The purpose of the event-driven base study is to determine the safety and efficacy, especially fracture risk reduction, of odanacatib in postmenopausal women diagnosed with osteoporosis. In a placebo-controlled extension of the base study, participants continued to receive the same blinded study medication for a total of up to 5 years of blinded study medication combined between the base study and the extension. After participants received 5 years of blinded study medication, they received open-label odanacatib through the end of the first extension. Participants were then invited to enroll in a second extension study in which they received open-label odanacatib for an additional 5 years. Two imaging substudies (PN032-Base/Extension and PN035) were conducted for participants in the MK-0822-018 Study. Additional safety information was collected for participants who discontinued from the base study or the blinded first extension in an observational follow-up study, MK-0822-083 (EudraCT number: 2007-002693-66) .
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
16,071
50 mg tablet orally once weekly (OW)
50 mg tablet orally OW
5600 IU orally OW
If needed. Total daily calcium intake (from both dietary and supplemental sources) will be approximately 1200 mg but not to exceed 1600 mg
Base Study: Time From Baseline to First Morphometrically-Assessed Vertebral Fracture
Morphometric vertebral fractures were assessed by central adjudication on lumbar and thoracic spinal radiographs acquired at baseline and at Months 6, 12, and subsequent yearly time points. Incident fractures (i.e., occurring after baseline) in previously normal vertebral bodies and/or those occurring after baseline in previously fractured vertebral bodies (Genant semiquantitative \[SQ\] Grade 1-3) (T4 to L4) were confirmed by quantitative morphometric (QM) and either SQ or binary SQ (yes/no) methodologies. A time-to-event methodology was used to evaluate results: life-table estimates of the incidence proportion (cumulative incidence) of participants with at least one morphometric vertebral fracture were assessed at Months 6, 12, and subsequent yearly intervals; an interval-censored approach was then used to determine incidence rate (number of participants with a morphometric fracture per 100 person-years of follow-up).
Time frame: Up to approximately 60 months of observation
Base Study: Time From Baseline to First Osteoporotic Clinical Hip Fracture (Adjudicated)
Osteoporotic clinical hip fractures were confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Hip fractures were fractures of the proximal femur confirmed as being located in the hip (i.e., sub-region not specified; cervical, and intertrochanteric). Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence rate of participants with fracture (number of participants with a fracture per 100 person-years of follow-up) is provided.
Time frame: Up to approximately 60 months of observation
Base Study: Time From Baseline to First Osteoporotic Clinical Non-Vertebral Fracture (Adjudicated)
Osteoporotic non-vertebral clinical fractures were confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Non-vertebral fractures were assessed across multiple anatomical sites including clavicle, distal femur or shaft, fibula, hip, humerus, pelvis, radius, ribs, sacrum, tibia, ulna, and wrist. Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence rate of participants with fracture (number of participants with a fracture per 100 person-years of follow-up) is provided.
Time frame: Up to approximately 60 months of observation
Base Study + First Extension: Time From Baseline to First Morphometrically-Assessed Vertebral Fracture
Morphometric vertebral fractures were confirmed by central adjudication on lumbar and thoracic spinal radiographs acquired at baseline and at Months 6, 12, and subsequent yearly time points. Incident fractures (i.e., occurring after baseline) in previously normal vertebral bodies and/or those occurring after baseline in previously fractured vertebral bodies (Genant SQ Grade 1-3) (T4 to L4) were confirmed by QM and either SQ or binary SQ (yes/no) methodologies. A time-to-event methodology was used to evaluate results: life-table estimates of the incidence proportion (cumulative incidence) of participants with at least one morphometric vertebral fracture were assessed at Months 6, 12, and subsequent yearly intervals; an interval-censored approach was then used to determine incidence rate (number of participants with a morphometric fracture per 100 person-years of follow-up).
Time frame: Up to approximately 74 months of observation
Base Study + First Extension: Time From Baseline to First Osteoporotic Clinical Hip Fracture (Adjudicated)
Osteoporotic clinical hip fractures was confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Hip fractures were fractures of the proximal femur confirmed as being located in the hip (i.e., sub-region not specified; cervical, and intertrochanteric). Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence rate of participants with fracture (number of participants with a fracture per 100 person-years of follow-up) is provided.
Time frame: Up to approximately 74 months of observation
Base Study + First Extension: Time From Baseline to First Osteoporotic Clinical Non-Vertebral Fracture (Adjudicated)
Osteoporotic non-vertebral clinical fractures were confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Non-vertebral fractures were assessed across multiple anatomical sites including clavicle, distal femur and shaft, fibula, hip, humerus, pelvis, radius, ribs, sacrum, tibia, ulna, and wrist. Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence rate of participants with fracture (number of participants with a fracture per 100 person-years of follow-up) is provided.
Time frame: Up to approximately 74 months of observation
Base Study + First Extension: Rate of Adverse Events
An adverse event is defined as any untoward medical occurrence in a person or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The incidence rate of participants with adverse events (number of participants with an event per 100 person-years of follow-up) is provided.
Time frame: Up to approximately 74 months of observation
Base Study + First Extension: Rate of Discontinuations From Study Treatment Due to an Adverse Event
An adverse event is defined as any untoward medical occurrence in a person or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The incidence rate of participant discontinuations from treatment due to adverse events (number of participants with an event per 100 person-years of follow-up) is provided.
Time frame: Up to approximately 74 months of observation
Base Study + First Extension + Second Extension: Percent Change From Baseline in Bone Mineral Density (BMD) Measurements of the Total Hip
BMD was measured by dual-energy x-ray absorptiometry (DXA) at the total hip starting at screening, and at yearly intervals until the end of the study (second extension study) for all participants who entered the second extension study. Least squares (LS) means percent change in BMD from original baseline are provided through Month 108 (Year 9). At Months 96 (Year 8) and 108 (Year 9), approximately 3% or fewer participants in each treatment group had BMD data, and results at those time points should be viewed with caution. NOTE: The mean percent change in BMD from baseline in participants originally randomized to placebo includes BMD results obtained after those participants were switched to open-label odanacatib, which occurred at different times relative to their start of blinded study medication in the base study.
Time frame: Baseline and once yearly, up to approximately 108 months of observation
Second Extension: Number of Participants Who Experienced an Adverse Event
An adverse event is defined as any untoward medical occurrence in a person or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to approximately 34 months of observation
Second Extension: Number of Participants Discontinuing Study Treatment Due to an Adverse Event
An adverse event is defined as any untoward medical occurrence in a person or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to approximately 34 months of observation
Imaging Substudy PN032-Base: Percent Change From Baseline in Volumetric Bone Mineral Density (vBMD) at the Lumbar Spine Using Quantitative Computed Tomography
Compartment-specific effects of osteoporosis were assessed by measuring trabecular vBMD at the lumbar spine (L1 total vertebral body) using quantitative computed tomography. The percent change from baseline at Month 24 (base study) was then assessed using a longitudinal data analysis model including terms for treatment, stratum (prior vertebral fracture \[yes/no\]) and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 24
Imaging Substudy PN032-Base + Extension: Percent Change From Baseline in vBMD at the Lumbar Spine Using Quantitative Computed Tomography
Compartment-specific effects of osteoporosis were assessed by measuring trabecular vBMD at the lumbar spine (L1 total vertebral body) using quantitative computed tomography. The percent change from baseline at Month 60 (base study + extension study) was then assessed using a longitudinal data analysis model including terms for treatment, stratum (prior vertebral fracture \[yes/no\]) and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 60
Sarcopenia Substudy PN035: Change From Baseline in Appendicular Lean Body Mass (aLBM)
Sarcopenia is the age-related loss of skeletal muscle mass and associated loss of strength. Progression of sarcopenia was assessed using aLBM as measured by total body DXA. The change from baseline at yearly intervals was then assessed using a longitudinal data analysis model with terms for treatment, stratum (sarcopenia, non-sarcopenia), time and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline and once yearly up to 4 years
Sarcopenia Substudy PN035: Change From Baseline in Short Physical Performance Battery (SPPB) Score
The Short Physical Performance Battery (SPPB) Score is used to assess physical function in older persons. The SPPB consists of 3 types of physical activities: standing balance, gait speed, and chair rise. Component activities are timed and then reduced to a categorical 0 to 4 scale based on time achieved. A higher composite score (range 0 to 12) indicates an improved function level. The change from baseline at yearly intervals was then assessed using a longitudinal data analysis model with terms for treatment, stratum (sarcopenia, non-sarcopenia), time and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline and once yearly up to 4 years
Sarcopenia Substudy PN035: Change From Baseline in Gait Speed
Gait speed is a component of the Short Physical Performance Battery (SPPB) Score. Participants are asked to walk a distance of 4 meters at their normal pace. The test is performed 2 times, and the walk done in the shortest time is used for scoring. The activity is timed and then reduced to a categorical 0 to 4 scale based on time achieved. Higher scores indicate an improved function level. The change from baseline at yearly intervals was then assessed using a longitudinal data analysis model with terms for treatment, stratum (sarcopenia, non-sarcopenia), time and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline and once yearly up to 4 years.
Base Study: Rate of Adverse Events
An adverse event is defined as any untoward medical occurrence in a person or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The incidence rate of participants with adverse events (number of participants with an event per 100 person-years of follow-up) is provided.
Time frame: Up to approximately 60 months of observation
Base Study: Rate of Discontinuation From Study Treatment Due to an Adverse Event
An adverse event is defined as any untoward medical occurrence in a person or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The incidence rate of participant discontinuations from treatment due to adverse events (number of participants with an event per 100 person-years of follow-up) is provided.
Time frame: Up to approximately 60 months of observation
Base Study: Time From Baseline to First Osteoporotic Clinical Vertebral Fracture (Adjudicated)
Osteoporotic vertebral clinical fractures were confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Vertebral fractures were assessed for all vertebral levels (C7, T1 to T12, L1 to L5). Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence rate of participants with fracture (number of participants with a fracture per 100 person-years of follow-up) is provided.
Time frame: Up to approximately 60 months of observation
Base Study: Yearly Rate of Height Loss
Height was measured by wall-mounted stadiometer at randomization and at yearly intervals in the base study.
Time frame: Up to approximately 60 months of observation
Base Study: Number of Participants With Height Loss of > 1 cm
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Height was measured by wall-mounted stadiometer at randomization and at yearly intervals in the base study.
Time frame: Baseline and once yearly, up to approximately 60 months of observation
Base Study: Percent Change From Baseline in BMD Measurements of the Total Hip
BMD was measured by DXA for all participants at the total hip at screening, Months 6, 12, and subsequent yearly intervals until the end of the study (base study).
Time frame: Baseline, Month 6, and once yearly, up to approximately 60 months of observation
Base Study: Percent Change From Baseline in BMD Measurements of the Lumbar Spine
BMD was measured by DXA for all participants at the lumbar spine at randomization, Months 6, 12, and subsequent yearly intervals until the end of the study (base study). Measurements were made on at least 3 vertebrae for all time points; vertebrae with fractures were excluded from analyses. at
Time frame: Baseline, Month 6, and once yearly, approximately 60 months of observation
Base Study: Percent Change From Baseline in BMD Measurements of the Femoral Neck
BMD was measured by DXA for all participants at the femoral neck-hip at screening, Months 6, 12, and subsequent yearly intervals until the end of the study (base study).
Time frame: Baseline, Month 6, and once yearly, up to approximately 60 months of observation
Base Study: Percent Change From Baseline in BMD Measurements of the Trochanter
BMD was measured by DXA for all participants at the trochanter-hip at screening, Months 6, 12, and subsequent yearly intervals until the end of the study (base study).
Time frame: Baseline, Month 6, and once yearly, up to approximately 60 months of observation
Base Study: Percent Change From Baseline in BMD Measurements of the Distal-Third Forearm
BMD was measured by DXA at the distal one-third radius at randomization and at yearly intervals until the end of the study (base study) in an approximate 10% random subset of participants at selected sites.
Time frame: Baseline and once yearly, up to approximately 60 months of observation
Base Study: Percent Change From Baseline in BMD Measurements of the Lumbar Spine in Bisphosphonate-Intolerant Participants
BMD was measured by DXA in bisphosphonate-intolerant participants at the lumbar spine at randomization, and at yearly intervals until the end of the study (base study). Measurements were made on at least 3 vertebrae for all time points; vertebrae with fractures were excluded from analyses. Bisphosphonates are anti-resorptive agents used in the treatment of osteoporosis. Bisphosphonate-intolerance was defined by contraindication or history of intolerance to bisphosphonates, or physician's determination of unsuitability for bisphosphonate treatment.
Time frame: Baseline, Month 6, and once yearly, up to approximately 60 months of observation
Base Study: Percent Change From Baseline in BMD Measurements of the Total Hip in Bisphosphonate-Intolerant Participants
BMD was measured by DXA in bisphosphonate-intolerant participants at the total hip at screening, and at yearly intervals until the end of the study (base study). Bisphosphonates are anti-resorptive agents used in the treatment of osteoporosis. Bisphosphonate-intolerance was defined by contraindication or history of intolerance to bisphosphonates, or physician's determination of unsuitability for bisphosphonate treatment.
Time frame: Baseline, Month 6, and once yearly, up to approximately 60 months of observation
Base Study: Percent Change From Baseline in BMD Measurements of the Femoral Neck in Bisphosphonate-Intolerant Participants
BMD was measured by DXA in bisphosphonate-intolerant participants at the femoral neck-hip at screening, and at yearly intervals until the end of the study (base study). Bisphosphonates are anti-resorptive agents used in the treatment of osteoporosis. Bisphosphonate-intolerance was defined by contraindication or history of intolerance to bisphosphonates, or physician's determination of unsuitability for bisphosphonate treatment.
Time frame: Baseline, Month 6, and once yearly, up to approximately 60 months of observation
Base Study: Percent Change From Baseline in BMD Measurements of the Trochanter in Bisphosphonate-Intolerant Participants
BMD was measured by DXA in bisphosphonate-intolerant participants at the trochanter-hip at screening, and at yearly intervals until the end of the study (base study). Bisphosphonates are anti-resorptive agents used in the treatment of osteoporosis. Bisphosphonate-intolerance was defined by contraindication or history of intolerance to bisphosphonates, or physician's determination of unsuitability for bisphosphonate treatment.
Time frame: Baseline, Month 6, and once yearly, up to approximately 60 months of observation
Base Study: Percent Change From Baseline in BMD Measurements of the Distal-Third Forearm in Bisphosphonate-Intolerant Participants
BMD was measured by DXA at the distal one-third radius at randomization and at yearly intervals until the end of the study (base study) in an approximate 10% random subset of bisphosphonate-intolerant participants at selected sites. Bisphosphonates are anti-resorptive agents used in the treatment of osteoporosis. Bisphosphonate-intolerance was defined by contraindication or history of intolerance to bisphosphonates, or physician's determination of unsuitability for bisphosphonate treatment.
Time frame: Baseline and once yearly, up to approximately 60 months of observation
Base Study: Percent Change From Baseline in Serum C-Telopeptides of Type I Collagen (s-CTx) After Log-Transformation
s-CTx, a biochemical marker of bone resorption by osteoclasts reflecting collagen breakdown products, was assessed at randomization, Month 6, and at yearly intervals until the end of the study (base study) in an approximate 10% random subset participants at selected sites. The log-transformed fraction from baseline in s-CTx was determined using a longitudinal model with terms for treatment, stratum, region and interaction between treatment and time as fixed effects (LS means weighted for region and stratum size). Back-transformed weighted geometric LS means values for percent change from baseline are provided.
Time frame: Baseline, Month 6, and once yearly up to 4 years
Base Study: Percent Change From Baseline in Urinary N-Telopeptides of Type I Collagen/Creatinine (u-NTx/Cr) Ratio After Log-Transformation
u-NTx, a biochemical marker of bone resorption, was assessed at randomization, Month 6, and at yearly intervals until the end of the study (base study) in an approximate 10% random subset participants at selected sites. Urine NTx measurements (in bone collagen equivalents \[BCE\]) were normalized to urine Cr concentration (i.e., u-NTx/Cr ratio) and the log-transformed fraction from baseline in u-NTx/Cr ratio was then determined using a longitudinal model with terms for treatment, stratum, region and interaction between treatment and time as fixed effects (LS means weighted for region and stratum size). Back-transformed weighted geometric LS means values for percent change from baseline are provided.
Time frame: Baseline, Month 6, and once yearly up to 4 years
Base Study: Percent Change From Baseline in Bone-Specific Alkaline Phosphatase (BSAP) After Log-Transformation
BSAP is an enzyme produced by matrix-synthesizing osteoblasts during the synthesis of collagenous bone matrix (type 1 collagen) used as a biochemical marker of bone formation. Serum BSAP was assessed at randomization, Month 6, and at yearly intervals until the end of the study (base study) in an approximate 10% random subset participants at selected sites. The log-transformed fraction from baseline in BSAP was determined using a longitudinal model with terms for treatment, stratum, and interaction between treatment and time as fixed effects (LS means weighted for stratum size). Back-transformed weighted geometric LS means values for percent change from baseline are provided.
Time frame: Baseline, Month 6, and once yearly up to 4 years
Base Study: Percent Change From Baseline in N-Terminal Propeptide of Type 1 Collagen (P1NP) After Log-Transformation
P1NP is a cleavage fragment produced during the synthesis of collagenous bone matrix (type 1 collagen) used as a biochemical marker of bone formation. Serum P1NP was assessed at randomization, Month 6, and at yearly intervals until the end of the study (base study) in an approximate 10% random subset participants at selected sites. The log-transformed fraction from baseline in P1NP was determined using a longitudinal model with terms for treatment, stratum, and interaction between treatment and time as fixed effects (LS means weighted for stratum size). Back-transformed weighted geometric LS means values for percent change from baseline are provided.
Time frame: Baseline, Month 6, and once yearly up to 4 years
Base Study: Time to First 3-Point Major Adverse Cardiac Event (MACE) Confirmed by Thrombolysis in Myocardial Infarction Study Group (TIMI) Adjudication
The time to first TIMI-adjudicated 3-point MACE (a composite outcome measure of 1. cardiovascular death, 2. non-fatal definite MI, or 3. non-fatal definite stroke) was determined for the base study using a Cox proportional hazards model with terms for treatment, stratum and geographic region. Results are expressed as number of participants with an event per 100 person-years of follow-up. Results from MK-0822-083, a follow up study to the MK-088-018 base study and the double-blind period of the first extension study for participants who discontinued prior to 5 years follow-up, are not included.
Time frame: Up to approximately 60 months of observation
Base Study: Time to First New Onset Atrial Fibrillation or Atrial Flutter Confirmed by TIMI Adjudication
The time to first TIMI-adjudicated new or presumed new onset atrial fibrillation or atrial flutter was determined for the base study using a Cox proportional hazards model with terms for treatment, stratum and geographic region. Participants with known history of atrial fibrillation or atrial flutter were excluded and electrocardiogram confirmation was not required. Results are expressed as number of participants with an event per 100 person-years of follow-up. Results from MK-0822-083, a follow up study to the MK-088-018 base study and the double-blind period of the first extension study for participants who discontinued prior to 5 years follow-up, are not included.
Time frame: Up to approximately 60 months of observation
Base Study: Time to First 4-Point MACE Confirmed by TIMI Adjudication
The time to first TIMI-adjudicated 4-point MACE (a composite outcome measure of 1. cardiovascular death, 2. non-fatal definite MI, 3. non-fatal definite stroke, or 4. hospitalization for unstable angina) was determined for the base study using a Cox proportional hazards model with terms for treatment, stratum and geographic region. Results are expressed as number of participants with an event per 100 person-years of follow-up. Results from MK-0822-083, a follow up study to the MK-088-018 base study and the double-blind period of the first extension study for participants who discontinued prior to 5 years follow-up, are not included.
Time frame: Up to approximately 60 months of observation
Base Study: Time to First Hospitalization for Unstable Angina Confirmed by TIMI Adjudication
The time to first TIMI-adjudicated hospitalization for unstable angina was determined for the base study using a Cox proportional hazards model with terms for treatment, stratum and geographic region. Results are expressed as number of participants with an event per 100 person-years of follow-up. Results from MK-0822-083, a follow up study to the MK-088-018 base study and the double-blind period of the first extension study for participants who discontinued prior to 5 years follow-up, are not included.
Time frame: Up to approximately 60 months of observation
Base Study: Time to First New Onset ECG-Confirmed Atrial Fibrillation or Atrial Flutter Confirmed by TIMI Adjudication
The time to first TIMI-adjudicated new or presumed new onset atrial fibrillation or atrial flutter was determined for the base study using a Cox proportional hazards model with terms for treatment, stratum and geographic region. Participants with known history of atrial fibrillation or atrial flutter were excluded and electrocardiogram confirmation was required. Results are expressed as number of participants with an event per 100 person-years of follow-up. Results from MK-0822-083, a follow up study to the MK-088-018 base study and the double-blind period of the first extension study for participants who discontinued prior to 5 years follow-up, are not included.
Time frame: Up to approximately 60 months of observation
Base Study: Time to First Any Atrial Fibrillation or Atrial Flutter Confirmed by TIMI Adjudication
The time to first TIMI-adjudicated any reported episode of atrial fibrillation or atrial flutter was determined for the base study using a Cox proportional hazards model with terms for treatment, stratum and geographic region. Participants with known history of atrial fibrillation or atrial flutter were included and electrocardiogram confirmation was not required. Results are expressed as number of participants with an event per 100 person-years of follow-up. Results from MK-0822-083, a follow up study to the MK-088-018 base study and the double-blind period of the first extension study for participants who discontinued prior to 5 years follow-up, are not included.
Time frame: Up to approximately 60 months of observation
Base Study: Time to First All-Cause Death Confirmed by TIMI Adjudication
The time to first TIMI-adjudicated all-cause death was determined for the base study using a Cox proportional hazards model with terms for treatment, stratum and geographic region. Results are expressed as number of participants with an event per 100 person-years of follow-up. The analysis includes data obtained from vital status data collections of participants no longer followed in the base study. Results from MK-0822-083, a follow up study to the MK-088-018 base study and the double-blind period of the first extension study for participants who discontinued prior to 5 years follow-up, are not included.
Time frame: Up to approximately 60 months of observation
Base Study: Time to First Cardiovascular Death Confirmed by TIMI Adjudication
The time to first TIMI-adjudicated cardiovascular death was determined for the base study using a Cox proportional hazards model with terms for treatment, stratum and geographic region. Results are expressed as number of participants with an event per 100 person-years of follow-up. The analysis includes data obtained from vital status data collections of participants no longer followed in the base study. Results from MK-0822-083, a follow up study to the MK-088-018 base study and the double-blind period of the first extension study for participants who discontinued prior to 5 years follow-up, are not included.
Time frame: Up to approximately 60 months of observation
Base Study: Time to First Fatal or Non-Fatal Myocardial Infarction Confirmed by TIMI Adjudication
The time to first TIMI-adjudicated fatal or non-fatal definite myocardial infarction was determined for the base study using a Cox proportional hazards model with terms for treatment, stratum and geographic region. Results are expressed as number of participants with an event per 100 person-years of follow-up. Results from MK-0822-083, a follow up study to the MK-088-018 base study and the double-blind period of the first extension study for participants who discontinued prior to 5 years follow-up, are not included.
Time frame: Up to approximately 60 months of observation
Base Study: Time to First Fatal Myocardial Infarction Confirmed by TIMI Adjudication
The time to first TIMI-adjudicated fatal definite myocardial infarction was determined for the base study using a Cox proportional hazards model with terms for treatment, stratum and geographic region. Results are expressed as number of participants with an event per 100 person-years of follow-up. Results from MK-0822-083, a follow up study to the MK-088-018 base study and the double-blind period of the first extension study for participants who discontinued prior to 5 years follow-up, are not included.
Time frame: Up to approximately 60 months of observation
Base Study: Time to First Fatal or Non-Fatal Stroke Confirmed by TIMI Adjudication
The time to first TIMI-adjudicated fatal or non-fatal definite stroke was determined for the base study using a Cox proportional hazards model with terms for treatment, stratum and geographic region. Results are expressed as number of participants with an event per 100 person-years of follow-up. Results from MK-0822-083, a follow up study to the MK-088-018 base study and the double-blind period of the first extension study for participants who discontinued prior to 5 years follow-up, are not included.
Time frame: Up to approximately 60 months of observation
Base Study: Time to First Fatal Stroke Confirmed by TIMI Adjudication
The time to first TIMI-adjudicated fatal definite stroke was determined for the base study using a Cox proportional hazards model with terms for treatment, stratum and geographic region. Results are expressed as number of participants with an event per 100 person-years of follow-up. Results from MK-0822-083, a follow up study to the MK-088-018 base study and the double-blind period of the first extension study for participants who discontinued prior to 5 years follow-up, are not included.
Time frame: Up to approximately 60 months of observation
Base Study + First Extension: Percent Change From Baseline in BMD Measurements of the Femoral Neck
BMD was measured by DXA for all participants at the femoral neck-hip at screening, Months 6, 12, and subsequent yearly intervals until the end of the study (base study + first extension-dbp).
Time frame: Baseline, Month 6, and once yearly, up to approximately 74 months of observation
Base Study + First Extension: Percent Change From Baseline in BMD Measurements of the Distal-Third Forearm
BMD was measured by DXA at the distal one-third radius at randomization and at yearly intervals until the end of the study (base study + first extension-dbp) in an approximate 10% random subset of participants at selected sites.
Time frame: Baseline and once yearly, up to approximately 74 months of observation
Base Study + First Extension: Time From Baseline to First Osteoporotic Clinical Vertebral Fracture (Adjudicated)
Osteoporotic vertebral clinical fractures were confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Vertebral fractures were assessed for all vertebral levels (C7, T1 to T12, L1 to L5). Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence rate of participants with fracture (number of participants with a fracture per 100 person-years of follow-up) is provided.
Time frame: Up to approximately 74 months of observation
Base Study + First Extension: Time From Baseline to First Osteoporotic Clinical Fracture (Adjudicated)
Osteoporotic clinical fractures (combining vertebral and non-vertebral) were confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Vertebral fractures were assessed for all vertebral levels (C7, T1 to T12, L1 to L5). Non-vertebral fractures were assessed across multiple anatomical sites including clavicle, distal femur or shaft, fibula, hip, humerus, pelvis, radius, ribs, sacrum, tibia, ulna, and wrist. Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence rate of participants with fracture (number of participants with a fracture per 100 person-years of follow-up) is provided.
Time frame: Up to approximately 74 months of observation
Base Study + First Extension: Percent Change From Baseline in BMD Measurements of the Total Hip
BMD was measured by DXA for all participants at the total hip at screening, Months 6, 12, and subsequent yearly intervals until the end of the study (base study + first extension-dbp).
Time frame: Baseline, Month 6, and once yearly, up to approximately 74 months of observation
Base Study + First Extension: Percent Change From Baseline in BMD Measurements of the Trochanter
BMD was measured by DXA for all participants at the trochanter-hip at screening, Months 6, 12, and subsequent yearly intervals until the end of the study (base study + first extension-dbp).
Time frame: Baseline, Month 6, and once yearly, up to approximately 74 months of observation
Base Study + First Extension: Percent Change From Baseline in BMD Measurements of the Lumbar Spine
BMD was measured by DXA for all participants at the lumbar spine at randomization, Months 6, 12, and subsequent yearly intervals until the end of the study (base study + first extension-dbp). Measurements were made on at least 3 vertebrae for all time points; vertebrae with fractures were excluded from analyses.
Time frame: Baseline, Month 6, and once yearly, up to approximately 74 months of observation
Base Study + First Extension + Second Extension: Time From Baseline to First Morphometrically-Assessed Vertebral Fracture
Morphometric vertebral fractures were assessed by central adjudication on lumbar and thoracic spinal radiographs acquired at baseline (base study) and at Months 6, 12, and subsequent yearly time points. Incident fractures (i.e., occurring after baseline) in previously normal vertebral bodies and/or those occurring after baseline in previously fractured vertebral bodies (Genant semiquantitative \[SQ\] Grade 1-3) (T4 to L4) were confirmed by quantitative morphometric (QM) and either SQ or binary SQ (yes/no) methodologies. A time-to-event methodology was used to evaluate results: life-table estimates of the incidence proportion (cumulative incidence) of participants with at least one morphometric vertebral fracture were assessed at Months 6, 12, and subsequent yearly intervals; an interval-censored approach was then used to determine incidence rate (number of participants with a morphometric fracture per 100 person-years of follow-up).
Time frame: Up to approximately 108 months of observation
Base Study + First Extension + Second Extension: Change in Height From Baseline Stature
Height was measured by wall-mounted stadiometer at randomization and at yearly intervals across the base study and the two extension studies.
Time frame: Baseline and once yearly, up to approximately 108 months of observation
Base Study + First Extension + Second Extension: Percent Change From Baseline in BMD Measurements of the Lumbar Spine
BMD was measured by DXA at the lumbar spine starting at randomization, and at yearly intervals until the end of the study (2nd extension study) for all participants who entered the 2nd extension study. Measurements were made on at least 3 vertebrae for all time points; vertebrae with fractures were excluded from analyses. At Months 96 and 108, approximately 3% or fewer participants in each treatment group had BMD data, and results at those time points should be viewed with caution. NOTE: The mean percent change in BMD from baseline in participants originally randomized to placebo includes BMD results obtained after those participants were switched to open-label odanacatib, which occurred at different times relative to their start of blinded study medication in the base study. A longitudinal model with terms for treatment, stratum, region \& interaction between treatment and time as fixed effects (LS means weighted for region \& stratum size) was used for analysis.
Time frame: Baseline and once yearly, up to approximately 108 months of observation
Base Study + First Extension + Second Extension: Percent Change From Baseline in BMD Measurements of the Femoral Neck
BMD was measured by DXA at the femoral neck starting at screening, and at yearly intervals until the end of the study (2nd extension study) for all participants who entered the 2nd extension study. LS means percent change in BMD from original baseline are provided through Month 108. At Months 96 and 108, approximately 3% or fewer participants in each treatment group had BMD data, and results at those time points should be viewed with caution. NOTE: The mean percent change in BMD from baseline in participants originally randomized to placebo includes BMD results obtained after those participants were switched to open-label odanacatib, which occurred at different times relative to their start of blinded study medication in the base study. A longitudinal model with terms for treatment, stratum, region and interaction between treatment and time as fixed effects (LS means weighted for region and stratum size) was used for analysis.
Time frame: Baseline and once yearly, up to approximately 108 months of observation
Base Study + First Extension + Second Extension: Percent Change From Baseline in BMD Measurements of the Trochanter
BMD was measured by DXA at the trochanter starting at screening, and at yearly intervals until the end of the study (2nd extension study) for all participants who entered the 2nd extension study. LS means percent change in BMD from original baseline are provided through Month 108. At Months 96 and 108, approximately 3% or fewer participants in each treatment group had BMD data, and results at those time points should be viewed with caution. NOTE: The mean percent change in BMD from baseline in participants originally randomized to placebo includes BMD results obtained after those participants were switched to open-label odanacatib, which occurred at different times relative to their start of blinded study medication in the base study. A longitudinal model with terms for treatment, stratum, region and interaction between treatment and time as fixed effects (LS means weighted for region and stratum size) was used for analysis.
Time frame: Baseline and once yearly, up to approximately 108 months of observation
Second Extension: Incidence of Osteoporotic Clinical Lumbar Vertebral Fracture (Adjudicated)
Osteoporotic vertebral clinical fractures were confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Vertebral fractures were assessed for all lumbar vertebral levels (L1 to L5). Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence of participants in the second extension study with osteoporotic vertebral clinical fractures is provided. Due to early termination of the study, the cumulative incidence using a time-to-event methodology was not assessed across base and extension studies.
Time frame: Up to approximately 34 months of observation
Second Extension: Incidence of Osteoporotic Clinical Thoracic Vertebral Fracture (Adjudicated)
Osteoporotic vertebral clinical fractures were confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Vertebral fractures were assessed for all thoracic vertebral levels (T1 to T12). Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence of participants in the second extension study with osteoporotic vertebral clinical fractures is provided. Due to early termination of the study, the cumulative incidence using a time-to-event methodology was not assessed across base and extension studies.
Time frame: Up to approximately 34 months of observation
Second Extension: Time From Baseline to First Osteoporotic Clinical Fracture of Any Type (Adjudicated)
Osteoporotic clinical fractures of any type were confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Non-vertebral fractures were assessed across multiple anatomical sites including clavicle, distal femur or shaft, fibula, hip, humerus, pelvis, radius, ribs, sacrum, tibia, ulna, and wrist; Vertebral fractures assessed across all vertebral levels (C7, T1 to T12, L1 to L5) were included in the analysis. Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence proportion (cumulative incidence) of participants in the second extension study with at least one osteoporotic clinical fracture of any type is provided.
Time frame: Up to approximately 34 months of observation
Imaging Substudy PN032-Base: Percent Change From Baseline in Cortical vBMD of the Total Hip Using Quantitative Computed Tomography
Compartment-specific effects of osteoporosis were assessed by measuring cortical vBMD at the total hip using quantitative computed tomography. The percent change from baseline at Month 24 was then assessed using a longitudinal data analysis model including terms for treatment, stratum (prior vertebral fracture \[yes/no\]) and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 24
Imaging Substudy PN032-Base: Percent Change From Baseline in Areal BMD (aBMD) of the Lumbar Spine Using DXA
aBMD was measured at the lumbar spine (L1 to L4) at baseline and Month 24 using DXA . If a vertebra was fractured at baseline or became fractured during the study, its BMD measurement was excluded from analysis. The percent change from baseline was assessed using a longitudinal data analysis model including terms for treatment, stratum and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 24
Imaging Substudy PN032-Base: Percent Change From Baseline in aBMD of the Femoral Neck Using DXA
aBMD was measured at the femoral neck at baseline and Month 24 using DXA. The percent change from baseline was assessed using a longitudinal data analysis model including terms for treatment, stratum and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 24
Imaging Substudy PN032-Base: Percent Change From Baseline in aBMD of the Total Hip Using DXA
aBMD was measured at the total hip at baseline and Month 24 using DXA. The percent change from baseline was assessed using a longitudinal data analysis model including terms for treatment, stratum and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 24
Imaging Substudy PN032-Base: Percent Change From Baseline in aBMD of the Trochanter Using DXA
aBMD was measured at the trochanter at baseline and Month 24 using DXA. The percent change from baseline was assessed using a longitudinal data analysis model including terms for treatment, stratum and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 24
Imaging Substudy PN032-Base: Percent Change From Baseline in s-CTx After Log-Transformation
s-CTx, a biochemical marker of bone resorption by osteoclasts reflecting collagen breakdown products, was assessed at baseline and Month 24 in an approximate 10% random subset participants at selected sites in the P018 base study who were additionally included in the imaging substudy PN032-base study. The log-transformed fraction from baseline in s-CTx was determined using a longitudinal model with terms for treatment, stratum, and interaction between treatment and time as fixed effects (LS means weighted for stratum size). Back-transformed weighted geometric LS means values for percent change from baseline are provided.
Time frame: Baseline, Month 24
Imaging Substudy PN032-Base: Percent Change From Baseline in P1NP After Log-Transformation
P1NP is a cleavage fragment produced during the synthesis of collagenous bone matrix (type 1 collagen) used as a biochemical marker of bone formation. Serum P1NP was assessed at baseline and Month 24 in an approximate 10% random subset participants at selected sites in the P018 base study who were additionally included in the imaging substudy PN032-base study. The log-transformed fraction change from baseline in P1NP was determined using a longitudinal model with terms for treatment, stratum, and interaction between treatment and time as fixed effects (LS means weighted for stratum size). Back-transformed weighted geometric LS means values for percent change from baseline are provided.
Time frame: Baseline, Month 24
Imaging Substudy PN032-Base: Percent Change From Baseline in aBMD of the Distal-Third Forearm Using DXA
aBMD was measured at the the distal one-third radius at baseline and Month 24 using DXA. The percent change from baseline was assessed using a longitudinal data analysis model including terms for treatment, stratum and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 24
Imaging Substudy PN032-Base: Percent Change From Baseline in BSAP After Log-Transformation
BSAP is an enzyme produced by matrix-synthesizing osteoblasts during the synthesis of collagenous bone matrix (type 1 collagen) used as a biochemical marker of bone formation. Serum BSAP was assessed at baseline and Month 24 in an approximate 10% random subset participants at selected sites in the P018 base study who were additionally included in the imaging substudy PN032-base study. The log-transformed fraction from baseline in BSAP was determined using a longitudinal model with terms for treatment, stratum, and interaction between treatment and time as fixed effects (LS means weighted for stratum size). Back-transformed weighted geometric LS means values for percent change from baseline are provided.
Time frame: Baseline, Month 24
Imaging Substudy PN032-Base: Percent Change From Baseline in u-NTx/Cr Ratio After Log-Transformation
u-NTx, a biochemical marker of bone resorption by osteoclasts reflecting collagen breakdown products, was assessed at baseline and Month 24 in an approximate 10% random subset participants at selected sites in the P018 base study who were additionally included in the imaging substudy PN032-base study. Urine NTx measurements (in BCE) were normalized to urine Cr concentration (i.e., u-NTx/Cr ratio) and the log-transformed fraction from baseline in u-NTx/Cr ratio was then determined using a longitudinal model with terms for treatment, stratum, and interaction between treatment and time as fixed effects (LS means weighted for stratum size). Back-transformed weighted geometric LS means values for percent change from baseline are provided.
Time frame: Baseline, Month 24
Imaging Substudy PN032-Base + Extension: Percent Change From Baseline in Cortical vBMD of the Total Hip Using Quantitative Computed Tomography
Compartment-specific effects of osteoporosis were assessed by measuring cortical vBMD at the total hip using quantitative computed tomography. The percent change from baseline at Month 60 (base study + extension study) was then assessed using a longitudinal data analysis model including terms for treatment, stratum (prior vertebral fracture \[yes/no\]) and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 60
Imaging Substudy PN032-Base + Extension: Percent Change From Baseline in aBMD of the Lumbar Spine Using DXA
aBMD was measured at the lumbar spine (L1 to L4) at baseline and Month 60 using DXA . If a vertebra was fractured at baseline or became fractured during the study, its BMD measurement was excluded from analysis. The percent change from baseline was assessed using a longitudinal data analysis model including terms for treatment, stratum and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 60
Imaging Substudy PN032-Base + Extension: Percent Change From Baseline in aBMD of the Total Hip Using DXA
aBMD was measured at the total hip at baseline and Month 60 using DXA. The percent change from baseline was assessed using a longitudinal data analysis model including terms for treatment, stratum and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 60
Imaging Substudy PN032-Base + Extension: Percent Change From Baseline in aBMD of the Femoral Neck Using DXA
aBMD was measured at the femoral neck at baseline and Month 60 using DXA. The percent change from baseline was assessed using a longitudinal data analysis model including terms for treatment, stratum and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 60
Imaging Substudy PN032-Base + Extension: Percent Change From Baseline in aBMD of the Trochanter Using DXA
aBMD was measured at the trochanter at baseline and Month 60 using DXA. The percent change from baseline was assessed using a longitudinal data analysis model including terms for treatment, stratum and interaction between treatment and time as fixed effects (LS means weighted for stratum size).
Time frame: Baseline, Month 60