Post-menopausal OsteoporosisPhase 2/3VITKANDOPNCT01232647
Vitamin K as Additive Treatment in Osteoporosis
A Phase 2/3 study testing Phylloquinone and Menatetrenone (MK4) in people with Post-menopausal Osteoporosis, run by Guy's and St Thomas' NHS Foundation Trust at 2 sites in United Kingdom.
Trial summary
Vitamin K is thought to be important for bone health because it activates several proteins involved in bone formation. Poor dietary intake of vitamin K (mainly found in dark green leafy vegetables) is associated with bone loss and fractures. Read more about this study
- Who is it for?
- Ages 55 to 85 years, women only
- Conditions the study is for
- Post-menopausal Osteoporosis
- What is being tested?
- Phylloquinone and Menatetrenone (MK4)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 105 participants
- Where
- 2 sitesUnited Kingdom
- Study dates
- Apr 2015to 31 Mar 2020
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
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 55 to 85 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Inclusion in the cross-sectional part of the study which involves assessment of vitamin K status
- Informed consent to screening stage : assessment of vitamin K status
- serum vitamin K concentration < 0.35 ug/ml
- 1. ambulatory post-menopausal women aged between 55-85 years 2. Post-menopausal osteoporosis ( history of previous fragility fractures or BMD evidence of osteoporosis or osteopenia with at least one clinical risk factors such as low BMI, positive family history of osteoporosis) 3. Treatment with a bisphosphonate and calcium/vitamin D supplements for at least 12 months 4. Informed written consent 5. e GFR >30 ml/min 6. normocalcaemia
Who cannot join
- Age <55 years, or > 85 years
- Male gender
- severe renal impairment (CKD stage 4 and 5)
- poor mobility (inability to walk 100 yards unaided)
- malabsorption (extensive bowel surgery, short bowel)
- generalised carcinomatosis
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- glucocorticoid therapy
- inflammatory disorders (e.g. active rheumatoid arthritis, inflammatory bowel disease requiring oral glucocorticoids),
- endocrine diseases (e.g. primary hyperparathyroidism, hyperthyroidism).
- chronic liver disease
- current treatment with teriparatide, strontium ranelate
- Participation in a trial with an investigational product within the previous 3 months
- Serum vitamin K > 0.35 µg/ml
- patients on anti-coagulants such as warfarin
Trial locations and contacts
2 sites in 1 country.
United Kingdom2 sites
Guy's and St Thomas' Hospital NHS foundation Trust
London, SE1 7EH
Osteoporosis Unit, Guy's Hospital
London, SE1 9RT
About this study
Official title: The Additive Effect of Vitamin K Supplementation and Bisphosphonate on Fracture Risk in Post-menopausal Osteoporosis
Vitamin K is thought to be important for bone health because it activates several proteins involved in bone formation. Poor dietary intake of vitamin K (mainly found in dark green leafy vegetables) is associated with bone loss and fractures. Giving supplements of the main dietary form of vitamin K (called K1) or another common form which our bodies make from K1(called MK4), to improve bone health have given mixed results. This confusion is thought to have arisen because these studies involved people who already had enough vitamin K or did not have osteoporosis. We want to test the hypothesis that treatment with bisphosphonates combined with vitamin K, in vitamin K deplete elderly women with osteoporosis, may offer additional benefit on skeletal metabolism and reduction of fracture risk. We want to test this by measuring vitamin K status in post-menopausal women with osteoporosis who are on the recommended treatment with a bisphosphonate and calcium/vitamin D supplements. Those with low vitamin K will then be recruited to study the effect of supplementation with either K1 or MK4.
Read the detailed description
Vitamin K is important for skeletal health. Vitamin K is essential for the carboxylation of several Gla proteins in bone which are implicated in bone formation and mineralization. These include osteocalcin (OC) and matrix Gla protein (MGP). Carboxylation of the glutamic acid residues of these proteins optimises their function. Vitamin K occurs as either phylloquinone (vitamin K1) which is the major dietary form or menaquinones (MKs or vitamin K2) which are mainly of bacterial origin. MK4 of the vitamin K2 series has additional, carboxylation-independent, functions including the regulation of osteoblastic specific markers such as alkaline phosphatase (BALP), and osteoprotegerin (OPG) and has inhibitory effects on osteoclast activity. Several observational studies have shown that low vitamin K status is associated with low bone mineral density (BMD) and increased fracture risk, although proof of causality is lacking. The results of several placebo-controlled clinical trials of vitamin K1 and MK4 have been conflicting with some, but not all, showing a positive effect of vitamin K1 on BMD or bone turnover. Positive fracture efficacy has been demonstrated with high-dose MK4, although most trials were on Japanese women. These intervention studies may have been hampered by the study design such as inclusion of vitamin K replete subjects or healthy non-osteoporotic women. The use of vitamin K in the prevention of bone loss and/or fractures in high-risk post-menopausal women with osteoporosis who are vitamin K deplete merits further investigations. The prevalence of low vitamin K stores is high in elderly subjects with osteoporosis. Preliminary data in Japanese women suggest that combined treatment with a bisphosphonate and vitamin K, at least vitamin K2 (MK4), appears to have an additive beneficial effect on BMD and bone resorption. There have been no such studies in a caucasian osteoporotic population. We want to test the hypothesis that treatment with bisphosphonates combined with vitamin K, in vitamin K deplete elderly women with osteoporosis, may offer additional benefit on skeletal metabolism and reduction of fracture risk.
The first part will be a cross-sectional study of post-menopausal women with osteoporosis aged between 60-80 years who are on treatment with bisphosphonate. Their vitamin K status will be determined and those patients who are found to have low vitamin K concentrations defined as <0.35 ug/ml will be invited to take part in an 18 months prospective randomised placebo controlled trial.
Eligible patients will be randomised to 3 arms (35 patients in each arm). All 3 groups will continue to receive weekly oral bisphosphonate (commonly Alendronate 70 mg weekly) and adjunctive calcium/vitamin D supplements (1.0g of calcium and 800 I.U of cholecalciferol). The control arm (Group A) will receive placebo. Group B will receive 1.0mg daily of vitamin K1 and MK4 placebo. Group C will receive vitamin K2 (MK4) 45 mg daily and vitamin K1 placebo. Patients will be seen at baseline and at 3, 6, 12 and 18 months. Changes in BMD at the lumbar spine, hip, fore-arm at 18 months and the biochemical parameters at each time point will be compared between the groups.
- Conditions
- Post-menopausal Osteoporosis
- Being tested
- Phylloquinone, Menatetrenone (MK4), placebo
- Keywords
- osteoporosis, vitamin K, BONE MINERAL DENSITY, BIOCHEMICAL MARKERS OF BONE TURNOVER
- Medical subject headings
- Osteoporosis, Postmenopausal, Osteoporosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PhylloquinoneDrug
Also called Vitamin K1
1.0 mg daily of vitamin K1
Menatetrenone (MK4)Drug
Also called Vitamin K2
Menatetrenone (MK4) 45 mg daily
placeboDrug
Also called dummy pill
placebo vitamin K1 and placebo MK4 given daily for 18 months
| Study group | Role | What they receive |
|---|---|---|
| Vitamin k1 | Active comparator | 1.0 mg of vitamin K1 (phylloquinone) and placebo MK4 will be given to one of the treatment arm for 18 months Receives: Drug: Phylloquinone |
| placebo vitamin K1 and MK4 | Placebo comparator | placebo pill of both vitamin K1 and MK4 given for 18 months to the control arm Receives: Drug: placebo |
| Menatetrenone MK4 | Active comparator | 45 mg MK4 given daily and placebo vitamin K1 will be given to one of treatment arm for 18 months Receives: Drug: Menatetrenone (MK4) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Primary outcome measures- Changes in BMD at the Lumber spine, hip, fore-arm at 18 months.
Measurement of changes in bone mineral density by DXA scan.
Measured: 18 months
Secondary outcomes (1)
Secondary outcome measure- Bone Turnover as assessed by the biochemical markers (serum CTX, P1NP, BALP, carboxylated and undercarboxylated osteocalcin (OC), OPG). These markers will be measured at the same time point during each clinic visit.
Laboratory analyses of serum and/or plasma at baseline, 3, 6, 12 and 18 months.
Measured: 18 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Nov 2010 (estimated)
- Study startApr 2015
- Primary completion31 Mar 2020 (estimated)
- Study completion31 Mar 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Post-menopausal OsteoporosisStudies of the same condition, open and under way.
- More trials run by Guy's and St Thomas' NHS Foundation TrustThe sponsor's other registered studies.
- 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
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 105 participants (actual)
Sponsor and investigators
- Lead sponsor
- Guy's and St Thomas' NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Geeta Hampson, MD, Study director, Guy's and St Thomas' NHS Foundation Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01232647
- Sponsor's protocol ID
- Eudract number - 2010-02258712
- Acronym
- VITKANDOP
- Status last verified
- Feb 2020
- First submitted
- 1 Nov 2010
- Last updated
- 13 Feb 2020
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Publications
Moore AE, Dulnoan D, Voong K, Ayis S, Mangelis A, Gorska R, Harrington DJ, Tang JCY, Fraser WD, Hampson G. The additive effect of vitamin K supplementation and bisphosphonate on fracture risk in post-menopausal osteoporosis: a randomised placebo controlled trial. Arch Osteoporos. 2023 Jun 20;18(1):83. doi: 10.1007/s11657-023-01288-w.
PubMed 37338608
Study at a glance
From the registry record, last updated by the sponsor on 13 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Additive Effect of Vitamin K Supplementation and Bisphosphonate on Fracture Risk in Post-menopausal Osteoporosis
- ClinicalTrials.gov ID
- NCT01232647
- Acronym / sponsor ID
- VITKANDOP / Eudract number - 2010-02258712
- Conditions
- Post-menopausal Osteoporosis
- Keywords
- osteoporosis, vitamin K, BONE MINERAL DENSITY, BIOCHEMICAL MARKERS OF BONE TURNOVER
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 105 participants (actual)
- Lead sponsor
- Guy's and St Thomas' NHS Foundation TrustUniversity, hospital or other
- Study start
- Apr 2015 (actual)
- Primary completion
- 31 Mar 2020 (estimated)
- Study completion
- 31 Mar 2020 (estimated)
- First posted
- 2 Nov 2010 (estimated)
- 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.
Vitamin K is thought to be important for bone health because it activates several proteins involved in bone formation. Poor dietary intake of vitamin K (mainly found in dark green leafy vegetables) is associated with bone loss and fractures. Giving supplements of the main dietary form of vitamin K (called K1) or another common form which our bodies make from K1(called MK4), to improve bone health have given mixed results. This confusion is thought to have arisen because these studies involved people who already had enough vitamin K or did not have osteoporosis. We want to test the hypothesis that treatment with bisphosphonates combined with vitamin K, in vitamin K deplete elderly women with osteoporosis, may offer additional benefit on skeletal metabolism and reduction of fracture risk. We want to test this by measuring vitamin K status in post-menopausal women with osteoporosis who are on the recommended treatment with a bisphosphonate and calcium/vitamin D supplements. Those with low vitamin K will then be recruited to study the effect of supplementation with either K1 or MK4.
Detailed description
Vitamin K is important for skeletal health. Vitamin K is essential for the carboxylation of several Gla proteins in bone which are implicated in bone formation and mineralization. These include osteocalcin (OC) and matrix Gla protein (MGP). Carboxylation of the glutamic acid residues of these proteins optimises their function. Vitamin K occurs as either phylloquinone (vitamin K1) which is the major dietary form or menaquinones (MKs or vitamin K2) which are mainly of bacterial origin. MK4 of the vitamin K2 series has additional, carboxylation-independent, functions including the regulation of osteoblastic specific markers such as alkaline phosphatase (BALP), and osteoprotegerin (OPG) and has inhibitory effects on osteoclast activity. Several observational studies have shown that low vitamin K status is associated with low bone mineral density (BMD) and increased fracture risk, although proof of causality is lacking. The results of several placebo-controlled clinical trials of vitamin K1 and MK4 have been conflicting with some, but not all, showing a positive effect of vitamin K1 on BMD or bone turnover. Positive fracture efficacy has been demonstrated with high-dose MK4, although most trials were on Japanese women. These intervention studies may have been hampered by the study design such as inclusion of vitamin K replete subjects or healthy non-osteoporotic women. The use of vitamin K in the prevention of bone loss and/or fractures in high-risk post-menopausal women with osteoporosis who are vitamin K deplete merits further investigations. The prevalence of low vitamin K stores is high in elderly subjects with osteoporosis. Preliminary data in Japanese women suggest that combined treatment with a bisphosphonate and vitamin K, at least vitamin K2 (MK4), appears to have an additive beneficial effect on BMD and bone resorption. There have been no such studies in a caucasian osteoporotic population. We want to test the hypothesis that treatment with bisphosphonates combined with vitamin K, in vitamin K deplete elderly women with osteoporosis, may offer additional benefit on skeletal metabolism and reduction of fracture risk.
The first part will be a cross-sectional study of post-menopausal women with osteoporosis aged between 60-80 years who are on treatment with bisphosphonate. Their vitamin K status will be determined and those patients who are found to have low vitamin K concentrations defined as <0.35 ug/ml will be invited to take part in an 18 months prospective randomised placebo controlled trial.
Eligible patients will be randomised to 3 arms (35 patients in each arm). All 3 groups will continue to receive weekly oral bisphosphonate (commonly Alendronate 70 mg weekly) and adjunctive calcium/vitamin D supplements (1.0g of calcium and 800 I.U of cholecalciferol). The control arm (Group A) will receive placebo. Group B will receive 1.0mg daily of vitamin K1 and MK4 placebo. Group C will receive vitamin K2 (MK4) 45 mg daily and vitamin K1 placebo. Patients will be seen at baseline and at 3, 6, 12 and 18 months. Changes in BMD at the lumbar spine, hip, fore-arm at 18 months and the biochemical parameters at each time point will be compared between the groups.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Vitamin k1 | Active comparator | Drug: Phylloquinone1.0 mg of vitamin K1 (phylloquinone) and placebo MK4 will be given to one of the treatment arm for 18 months |
| placebo vitamin K1 and MK4 | Placebo comparator | Drug: placeboplacebo pill of both vitamin K1 and MK4 given for 18 months to the control arm |
| Menatetrenone MK4 | Active comparator | Drug: Menatetrenone (MK4)45 mg MK4 given daily and placebo vitamin K1 will be given to one of treatment arm for 18 months |
Who may qualify
- Ages
- 55 to 85 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Inclusion in the cross-sectional part of the study which involves assessment of vitamin K status
- Informed consent to screening stage : assessment of vitamin K status
- serum vitamin K concentration < 0.35 ug/ml
- 1. ambulatory post-menopausal women aged between 55-85 years 2. Post-menopausal osteoporosis ( history of previous fragility fractures or BMD evidence of osteoporosis or osteopenia with at least one clinical risk factors such as low BMI, positive family history of osteoporosis) 3. Treatment with a bisphosphonate and calcium/vitamin D supplements for at least 12 months 4. Informed written consent 5. e GFR >30 ml/min 6. normocalcaemia
Key exclusion criteria (14 listed)
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 |
|---|---|---|
| PhylloquinoneAlso: Vitamin K11.0 mg daily of vitamin K1 | Drug | Vitamin k1 |
| Menatetrenone (MK4)Also: Vitamin K2Menatetrenone (MK4) 45 mg daily | Drug | Menatetrenone MK4 |
| placeboAlso: dummy pillplacebo vitamin K1 and placebo MK4 given daily for 18 months | Drug | placebo vitamin K1 and MK4 |
Primary outcome
Primary outcome measures- Changes in BMD at the Lumber spine, hip, fore-arm at 18 months.
Time frame: 18 months
Measurement of changes in bone mineral density by DXA scan.
1 secondary outcome
Secondary outcome measure- Bone Turnover as assessed by the biochemical markers (serum CTX, P1NP, BALP, carboxylated and undercarboxylated osteocalcin (OC), OPG). These markers will be measured at the same time point during each clinic visit.
Time frame: 18 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Feb 2020.
- Derived from this study: PubMed 37338608Moore AE, Dulnoan D, Voong K, Ayis S, Mangelis A, Gorska R, Harrington DJ, Tang JCY, Fraser WD, Hampson G. The additive effect of vitamin K supplementation and bisphosphonate on fracture risk in post-menopausal osteoporosis: a randomised placebo controlled trial. Arch Osteoporos. 2023 Jun 20;18(1):83. doi: 10.1007/s11657-023-01288-w.
- Individual participant dataSharing planned: Undecided
Related trials for Post-menopausal Osteoporosis
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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. This study is not recruiting at the moment.
Geeta Hampson, MD study director
Guy's and St Thomas' NHS Foundation Trust
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Phylloquinone and Menatetrenone (MK4) in people with Post-menopausal Osteoporosis, run by Guy's and St Thomas' NHS Foundation Trust at 2 sites in United Kingdom.
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 4 inclusion and 14 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: status not confirmed, as of the sponsor's last update on 13 Feb 2020. 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 United Kingdom. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Primary outcome measures- Changes in BMD at the Lumber spine, hip, fore-arm at 18 months. (time frame: 18 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 NCT01232647, which also lists 1 linked publication.
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 13 Feb 2020.