Post-Menopausal Osteopenia, Post-Menopausal Osteoporosis
Conditions
Keywords
vitamin K, bone mineral density, post-menopausal women, randomized double blind placebo controlled trial, osteoporosis, women's health
Brief summary
The purpose of this study is to determine whether supplementation with 5 mg vitamin K daily over a 2-year period will prevent bone loss in post-menopausal women with osteopenia.
Detailed description
Osteoporosis is major cause of morbidity and mortality in Canadian postmenopausal women. It is a systemic disease characterized by low bone mass and deterioration of bone microarchitecture, resulting in bone fragility and an increased risk of fractures. One in six women over the age of 50 have osteoporosis. The lifetime risk of an osteoporotic fracture for an average 50 year-old Canadian woman is \>40%. The annual health care costs for osteoporotic fractures in Canada have been estimated to exceed $1.3 billion. Recent data suggest that vitamin K supplements may decrease bone loss and prevent fractures. Vitamin K is a co-factor of gamma-glutamyl carboxylase, an enzyme that catalyzes the gamma-carboxylation of glutamic acid residues in bone matrix proteins such as osteocalcin. Vitamin K has been reported to enhance bone formation in both in vitro studies and in vivo studies in animals. Vitamin K levels are low in individuals with osteoporosis and in patients with osteoporotic fractures. The few studies examining vitamin K supplementation in humans have showed promising results with no significant side effects, but these studies had significant methodological shortcomings such as inadequate sample size and lack of randomization. The primary objective of our study is to examine whether vitamin K supplementation will increase bone mineral density in postmenopausal women with osteopenia. Our secondary objectives are to examine the possible adverse effects from long-term vitamin K supplementation, to investigate whether vitamin K will decrease risk of fractures and to determine if vitamin K affects quality of life. Our hypotheses are that vitamin K increases bone mineral density in postmenopausal women, and that there are no significant adverse effects from vitamin K supplementation.
Interventions
DIETARY_SUPPLEMENTvitamin K1 (phylloquinone)
DIETARY_SUPPLEMENTplacebo
1 pill daily
Sponsors
Canadian Institutes of Health Research (CIHR)
University Health Network, Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 100 Years
Healthy volunteers
Yes
Inclusion criteria
Postmenopausal: One year since the natural cessation of menses, or Hysterectomy with either postmenopausal status confirmed by FSH lab values, or age 55 and above AND 2. Osteopenic: T-score at baseline has to be between (and including) -1.0 and -2.0 in the lumbar spine (L1-L4), total hip or femoral neck, and the lowest reading of the above three measurements must be between -1.0 and -2.0
Exclusion criteria
1. Women ever having had a fragility fracture after age 40; 2. Women currently on anticoagulants, previously on anticoagulants in the past 3 months, or expected to be on anticoagulants in the near future; 3. Women on hormone replacement therapy, raloxifene, bisphosphonates or calcitonin during the past 3 months; 4. Women who have ever been on a bisphosphonate for more than 6 months; 5. Women previously diagnosed with Paget's disease, hyperparathyroidism, hyperthyroidism or other metabolic bone diseases; 6. Women with decompensated diseases of the liver, kidney, pancreas, lung, or heart; 7. Women with a history of active cancer in the past 5 years; 8. Women taking mega-doses of vitamin A (more than 10,000 iu per day) or E (more than 400 iu per day); 9. Women involved in other clinical trials; 10. Any women who, in the opinion of the principal investigator, is at poor medical or psychiatric risk for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Bone Mineral Density (BMD) at the Lumbar Spine (L1-L4) Between Treatment Arms. | 0 to 24 months | BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer |
| Percent Change in Bone Mineral Density (BMD) at the Total Hip Between Treatment Arms. | 0 to 24 months | BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Vitamin K1 Supplementation on Levels of Bone Formation Marker | 0-24 months | measured by osteocalcin on elecsys platform |
| Effect of Vitamin K1 Supplementation on Level of Bone Resorption Markers (C-telopeptide: CTX) | 0-24 months | measured by CTX Elisa assay on elecsys platform |
| Effect of Vitamin K1 Supplementation on Percent of Carboxylation of Osteocalcin | 0 to 24 months | measured by osteocalcin hydroxyapatite binding assay |
| Percent Change in Bone Mineral Density (BMD) at the Total Hip Between Treatment Arms. | 0 to 48 months | BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer |
| Percent Change in Bone Mineral Density (BMD) at the Femoral Neck Between Treatment Arms. | 0 to 24 months | BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer |
| Difference in Serious Adverse Events | up to 48 months | These include hospitalizations for pneumonia, heart failure, gastro-intestinal bleeding, elective and non-elective surgery, cancer and death. |
| Difference in Number of New Cancers by Treatment Arm. | up to 48 months | — |
| Difference in Number of New Clinical Fractures by Treatment Arm. | up to 48 months | these included fragility fractures |
| Percent Change in Bone Mineral Density (BMD) at the Lumbar Spine (L1-L4) Between Treatment Arms. | 0 to 48 months | BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer |
| Percent Change in Bone Mineral Density (BMD) at the Ultra-distal Radius Between Treatment Arms. | 0 to 24 months | BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer |
Countries
Canada
Participant flow
Recruitment details
recruitment from January 2002 to September 2006 through health fairs, community posters and advertisements.
Pre-assignment details
453 participants signed consent. 13 were not included in analysis(10 screen failure,3 drop out at baseline)
Participants by arm
| Arm | Count |
|---|---|
| Phyloquinone 5 mg Vitamin K1 | 217 |
| Placebo dummy pill identicle to vitamin k | 223 |
| Total | 440 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 24-48 Month Extension | Adverse Event | 1 | 3 |
| 24-48 Month Extension | Lack of Efficacy | 0 | 1 |
| 24-48 Month Extension | Other Reason | 81 | 91 |
| 24-48 Month Extension | Withdrawal by Subject | 6 | 5 |
| 24 Month Main Study | Adverse Event | 3 | 4 |
| 24 Month Main Study | Death | 1 | 1 |
| 24 Month Main Study | Lack of Efficacy | 1 | 8 |
| 24 Month Main Study | Lost to Follow-up | 3 | 2 |
| 24 Month Main Study | Protocol Violation | 4 | 2 |
| 24 Month Main Study | Withdrawal by Subject | 7 | 4 |
Baseline characteristics
| Characteristic | Phyloquinone | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.9 years | 59.2 years | 59.0 years |
| Sex: Female, Male Female | 217 Participants | 223 Participants | 440 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 217 | 10 / 223 |
| serious Total, serious adverse events | 15 / 217 | 25 / 223 |
Outcome results
Primary
Percent Change in Bone Mineral Density (BMD) at the Lumbar Spine (L1-L4) Between Treatment Arms.
BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer
Time frame: 0 to 24 months
Population: For our 2 year BMD anlayses we included all 440 women based on intention to treat using last observation carried forward for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phyloquinone | Percent Change in Bone Mineral Density (BMD) at the Lumbar Spine (L1-L4) Between Treatment Arms. | -1.28 percentage change in BMD | Standard Deviation 3.5 |
| Placebo | Percent Change in Bone Mineral Density (BMD) at the Lumbar Spine (L1-L4) Between Treatment Arms. | -1.22 percentage change in BMD | Standard Deviation 3 |
p-value: <0.05t-test, 2 sided
Primary
Percent Change in Bone Mineral Density (BMD) at the Total Hip Between Treatment Arms.
BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer
Time frame: 0 to 24 months
Population: For our 2 year BMD anlayses we included all 440 women based on intention to treat using last observation carried forward for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phyloquinone | Percent Change in Bone Mineral Density (BMD) at the Total Hip Between Treatment Arms. | -0.69 percentage change in BMD | Standard Deviation 2.8 |
| Placebo | Percent Change in Bone Mineral Density (BMD) at the Total Hip Between Treatment Arms. | -0.88 percentage change in BMD | Standard Deviation 3.2 |
p-value: <0.05t-test, 2 sided
Secondary
Difference in Number of New Cancers by Treatment Arm.
Time frame: up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phyloquinone | Difference in Number of New Cancers by Treatment Arm. | 3 events |
| Placebo | Difference in Number of New Cancers by Treatment Arm. | 12 events |
Secondary
Difference in Number of New Clinical Fractures by Treatment Arm.
these included fragility fractures
Time frame: up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phyloquinone | Difference in Number of New Clinical Fractures by Treatment Arm. | 11 events |
| Placebo | Difference in Number of New Clinical Fractures by Treatment Arm. | 21 events |
Secondary
Difference in Serious Adverse Events
These include hospitalizations for pneumonia, heart failure, gastro-intestinal bleeding, elective and non-elective surgery, cancer and death.
Time frame: up to 48 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phyloquinone | Difference in Serious Adverse Events | 15 events |
| Placebo | Difference in Serious Adverse Events | 25 events |
Secondary
Effect of Vitamin K1 Supplementation on Level of Bone Resorption Markers (C-telopeptide: CTX)
measured by CTX Elisa assay on elecsys platform
Time frame: 0-24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phyloquinone | Effect of Vitamin K1 Supplementation on Level of Bone Resorption Markers (C-telopeptide: CTX) | 0.58 ng/ml | Standard Deviation 0.21 |
| Placebo | Effect of Vitamin K1 Supplementation on Level of Bone Resorption Markers (C-telopeptide: CTX) | 0.54 ng/ml | Standard Deviation 0.21 |
Secondary
Effect of Vitamin K1 Supplementation on Levels of Bone Formation Marker
measured by osteocalcin on elecsys platform
Time frame: 0-24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phyloquinone | Effect of Vitamin K1 Supplementation on Levels of Bone Formation Marker | 21 ng/ml | Standard Deviation 7.3 |
| Placebo | Effect of Vitamin K1 Supplementation on Levels of Bone Formation Marker | 24 ng/ml | Standard Deviation 7.5 |
Secondary
Effect of Vitamin K1 Supplementation on Percent of Carboxylation of Osteocalcin
measured by osteocalcin hydroxyapatite binding assay
Time frame: 0 to 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phyloquinone | Effect of Vitamin K1 Supplementation on Percent of Carboxylation of Osteocalcin | -21.4 percentage of undercarboxylated OC | Standard Deviation 10.3 |
| Placebo | Effect of Vitamin K1 Supplementation on Percent of Carboxylation of Osteocalcin | -2.0 percentage of undercarboxylated OC | Standard Deviation 6.8 |
Secondary
Percent Change in Bone Mineral Density (BMD) at the Femoral Neck Between Treatment Arms.
BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer
Time frame: 0 to 24 months
Population: For our 2 year BMD anlayses we included all 440 women based on intention to treat using last observation carried forward for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phyloquinone | Percent Change in Bone Mineral Density (BMD) at the Femoral Neck Between Treatment Arms. | -1.47 percentage change in BMD | Standard Deviation 3.7 |
| Placebo | Percent Change in Bone Mineral Density (BMD) at the Femoral Neck Between Treatment Arms. | -1.83 percentage change in BMD | Standard Deviation 3.5 |
Secondary
Percent Change in Bone Mineral Density (BMD) at the Femoral Neck Between Treatment Arms.
BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer
Time frame: 0 to 48 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phyloquinone | Percent Change in Bone Mineral Density (BMD) at the Femoral Neck Between Treatment Arms. | -2.05 percentage change in BMD | Standard Deviation 4.3 |
| Placebo | Percent Change in Bone Mineral Density (BMD) at the Femoral Neck Between Treatment Arms. | -2.71 percentage change in BMD | Standard Deviation 4.8 |
Secondary
Percent Change in Bone Mineral Density (BMD) at the Lumbar Spine (L1-L4) Between Treatment Arms.
BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer
Time frame: 0 to 48 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phyloquinone | Percent Change in Bone Mineral Density (BMD) at the Lumbar Spine (L1-L4) Between Treatment Arms. | -0.40 percentage change in BMD | Standard Deviation 4.7 |
| Placebo | Percent Change in Bone Mineral Density (BMD) at the Lumbar Spine (L1-L4) Between Treatment Arms. | -1.76 percentage change in BMD | Standard Deviation 3.8 |
Secondary
Percent Change in Bone Mineral Density (BMD) at the Total Hip Between Treatment Arms.
BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer
Time frame: 0 to 48 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phyloquinone | Percent Change in Bone Mineral Density (BMD) at the Total Hip Between Treatment Arms. | -1.39 percentage change in BMD | Standard Deviation 3.6 |
| Placebo | Percent Change in Bone Mineral Density (BMD) at the Total Hip Between Treatment Arms. | -1.52 percentage change in BMD | Standard Deviation 4.5 |
Secondary
Percent Change in Bone Mineral Density (BMD) at the Ultra-distal Radius Between Treatment Arms.
BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer
Time frame: 0 to 48 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phyloquinone | Percent Change in Bone Mineral Density (BMD) at the Ultra-distal Radius Between Treatment Arms. | -5.35 percentage change in BMD | Standard Deviation 5.1 |
| Placebo | Percent Change in Bone Mineral Density (BMD) at the Ultra-distal Radius Between Treatment Arms. | -5.23 percentage change in BMD | Standard Deviation 4.5 |
Secondary
Percent Change in Bone Mineral Density (BMD) at the Ultra-distal Radius Between Treatment Arms.
BMD was measured yearly on one scanner at UHN using DEXA Hologic 4500A densitometer
Time frame: 0 to 24 months
Population: For our 2 year BMD anlayses we included all 440 women based on intention to treat using last observation carried forward for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phyloquinone | Percent Change in Bone Mineral Density (BMD) at the Ultra-distal Radius Between Treatment Arms. | -2.49 percentage change in BMD | Standard Deviation 4 |
| Placebo | Percent Change in Bone Mineral Density (BMD) at the Ultra-distal Radius Between Treatment Arms. | -2.55 percentage change in BMD | Standard Deviation 4.7 |