar 2028 (estimated)
- First posted
- 1 Dec 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Other
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group 1 | – | Dietary Supplement: Group 1: calcium carbonate/cholecalciferolStandard therapy |
| Group 2 | – | Dietary Supplement: Group 2: Synostea® (calcium carbonate/cholecalciferol/vitamin K/α-lactalbumin/ d-chiro-inositol)Synostea® |
Who may qualify
- Ages
- 35 to 70 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (8 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Group 1: calcium carbonate/cholecalciferolIntake of calcium carbonate 500 mg + cholecalciferol 2000 IU | Dietary supplement | Group 1 |
| 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) | Dietary supplement | Group 2 |
Primary outcome
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
18 secondary outcomes
Evaluation of the differences in Hip Bone Mineral Density by D-XA between groups
Time frame: 12 months
Evaluation of the differences in lumbar fragility score by Radiofrequency Echographic Multi Spectrometry between groups
Time frame: 12 months
Evaluation of the differences in serum levels of total calcium betweeeng groups after 12 months
Time frame: 12 months
Evaluation of the differences in serum levels of parathyroid hormone betweeen groups after 12 months
Time frame: 12 months
Evaluation of the differences in serum levels of bone alkaline phosphatase betweeen groups after 12 months
Time frame: 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
Evaluation of the differences in 24-hour calciuria levels betweeen groups after 12 months
Time frame: 12 months
Evaluation of the differences in serum levels of total calcium betweeen groups after 6 months
Time frame: 6 months
Evaluation of the differences in serum levels of parathyroid hormone betweeen groups after 6 months
Time frame: 6 months
Evaluation of the differences in serum levels of bone alkaline phosphatase betweeen groups after 6 months
Time frame: 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
Evaluation of the differences in 24-hour calciuria levels betweeen groups after 6 months
Time frame: 6 months
Evaluation of the differences in Lumbar Bone Mineral Density by D-XA between groups
Time frame: 12 months
Evaluation of the differences in hip fragility score by Radiofrequency Echographic Multi Spectrometry between groups
Time frame: 12 months
Evaluation of the differences in serum levels of total alkaline phosphatase betweeen groups after 6 months
Time frame: 6 months
Evaluation of the differences in serum levels of total alkaline phosphatase betweeen groups after 12 months
Time frame: 12 months
Evaluation of the differences in treatment adherence betweeen groups after 12 months
Time frame: 12 months
Evaluation of the differences in treatment adherence betweeen groups after 6 months
Time frame: 6 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Dec 2025.
- Background: PubMed 39861434Atieh 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.
- Background: PubMed 24646824Weaver 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.
- Background: PubMed 32670820Caputo 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.
- Background: PubMed 33090422Ranaldi 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.
- Background: PubMed 36737996Wang 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.
- Background: PubMed 25927875Perego 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.
- Background: PubMed 32825311Permyakov EA. alpha-Lactalbumin, Amazing Calcium-Binding Protein. Biomolecules. 2020 Aug 20;10(9):1210. doi: 10.3390/biom10091210.
- Background: PubMed 18470667Hirao 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.
- Background: PubMed 23846118Kasukawa 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.
- Background: PubMed 39125301Aaseth 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.
- Background: PubMed 39680363Defeudis 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.
- Individual participant dataSharing planned: Yes. IPD will be published in GARRbox
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Marialuisa Appetecchia, MD principal investigator
Regina Elena National Cancer Insitute
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Osteoporosis Secondary and Breast Cancer Females, run by Regina Elena Cancer Institute at 2 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 1 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Marialuisa Appetecchia, MD (0039 0652666026, marialuisa.appetecchia@ifo.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07256769, which also lists 11 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Dec 2025.