Osteoporosis, Postmenopausal
Conditions
Brief summary
This study will evaluate whether the once weekly administration of the combination tablet alendronate/vitamin D3 (FOSAMAX PLUS) will increase lumbar spine bone mineral density (BMD) more than the daily use of calcitriol.
Detailed description
This was a 6-month, randomized, open-label, active-comparator controlled, parallel-group study with a 6-month extension to evaluate the safety and efficacy of alendronate sodium 70 mg plus vitamin D3 5600 IU combination tablets versus calcitriol in the treatment of osteoporosis in postmenopausal women in China. Participants were randomly assigned to receive alendronate 70 mg plus vitamin D3 5600 IU combination tablet once weekly orally or calcitriol 0.25 μg daily orally.
Interventions
DRUGalendronate 70-mg/vitamin D3 5600 IU combination tablet (Fosamax Plus)
one combination tablet once weekly
DRUGCalcitriol
0.25 μg once daily orally
DIETARY_SUPPLEMENTCalcium 500 mg
one 500 mg tablet once daily
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
56 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Meets one of the following BMD criteria: * Has BMD T-score ≤-2.5 in at least one of the anatomic sites including lumbar spine, total hip, and femoral neck, OR * Has prior non-pathological fragility fracture (of spine, wrist, humerus or clavicle) and BMD T-score ≤-1.5 in at least one of the anatomic sites including lumbar spine, total hip, and femoral neck sites * Must have a baseline 25-hydroxyvitamin D ≥8 ng/mL (20 nmol/L) * Is ambulatory * Has been postmenopausal for at least one year
Exclusion criteria
* Has any contraindication to alendronate, including abnormalities of the esophagus which delay esophageal emptying (such as stricture or achalasia), or inability to stand/sit upright for at least 30 minutes, or hypersensitivity to alendronate and vitamin D, or hypocalcemia * Has any contraindications to calcitriol, and/or vitamin D, including hypercalcemia, hypercalciuria, or active kidney stone disease * Had a prior hip fracture * Has received treatment with any of the following: anabolic steroid agent within the past 12 months, systemic glucocorticoids for more than 2 weeks in the past 6 months, oral bisphosphonates more than 3 months within the past 2 years, any lifetime use of an intravenous administration of zoledronate, immunosuppressant other than methotrexate, fluoride treatment at a dose greater than 1 mg/day for more than 2 weeks within the past 3 months, strontium containing products for more than 2 weeks within the past 6 months, Parathyroid hormone for more than 2 weeks within the past 3 months, current use of chemotherapy, or heparin, growth hormone for more than 2 weeks within the past 6 months, active hormonal vitamin D analogs (e.g., alphacalcidol, calcitriol) in the past 30 days, or more than 5 days treatment of active hormonal vitamin D analogs between 30 and 60 days prior to study entry., use of vitamin A (excluding beta carotene) \>10,000 IU daily, unless willing to discontinue this dose during the study, current use of, lithium, or anti-convulsants, current use of calcium supplement in amount excess of 1500 mg daily, unless willing to discontinue this dose during the study, estrogen with or without progestin within the prior 6 months, Raloxifene or other selective estrogen receptor modulator (\[SERM\] including tamoxifen), tibolone, or an aromatase inhibitor within the prior 6 months and/or sub-cutaneous calcitonin or intra-nasal calcitonin within the prior 6 months * Has a history of malignancy within previous 5 years * Has one or more of the following concomitant conditions: uncontrolled upper gastrointestinal disorders, myocardial infarction, unstable angina, stroke and revascularization condition within 3 months, malabsorption syndrome, uncontrolled primary or secondary hyperparathyroidism, uncontrolled thyroid disease, renal insufficiency, uncontrolled genitourinary, cardiovascular, hepatic, renal, endocrine, hematologic, neurological, psychiatric, or pulmonary diseases; unexplained laboratory test abnormality or other conditions, uncontrolled hypertension, new onset diabetes (within 3 months), poorly controlled hyperglycemia or abnormal fasting glucose, hypoglycemia for any cause, history of, or evidence for metabolic bone disease other than osteoporosis, abnormal serum calcium or phosphate, and/or active renal stone disease when a calcium supplement is contraindicated
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Extension Study: Percentage Change From Baseline in Lumbar Spine BMD at Month 12 | Baseline and Month 12 | BMD at the lumbar spine was assessed by DXA at baseline and Month 12. |
| Base Study: Percentage Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at Month 6 | Baseline and Month 6 | BMD at the lumbar spine was assessed by dual energy X-ray absorptiometry (DXA) at baseline and Month 6. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Base Study: Percentage Change From Baseline in Serum C-Telopeptides of Type 1 Collagen (s-CTx) at Month 6 | Baseline and Month 6 | s-CTx is a biochemical marker for bone turnover that has been shown to detect increased bone resorption, a process by which bone is broken down within the body. s-CTx was measured at baseline and Month 6. |
| Extension Study: Percentage Change From Baseline in s-CTx at Month 12 | Baseline and Month 12 | s-CTx is a biochemical marker for bone turnover that has been shown to detect increased bone resorption, a process by which bone is broken down within the body. s-CTx was measured at baseline and Month 12. |
| Extension Study: Percentage Change From Baseline in s-P1NP at Month 12 | Baseline and Month 12 | s-P1NP is a biochemical marker of bone turnover that is particularly useful in monitoring bone resorption, a process by which bone is broken down within the body. s-P1NP was measured at baseline and Month 12. |
| Base Study: Percentage Change From Baseline in Serum Procollagen Type 1 N-Terminal Propeptide (s-P1NP) at Month 6 | Baseline and Month 6 | s-P1NP is a biochemical marker of bone turnover that is particularly useful in monitoring bone resorption, a process by which bone is broken down within the body. s-P1NP was measured at baseline and Month 6. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Extension Study: Percentage of Participants With Serum 25-Hydroxyvitamin (OH) D <20 ng/mL at Month 12 | Baseline and Month 12 | The term vitamin D insufficiency is used to describe vitamin D levels that are low enough to cause secondary hyperparathyroidism, bone loss, and increased risk of skeletal fracture. In this study, a threshold for vitamin D insufficiency was a level of serum 25(OH) D \<20 ng/mL. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fosamax Plus Participants received alendronate 70 mg plus vitamin D3 5600 IU in a combination tablet (FOSAMAX PLUS D) once weekly for 6 months (base study), and then once weekly for another 6 months (extension study). | 101 |
| Calcitriol Participants received calcitriol 0.25 μg once daily orally for 6 months (base study), and then once daily orally for another 6 months (extension study). | 107 |
| Total | 208 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Base Study | Adverse Event | 6 | 0 |
| Base Study | Lost to Follow-up | 1 | 0 |
| Base Study | Non-Compliance With Study Drug | 2 | 0 |
| Base Study | Protocol Violation | 1 | 1 |
| Base Study | Withdrawal by Subject | 1 | 2 |
| Extension Study | Adverse Event | 2 | 1 |
| Extension Study | Lack of Efficacy | 0 | 1 |
| Extension Study | Lost to Follow-up | 2 | 0 |
| Extension Study | Protocol Violation | 1 | 1 |
| Extension Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Fosamax Plus | Calcitriol | Total |
|---|---|---|---|
| Age, Continuous | 65.6 Years STANDARD_DEVIATION 7.97 | 64.8 Years STANDARD_DEVIATION 7.44 | 65.2 Years STANDARD_DEVIATION 7.69 |
| Sex: Female, Male Female | 101 Participants | 107 Participants | 208 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 | 39 / 107 | 44 / 108 |
| serious Total, serious adverse events | 4 / 107 | 5 / 108 |
Outcome results
Primary
Base Study: Percentage Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at Month 6
BMD at the lumbar spine was assessed by dual energy X-ray absorptiometry (DXA) at baseline and Month 6.
Time frame: Baseline and Month 6
Population: Full Analysis Set (FAS) population, which consisted of all randomized participants who received at least one dose of study treatment, had at least one post-randomization observation for the analysis endpoint subsequent to at least one dose of study treatment, and had baseline data for analyses that required baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fosamax Plus | Base Study: Percentage Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at Month 6 | 3.54 Percent change | 95% Confidence Interval 0.107 |
| Calcitriol | Base Study: Percentage Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at Month 6 | 1.59 Percent change | 95% Confidence Interval 0.1101 |
p-value: <0.00195% CI: [0.8, 3.1]Longitudinal data analysis
Primary
Extension Study: Percentage Change From Baseline in Lumbar Spine BMD at Month 12
BMD at the lumbar spine was assessed by DXA at baseline and Month 12.
Time frame: Baseline and Month 12
Population: Full Analysis Set (FAS) population, which consisted of all randomized participants who received at least one dose of study treatment, had at least one post-randomization observation for the analysis endpoint subsequent to at least one dose of study treatment, and had baseline data for analyses that required baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Fosamax Plus | Extension Study: Percentage Change From Baseline in Lumbar Spine BMD at Month 12 | 5.17 Percent change |
| Calcitriol | Extension Study: Percentage Change From Baseline in Lumbar Spine BMD at Month 12 | 2.26 Percent change |
p-value: <0.00195% CI: [1.8, 4.1]Longitudinal data analysis
Secondary
Base Study: Percentage Change From Baseline in Serum C-Telopeptides of Type 1 Collagen (s-CTx) at Month 6
s-CTx is a biochemical marker for bone turnover that has been shown to detect increased bone resorption, a process by which bone is broken down within the body. s-CTx was measured at baseline and Month 6.
Time frame: Baseline and Month 6
Population: Per-Protocol Set (PPS) population, which consisted of participants who received one dose of study treatment, had baseline measurement and had a Month 6 observation for the analysis endpoint, but excluded participants with at least one major protocol deviation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Fosamax Plus | Base Study: Percentage Change From Baseline in Serum C-Telopeptides of Type 1 Collagen (s-CTx) at Month 6 | -79.23 Percent change |
| Calcitriol | Base Study: Percentage Change From Baseline in Serum C-Telopeptides of Type 1 Collagen (s-CTx) at Month 6 | -27.20 Percent change |
p-value: <0.00195% CI: [-59.04, -45.3]Constrained longitudinal data analysis
Secondary
Base Study: Percentage Change From Baseline in Serum Procollagen Type 1 N-Terminal Propeptide (s-P1NP) at Month 6
s-P1NP is a biochemical marker of bone turnover that is particularly useful in monitoring bone resorption, a process by which bone is broken down within the body. s-P1NP was measured at baseline and Month 6.
Time frame: Baseline and Month 6
Population: Per-Protocol Set (PPS) population, which consisted of participants who received one dose of study treatment, had baseline measurement and had a Month 6 observation for the analysis endpoint, but excluded participants with at least one major protocol deviation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Fosamax Plus | Base Study: Percentage Change From Baseline in Serum Procollagen Type 1 N-Terminal Propeptide (s-P1NP) at Month 6 | -59.12 Percent change |
| Calcitriol | Base Study: Percentage Change From Baseline in Serum Procollagen Type 1 N-Terminal Propeptide (s-P1NP) at Month 6 | -16.75 Percent change |
p-value: <0.00195% CI: [-48.16, -36.67]Constrained longitudinal data analysis
Secondary
Extension Study: Percentage Change From Baseline in s-CTx at Month 12
s-CTx is a biochemical marker for bone turnover that has been shown to detect increased bone resorption, a process by which bone is broken down within the body. s-CTx was measured at baseline and Month 12.
Time frame: Baseline and Month 12
Population: Per-Protocol Set (PPS) population, which consisted of participants who received one dose of study treatment, had baseline measurement and had a Month 12 observation for the analysis endpoint, but excluded participants with at least one major protocol deviation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Fosamax Plus | Extension Study: Percentage Change From Baseline in s-CTx at Month 12 | -76.15 Percent change |
| Calcitriol | Extension Study: Percentage Change From Baseline in s-CTx at Month 12 | -24.19 Percent change |
p-value: <0.00195% CI: [-58.77, -45.39]Constrained longitudinal data analysis
Secondary
Extension Study: Percentage Change From Baseline in s-P1NP at Month 12
s-P1NP is a biochemical marker of bone turnover that is particularly useful in monitoring bone resorption, a process by which bone is broken down within the body. s-P1NP was measured at baseline and Month 12.
Time frame: Baseline and Month 12
Population: Per-Protocol Set (PPS) population, which consisted of participants who received one dose of study treatment, had baseline measurement and had a Month 12 observation for the analysis endpoint, but excluded participants with at least one major protocol deviation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Fosamax Plus | Extension Study: Percentage Change From Baseline in s-P1NP at Month 12 | -68.07 Percent change |
| Calcitriol | Extension Study: Percentage Change From Baseline in s-P1NP at Month 12 | -17.00 Percent change |
p-value: <0.00195% CI: [-57.29, -44.99]Constrained longitudinal data analysis
Other Pre-specified
Extension Study: Percentage of Participants With Serum 25-Hydroxyvitamin (OH) D <20 ng/mL at Month 12
The term vitamin D insufficiency is used to describe vitamin D levels that are low enough to cause secondary hyperparathyroidism, bone loss, and increased risk of skeletal fracture. In this study, a threshold for vitamin D insufficiency was a level of serum 25(OH) D \<20 ng/mL.
Time frame: Baseline and Month 12
Population: Full Analysis Set (FAS) population, which consisted of all randomized participants who received at least one dose of study treatment, had at least one post-randomization observation for the analysis endpoint subsequent to at least one dose of study treatment, and had baseline data for analyses that required baseline data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fosamax Plus | Extension Study: Percentage of Participants With Serum 25-Hydroxyvitamin (OH) D <20 ng/mL at Month 12 | 4.1 Percentage of Participants |
| Calcitriol | Extension Study: Percentage of Participants With Serum 25-Hydroxyvitamin (OH) D <20 ng/mL at Month 12 | 47.1 Percentage of Participants |
Comparison: Odds Ratio comparison of percentage of participants with \<20 ng/mL of serum 25-hydroxyvitamin (OH) D between Fosamax Plus group and Calcitriol group.p-value: <0.00195% CI: [0.0074, 0.1048]Cochran-Mantel-Haenszel