Osteoporosis
Conditions
Brief summary
The purpose of this study is to determine how teriparatide or denosumab affects the bone of postmenopausal women with osteoporosis after 3 months of treatment, as determined by a bone biopsy sample taken from the iliac crest (upper part of the pelvis).
Interventions
DRUGTeriparatide
Administered SC
DRUGDenosumab
Administered SC
DRUGDemeclocycline
Administered orally
DRUGTetracycline
Administered orally
Administered orally
DRUGVitamin D
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
55 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
* Ambulatory, postmenopausal women (no vaginal bleeding for at least 2 years prior to screening) with osteoporosis * Bone mineral density (BMD) T-score of at least -2.5 at femoral neck (FN), total hip (TH), or lumbar spine (LS) (Lumbar vertebrae L1-L4, with at least 2 evaluable vertebrae), with or without atraumatic fracture after menopause, OR * BMD T-score of at least -1.5 at FN, TH, or LS (L1-L4, with at least 2 evaluable vertebrae), and 1 or more atraumatic fractures after menopause (vertebral or nonvertebral). Nonvertebral fracture sites allowed are wrist, hip, pelvis, rib, humerus, clavicle, leg (femur, tibia, and fibula, excluding ankle) * Laboratory values for serum calcium, parathyroid hormone (PTH), and alkaline phosphatase must be within the normal reference range
Exclusion criteria
* Has an increased risk of osteosarcoma (bone tumor); this includes Paget's disease of bone, a previous bone tumor, or radiation involving the skeleton * Has an allergy or intolerance to teriparatide or denosumab and/or is a poor candidate for teriparatide or denosumab treatment (investigator should refer to local product prescribing information) * Has a history of exposure to DEM or TET therapy in the 12 months prior to screening or a known allergy to DEM or TET * Has a condition that could put the participant at additional risk of an adverse event (AE) due to the bone biopsy procedure (for example, bleeding disorder) * Has undergone 2 previous iliac crest bone biopsies (1 in each iliac crest) * Has a 25-hydroxyvitamin D concentration of \<10 nanograms per milliliter (ng/mL) * Has currently active or suspected (within 1 year prior to enrollment) diseases that affect bone metabolism, other than osteoporosis (such as renal osteodystrophy, hyperthyroidism, osteomalacia, or hyperparathyroidism) * Has a history of certain cancers within 5 years prior to trial entry * Current or recent (within 1 year prior to enrollment) celiac disease, inflammatory bowel disease, gastric bypass, or other malabsorption syndrome * Has significantly impaired hepatic or renal function * Has had treatment with systemic glucocorticoids in doses ≥5 mg/day prednisone/day or equivalent in the 6 calendar months prior to screening * Has taken any intravenous osteoporosis medication * Has had prior treatment with other bisphosphonates and not been off of them for a specific period of time before trial entry * Has participated in any other clinical trial studying teriparatide, PTH, PTH analog, or denosumab, or prior or current treatment with teriparatide, PTH, PTH analog, or denosumab
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 3 Months in Mineralizing Surface (MS) /Bone Surface (BS) in the Cancellous Compartment (CC) of the Iliac Crest Bone Biopsies | Baseline, 3 months post first dose of study drug | MS /BS is a measure of the proportion of BS on which new mineralized bone is deposited at the time of DEM or TET labeling, and calculated as the sum of the total extent of double label (DL) plus half the extent of single label (SL) divided by BS. At baseline (18 days prior to randomization / study drug administration), DEM was administered (3 days on, 12 days off, 3 days on). 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered (same dosing schedule as DEM). Both DEM and TET temporarily bind to new bone and fluoresce under UV light. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation and a SL or no label (NL) suggested varying degrees of suppression of bone formation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | 3 months post first dose of study drug | — |
| Change From Baseline to 3 Months in MS/BS in the Endocortical Compartment (EC), Intracortical Compartment (IC), and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | Baseline, 3 months post first dose of study drug | MS /BS is a measure of the proportion of BS on which new mineralized bone is deposited at the time of DEM or TET labeling and is calculated as the sum of the total extent of DL plus half the extent of SL divided by BS. At baseline (18 days prior to randomization / study drug administration), DEM was administered (3 days on, 12 days off, 3 days on). 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered (same dosing schedule as DEM). Both DEM and TET temporarily bind to new bone and fluoresce under UV light. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation and a SL or NL suggested varying degrees of suppression of bone formation. |
| MS/BS in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies 3 Months Post First Dose of Study Drug | 3 months post first dose of study drug | MS /BS is a measure of the proportion of BS on which new mineralized bone is deposited at the time of DEM or TET labeling and is calculated as the sum of the total extent of DL plus half the extent of SL divided by BS. At baseline (18 days prior to randomization / study drug administration), DEM was administered (3 days on, 12 days off, 3 days on). 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered (same dosing schedule as DEM). Both DEM and TET temporarily bind to new bone and fluoresce under UV light. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation and a SL or NL suggested varying degrees of suppression of bone formation. |
| Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | 3 months post first dose of study drug | In this study, post-treatment DLs in the CC, EC, and PC were classified as remodeling-based or modeling-based bone formations which was determined by whether the underlying reversal line was scalloped or smooth and by the collagen fiber orientation. Percentage = (remodeling-based formation units or modeling-based formation units/ total bone formation units) \* 100. |
| Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | 3 months post first dose of study drug | The percentage of mineralizing surface where post-treatment DLs in the CC, EC, and PC were classified as remodeling-based or modeling based bone formation based on collagen fiber orientation and whether the underlying reversal line was scalloped or smooth. Percentage = percentage remodeling- or modeling-based formation units \* MS/BS |
| Percentage of Overfilled Remodeling Sites in the CC, EC and PC of the Iliac Crest Bone Biopsies | 3 months post first dose of study drug | The percentage of overfilled remodeling sites in the CC, EC, and PC were defined as the percentage of observed remodeling units in which the second DL (TET) extended beyond the limits of the scalloped reversal line and into the adjacent, previously unresorbed surface of the bone. Percentage = (overfilled remodeling bone formation unit / total bone formation unit) \* 100. |
| Change From Baseline to 3 Months in Label Length Within Each Basic Multicellular Unit (BMU) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | Baseline, 3 months post first dose of study drug | BMUs are local groups of osteoblasts and osteoclasts that act in concert to complete a single remodeling cycle. The label length is a measure of the extent of the mineralization front within each BMU in the CC, EC, IC and PC. At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation, and a SL or NL suggested suppression of bone formation. |
| Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | Baseline, 3 months post first dose of study drug | MAR is a measure of the linear rate of production of mineralized bone matrix by osteoblasts and is measured by the mean distance between 2 consecutive labels divided by the time interval. At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation, and a SL or NL suggested suppression of bone formation. SL cases were imputed to a value of 0.3 micrometers per day (µm/day) or counted as missing. NL cases were reported as missing. |
| Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | Baseline, 3 months post first dose of study drug | BFR/BS is the volume of mineralized bone formed per unit surface of bone per unit of time \[mm cubed per mm squared per year (mm³/mm²/year)\]. At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicates active bone formation, a SL or NL suggests suppression of bone formation. BFR = MAR \* (MS/BS). SL cases were imputed to a value of 0.3 mcm/day or counted as missing. NL cases were assigned a value of zero. |
| Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | 3 months post first dose of study drug | At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation and a SL or NL suggested suppression of bone formation. Percentage = (Single or double TET labels / BS) \*100. |
| Percentage Change From Baseline to 1, 3, and 6 Months in Serum Procollagen Type I N-terminal Propeptide (P1NP) | Baseline, 1, 3, and 6 months post first dose of study drug | P1NP is a marker of bone turnover and is a measure of bone formation. Percentage = (P1NP value at specified time points - P1NP value at baseline) / P1NP value at baseline \* 100. |
| Percentage Change From Baseline to 1, 3, and 6 Months in Serum Osteocalcin | Baseline, 1, 3, and 6 months post first dose of study drug | Osteocalcin is a marker of bone turnover and a measure of osteoblast function. Percentage = (osteocalcin value at specified time points - osteocalcin value at baseline) / (osteocalcin value at baseline) \* 100. |
| Percentage Change From Baseline to 1, 3, and 6 Months in Serum Carboxyterminal Cross-Linking Telopeptide of Type I Collagen (CTX) | Baseline, 1, 3, and 6 months post first dose of study drug | CTX is a marker of bone turnover and is a measure of bone resorption. Percentage = (CTX value at specified time points - CTX value at baseline) / (CTX value at baseline) \* 100. |
| Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | 3 months post first dose of study drug | Ac.f is the probability of new remodeling cycles initiated on the BS per year. Ac.f = (BFR/BS) / wall thickness. At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation and a SL or NL suggests suppression of bone formation. SL cases were imputed to a value of 0.3 µm/day or counted as missing. NL cases were assigned a value of zero. |
| Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | 3 months post first dose of study drug | Aj.AR is MAR averaged over the entire osteoid surface and in a steady state is an estimate of the mean rate of matrix apposition. At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation and a SL or NL suggested suppression of bone formation. BFR = MAR \* (MS/BS). SL cases were imputed to a value of 0.3 µm/day or counted as missing. NL cases were counted as missing. |
| Percentage of Osteoid Volume (OV)/Bone Volume (BV) in the CC of the Iliac Crest | 3 months post first dose of study drug | OV is the percentage of a given volume of bone tissue that consists of new unmineralized bone matrix (osteoid). Percentage = (OV/BV) \*100. |
| Percentage of Osteoid Surface (OS)/Bone Surface (BS) in the CC, EC and IC of the Iliac Crest | 3 months post first dose of study drug | OS is the percentage of the entire trabecular BS that is covered by osteoid. Percentage = (OS / BS) \*100. |
| Osteoid Thickness (O.Th) in the CC, EC and IC of the Iliac Crest | 3 months post first dose of study drug | O.Th is a measure of the average thickness of osteoid seams. |
| Wall Thickness (W.Th) in the CC, EC and IC of the Iliac Crest | 3 months post first dose of study drug | W.Th is the distance from the cement line to the marrow space of completed trabecular bone packets. |
| Percentage of Eroded Surface/Bone Surface (ES/BS) in the CC, EC and IC of the Iliac Crest | 3 months post first dose of study drug | ES/BS is the fraction of the entire trabecular surface occupied by resorption bays, including both those with and without osteoclasts. It is an indicator of bone resorption. Percentage = (ES/BS) \*100. |
| Percentage Change From Baseline to 1, 3, and 6 Months in Intact Parathyroid Hormone (PTH) | Baseline, 1, 3, and 6 months post first dose of study drug | PTH regulates calcium and phosphate metabolism in bone and kidney, and is typically measured in serum using the intact PTH assay. Percentage = (PTH value at specified time points - PTH value at baseline) / PTH value at baseline \* 100. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Average Length of DLs in the CC, EC, IC and PC of the Iliac Crest | 3 months post first dose of study drug | The length of TET DLs is a measure of the extent of bone formation in each compartment within individual remodeling units and is measured in mm. At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Tetracycline (TET) and demeclocycline (DEM) temporarily bind to new bone and are detected as different colors under ultraviolet light in bone biopsy samples. In this study, participants were administered DEM prior to randomization (baseline) and again with TET 22 days prior to bone biopsy obtained 3 months post first dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Teriparatide Teriparatide: 20-µg SC injection once daily for 6 months.
DEM: 150-mg tablets administered orally, on the following days, 18 days prior to randomization:
* Days 1, 2, 3, 16, 17, and 18: 150 mg DEM every 6 hours.
* Days 4 through 15: DEM was not administered.
TET: 250-mg capsules administered orally on the following days, 22 days prior to biopsy procedure:
* Days 1, 2, 3, 16, 17, and 18: 250 mg TET every 6 hours.
* Days 4 through 15: TET was not administered.
Calcium Supplements: Approximately 1000 mg/day administered orally for 6 months.
Vitamin D Supplements: Approximately 800 to 1200 IU/day administered orally for 6 months. | 33 |
| Denosumab Denosumab: A single 60-mg SC injection.
DEM: 150-mg tablets administered orally on the following days, 18 days prior to randomization:
* Days 1, 2, 3, 16, 17, and 18: 150 mg DEM every 6 hours.
* Days 4 through 15: DEM was not administered.
TET: 250-mg capsules administered orally on the following days, 22 days prior to biopsy procedure:
* Days 1, 2, 3, 16, 17, and 18: 250 mg TET every 6 hours.
* Days 4 through 15: TET was not administered.
Calcium Supplements: Approximately 1000 mg/day administered orally for 6 months.
Vitamin D Supplements: Approximately 800 to 1200 IU/day administered orally for 6 months. | 36 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Sponsor Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Teriparatide | Total | Denosumab |
|---|---|---|---|
| Age, Continuous | 61.58 years STANDARD_DEVIATION 5.84 | 63.45 years STANDARD_DEVIATION 7.42 | 65.17 years STANDARD_DEVIATION 8.32 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 63 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 31 Participants | 62 Participants | 31 Participants |
| Region of Enrollment Canada | 12 participants | 21 participants | 9 participants |
| Region of Enrollment United States | 21 participants | 48 participants | 27 participants |
| Sex: Female, Male Female | 33 Participants | 69 Participants | 36 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 | 27 / 33 | 23 / 36 |
| serious Total, serious adverse events | 2 / 33 | 2 / 36 |
Outcome results
Primary
Change From Baseline to 3 Months in Mineralizing Surface (MS) /Bone Surface (BS) in the Cancellous Compartment (CC) of the Iliac Crest Bone Biopsies
MS /BS is a measure of the proportion of BS on which new mineralized bone is deposited at the time of DEM or TET labeling, and calculated as the sum of the total extent of double label (DL) plus half the extent of single label (SL) divided by BS. At baseline (18 days prior to randomization / study drug administration), DEM was administered (3 days on, 12 days off, 3 days on). 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered (same dosing schedule as DEM). Both DEM and TET temporarily bind to new bone and fluoresce under UV light. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation and a SL or no label (NL) suggested varying degrees of suppression of bone formation.
Time frame: Baseline, 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with MS/BS measurements in the CC of the iliac crest.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Teriparatide | Change From Baseline to 3 Months in Mineralizing Surface (MS) /Bone Surface (BS) in the Cancellous Compartment (CC) of the Iliac Crest Bone Biopsies | 12.43 percentage of BS |
| Denosumab | Change From Baseline to 3 Months in Mineralizing Surface (MS) /Bone Surface (BS) in the Cancellous Compartment (CC) of the Iliac Crest Bone Biopsies | -2.51 percentage of BS |
p-value: <0.001ANCOVA
Secondary
Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest
Ac.f is the probability of new remodeling cycles initiated on the BS per year. Ac.f = (BFR/BS) / wall thickness. At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation and a SL or NL suggests suppression of bone formation. SL cases were imputed to a value of 0.3 µm/day or counted as missing. NL cases were assigned a value of zero.
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with Ac.f assessments in the CC, EC and IC of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | DL Only, in EC (n=30, 29) | 2.77 new cycles per year |
| Teriparatide | Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | DL Only, in IC (n=30, 25) | 1.88 new cycles per year |
| Teriparatide | Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | DL and Imputed SL, in IC (n=30, 35) | 1.88 new cycles per year |
| Teriparatide | Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | DL and Imputed SL, in CC (n=31, 35) | 1.41 new cycles per year |
| Teriparatide | Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | DL and Imputed SL, in EC (n=30, 35) | 2.77 new cycles per year |
| Teriparatide | Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | DL Only, in CC (n=31, 26) | 1.41 new cycles per year |
| Denosumab | Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | DL Only, in IC (n=30, 25) | 0.17 new cycles per year |
| Denosumab | Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | DL Only, in CC (n=31, 26) | 0.10 new cycles per year |
| Denosumab | Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | DL Only, in EC (n=30, 29) | 0.35 new cycles per year |
| Denosumab | Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | DL and Imputed SL, in EC (n=30, 35) | 0.34 new cycles per year |
| Denosumab | Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | DL and Imputed SL, in IC (n=30, 35) | 0.12 new cycles per year |
| Denosumab | Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest | DL and Imputed SL, in CC (n=31, 35) | 0.06 new cycles per year |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest
Aj.AR is MAR averaged over the entire osteoid surface and in a steady state is an estimate of the mean rate of matrix apposition. At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation and a SL or NL suggested suppression of bone formation. BFR = MAR \* (MS/BS). SL cases were imputed to a value of 0.3 µm/day or counted as missing. NL cases were counted as missing.
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with Aj.AR assessments in the CC, EC and IC of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | DL and Imputed SL, in CC (n=31, 33) | 0.58 µm/day |
| Teriparatide | Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | DL Only, in IC (n=30, 24) | 1.03 µm/day |
| Teriparatide | Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | DL Only, in EC (n=30, 25) | 0.76 µm/day |
| Teriparatide | Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | DL and Imputed SL, in IC (n=30, 33) | 1.03 µm/day |
| Teriparatide | Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | DL and Imputed SL, in EC (n=30, 30) | 0.76 µm/day |
| Teriparatide | Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | DL Only, in CC (n=31, 24) | 0.58 µm/day |
| Denosumab | Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | DL Only, in EC (n=30, 25) | 0.65 µm/day |
| Denosumab | Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | DL Only, in CC (n=31, 24) | 0.21 µm/day |
| Denosumab | Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | DL and Imputed SL, in CC (n=31, 33) | 0.14 µm/day |
| Denosumab | Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | DL and Imputed SL, in EC (n=30, 30) | 0.58 µm/day |
| Denosumab | Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | DL Only, in IC (n=30, 24) | 0.58 µm/day |
| Denosumab | Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest | DL and Imputed SL, in IC (n=30, 33) | 0.35 µm/day |
p-value: 0.002Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: 0.214Wilcoxon (Mann-Whitney)
p-value: 0.031Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies
BFR/BS is the volume of mineralized bone formed per unit surface of bone per unit of time \[mm cubed per mm squared per year (mm³/mm²/year)\]. At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicates active bone formation, a SL or NL suggests suppression of bone formation. BFR = MAR \* (MS/BS). SL cases were imputed to a value of 0.3 mcm/day or counted as missing. NL cases were assigned a value of zero.
Time frame: Baseline, 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with BFR/BS assessments in the specified compartments of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in CC (n=30, 26) | 0.0280 mm³/mm²/year |
| Teriparatide | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in CC (n=31, 35) | 0.0275 mm³/mm²/year |
| Teriparatide | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in EC (n=29, 28) | 0.0509 mm³/mm²/year |
| Teriparatide | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in EC (n=30, 35) | 0.0501 mm³/mm²/year |
| Teriparatide | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in IC (n=30, 25) | 0.0455 mm³/mm²/year |
| Teriparatide | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in IC (n=30, 35) | 0.0455 mm³/mm²/year |
| Teriparatide | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in PC (n=6, 16) | 0.0231 mm³/mm²/year |
| Teriparatide | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in PC (n=30, 35) | 0.0015 mm³/mm²/year |
| Denosumab | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in PC (n=6, 16) | 0.0000 mm³/mm²/year |
| Denosumab | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in CC (n=30, 26) | -0.0056 mm³/mm²/year |
| Denosumab | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in IC (n=30, 25) | -0.0184 mm³/mm²/year |
| Denosumab | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in CC (n=31, 35) | -0.0055 mm³/mm²/year |
| Denosumab | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in IC (n=30, 35) | -0.0184 mm³/mm²/year |
| Denosumab | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in EC (n=29, 28) | -0.0069 mm³/mm²/year |
| Denosumab | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in PC (n=30, 35) | -0.0005 mm³/mm²/year |
| Denosumab | Change From Baseline to 3 Months in Bone Formation Rate/Bone Surface (BFR/BS ) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in EC (n=30, 35) | -0.0069 mm³/mm²/year |
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
Secondary
Change From Baseline to 3 Months in Label Length Within Each Basic Multicellular Unit (BMU) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies
BMUs are local groups of osteoblasts and osteoclasts that act in concert to complete a single remodeling cycle. The label length is a measure of the extent of the mineralization front within each BMU in the CC, EC, IC and PC. At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation, and a SL or NL suggested suppression of bone formation.
Time frame: Baseline, 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with label lengths measured in the specified compartments of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Change From Baseline to 3 Months in Label Length Within Each Basic Multicellular Unit (BMU) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | CC (n=30, 24) | 0.19 millimeters (mm) |
| Teriparatide | Change From Baseline to 3 Months in Label Length Within Each Basic Multicellular Unit (BMU) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | EC (n=28, 25) | 0.25 millimeters (mm) |
| Teriparatide | Change From Baseline to 3 Months in Label Length Within Each Basic Multicellular Unit (BMU) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | IC (n=30, 24) | 0.18 millimeters (mm) |
| Teriparatide | Change From Baseline to 3 Months in Label Length Within Each Basic Multicellular Unit (BMU) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | PC (n=4, 1) | 0.12 millimeters (mm) |
| Denosumab | Change From Baseline to 3 Months in Label Length Within Each Basic Multicellular Unit (BMU) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | PC (n=4, 1) | 0.10 millimeters (mm) |
| Denosumab | Change From Baseline to 3 Months in Label Length Within Each Basic Multicellular Unit (BMU) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | CC (n=30, 24) | 0.05 millimeters (mm) |
| Denosumab | Change From Baseline to 3 Months in Label Length Within Each Basic Multicellular Unit (BMU) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | IC (n=30, 24) | 0.02 millimeters (mm) |
| Denosumab | Change From Baseline to 3 Months in Label Length Within Each Basic Multicellular Unit (BMU) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | EC (n=28, 25) | 0.03 millimeters (mm) |
p-value: <0.001ANCOVA
p-value: 0.004ANCOVA
p-value: <0.001ANCOVA
p-value: 0.85ANCOVA
Secondary
Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies
MAR is a measure of the linear rate of production of mineralized bone matrix by osteoblasts and is measured by the mean distance between 2 consecutive labels divided by the time interval. At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation, and a SL or NL suggested suppression of bone formation. SL cases were imputed to a value of 0.3 micrometers per day (µm/day) or counted as missing. NL cases were reported as missing.
Time frame: Baseline, 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with an evaluation of MAR in the CC, EC, IC and PC of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in CC (n=30, 24) | 0.00 mcm/day |
| Teriparatide | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in CC (n=31, 33) | 0.01 mcm/day |
| Teriparatide | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in EC (n=28, 25) | 0.03 mcm/day |
| Teriparatide | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in EC (n=29, 31) | 0.03 mcm/day |
| Teriparatide | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in IC (n=30, 24) | 0.20 mcm/day |
| Teriparatide | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in IC (n=30, 34) | 0.20 mcm/day |
| Teriparatide | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in PC (n=4, 1) | 0.05 mcm/day |
| Teriparatide | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in PC (n=19, 4) | 0.00 mcm/day |
| Denosumab | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in PC (n=4, 1) | -0.04 mcm/day |
| Denosumab | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in CC (n=30, 24) | -0.04 mcm/day |
| Denosumab | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in IC (n=30, 24) | -0.18 mcm/day |
| Denosumab | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in CC (n=31, 33) | -0.06 mcm/day |
| Denosumab | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in IC (n=30, 34) | -0.22 mcm/day |
| Denosumab | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL Only, in EC (n=28, 25) | -0.07 mcm/day |
| Denosumab | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in PC (n=19, 4) | -0.04 mcm/day |
| Denosumab | Change From Baseline to 3 Months in Mineral Apposition Rate (MAR) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | DL and Imputed SL, in EC (n=29, 31) | -0.09 mcm/day |
p-value: 0.004ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: 0.931ANCOVA
p-value: 0.549ANCOVA
Secondary
Change From Baseline to 3 Months in MS/BS in the Endocortical Compartment (EC), Intracortical Compartment (IC), and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies
MS /BS is a measure of the proportion of BS on which new mineralized bone is deposited at the time of DEM or TET labeling and is calculated as the sum of the total extent of DL plus half the extent of SL divided by BS. At baseline (18 days prior to randomization / study drug administration), DEM was administered (3 days on, 12 days off, 3 days on). 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered (same dosing schedule as DEM). Both DEM and TET temporarily bind to new bone and fluoresce under UV light. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation and a SL or NL suggested varying degrees of suppression of bone formation.
Time frame: Baseline, 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with MS/BS measurements in the specified compartments of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Change From Baseline to 3 Months in MS/BS in the Endocortical Compartment (EC), Intracortical Compartment (IC), and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | EC | 26.12 percentage of BS |
| Teriparatide | Change From Baseline to 3 Months in MS/BS in the Endocortical Compartment (EC), Intracortical Compartment (IC), and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | IC | 9.39 percentage of BS |
| Teriparatide | Change From Baseline to 3 Months in MS/BS in the Endocortical Compartment (EC), Intracortical Compartment (IC), and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | PC | 2.40 percentage of BS |
| Denosumab | Change From Baseline to 3 Months in MS/BS in the Endocortical Compartment (EC), Intracortical Compartment (IC), and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | EC | -2.97 percentage of BS |
| Denosumab | Change From Baseline to 3 Months in MS/BS in the Endocortical Compartment (EC), Intracortical Compartment (IC), and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | IC | -6.70 percentage of BS |
| Denosumab | Change From Baseline to 3 Months in MS/BS in the Endocortical Compartment (EC), Intracortical Compartment (IC), and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | PC | -0.39 percentage of BS |
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
Secondary
MS/BS in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies 3 Months Post First Dose of Study Drug
MS /BS is a measure of the proportion of BS on which new mineralized bone is deposited at the time of DEM or TET labeling and is calculated as the sum of the total extent of DL plus half the extent of SL divided by BS. At baseline (18 days prior to randomization / study drug administration), DEM was administered (3 days on, 12 days off, 3 days on). 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered (same dosing schedule as DEM). Both DEM and TET temporarily bind to new bone and fluoresce under UV light. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation and a SL or NL suggested varying degrees of suppression of bone formation.
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with MS/BS measurements in the specified compartments of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | MS/BS in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies 3 Months Post First Dose of Study Drug | IC (n=30, 35) | 21.69 percentage of BS |
| Teriparatide | MS/BS in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies 3 Months Post First Dose of Study Drug | EC (n=30, 35) | 39.50 percentage of BS |
| Teriparatide | MS/BS in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies 3 Months Post First Dose of Study Drug | PC (n=30, 35) | 4.69 percentage of BS |
| Teriparatide | MS/BS in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies 3 Months Post First Dose of Study Drug | CC (n=31, 35) | 18.73 percentage of BS |
| Denosumab | MS/BS in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies 3 Months Post First Dose of Study Drug | IC (n=30, 35) | 3.05 percentage of BS |
| Denosumab | MS/BS in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies 3 Months Post First Dose of Study Drug | CC (n=31, 35) | 0.96 percentage of BS |
| Denosumab | MS/BS in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies 3 Months Post First Dose of Study Drug | PC (n=30, 35) | 0.00 percentage of BS |
| Denosumab | MS/BS in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies 3 Months Post First Dose of Study Drug | EC (n=30, 35) | 5.42 percentage of BS |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with an assessment of the number of samples with specified labels in the various compartments of the iliac crest.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | SL Only, in CC (n=31, 35) | 0 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | No Label, in CC (n=31, 35) | 0 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL and SL, in PC (n=30, 35) | 10 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL Only, in PC (n=30, 35) | 0 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL and SL, in CC (n=31, 35) | 31 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL Only, in CC (n=31, 35) | 0 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL and SL, in EC (n=30, 35) | 30 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL Only, in EC (n=30, 35) | 0 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | SL Only, in EC (n=30, 35) | 0 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | No Label, in EC (n=30, 35) | 0 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL and SL, in IC (n=30, 35) | 30 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL Only, in IC (n=30, 35) | 0 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | SL Only, in IC (n=30, 35) | 0 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | No Label, in IC (n=30, 35) | 0 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | SL Only, in PC (n=30, 35) | 19 Samples |
| Teriparatide | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | No Label, in PC (n=30, 35) | 1 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | No Label, in PC (n=30, 35) | 30 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | SL Only, in CC (n=31, 35) | 9 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | SL Only, in EC (n=30, 35) | 6 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | No Label, in CC (n=31, 35) | 2 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | No Label, in IC (n=30, 35) | 1 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | SL Only, in IC (n=30, 35) | 10 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL and SL, in PC (n=30, 35) | 1 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | No Label, in EC (n=30, 35) | 4 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | SL Only, in PC (n=30, 35) | 4 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL and SL, in CC (n=31, 35) | 24 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL and SL, in IC (n=30, 35) | 24 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL Only, in CC (n=31, 35) | 0 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL Only, in PC (n=30, 35) | 0 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL and SL, in EC (n=30, 35) | 25 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL Only, in IC (n=30, 35) | 0 Samples |
| Denosumab | Number of Samples With Single or Double Tetracycline Labels, SL and DL, or No Tetracycline Labels in the CC, Endocortical Compartment (EC), Intracortical Compartment (IC) and Periosteal Compartment (PC) of the Iliac Crest Bone Biopsies | DL Only, in EC (n=30, 35) | 0 Samples |
p-value: <0.001Fisher Exact
p-value: 0.002Fisher Exact
p-value: 0.494Fisher Exact
p-value: 0.001Fisher Exact
p-value: 0.027Fisher Exact
p-value: 0.118Fisher Exact
p-value: <0.001Fisher Exact
p-value: 0.001Fisher Exact
p-value: >0.999Fisher Exact
p-value: 0.002Fisher Exact
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
Secondary
Osteoid Thickness (O.Th) in the CC, EC and IC of the Iliac Crest
O.Th is a measure of the average thickness of osteoid seams.
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with an O.Th assessment in the CC, EC and IC of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Osteoid Thickness (O.Th) in the CC, EC and IC of the Iliac Crest | EC (n= 30, 35) | 6.99 micrometers (mcm) |
| Teriparatide | Osteoid Thickness (O.Th) in the CC, EC and IC of the Iliac Crest | IC (n= 30, 35) | 7.08 micrometers (mcm) |
| Teriparatide | Osteoid Thickness (O.Th) in the CC, EC and IC of the Iliac Crest | CC (n= 31, 35) | 6.12 micrometers (mcm) |
| Denosumab | Osteoid Thickness (O.Th) in the CC, EC and IC of the Iliac Crest | CC (n= 31, 35) | 3.78 micrometers (mcm) |
| Denosumab | Osteoid Thickness (O.Th) in the CC, EC and IC of the Iliac Crest | EC (n= 30, 35) | 4.33 micrometers (mcm) |
| Denosumab | Osteoid Thickness (O.Th) in the CC, EC and IC of the Iliac Crest | IC (n= 30, 35) | 4.68 micrometers (mcm) |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Percentage Change From Baseline to 1, 3, and 6 Months in Intact Parathyroid Hormone (PTH)
PTH regulates calcium and phosphate metabolism in bone and kidney, and is typically measured in serum using the intact PTH assay. Percentage = (PTH value at specified time points - PTH value at baseline) / PTH value at baseline \* 100.
Time frame: Baseline, 1, 3, and 6 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had serum PTH assessed at baseline and the specified time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Percentage Change From Baseline to 1, 3, and 6 Months in Intact Parathyroid Hormone (PTH) | 1 month (n=28, 34) | -26.89 percentage change in PTH |
| Teriparatide | Percentage Change From Baseline to 1, 3, and 6 Months in Intact Parathyroid Hormone (PTH) | 3 months (n=18, 28) | -32.16 percentage change in PTH |
| Teriparatide | Percentage Change From Baseline to 1, 3, and 6 Months in Intact Parathyroid Hormone (PTH) | 6 months (n=27, 33) | -40.18 percentage change in PTH |
| Denosumab | Percentage Change From Baseline to 1, 3, and 6 Months in Intact Parathyroid Hormone (PTH) | 1 month (n=28, 34) | 72.24 percentage change in PTH |
| Denosumab | Percentage Change From Baseline to 1, 3, and 6 Months in Intact Parathyroid Hormone (PTH) | 3 months (n=18, 28) | 46.68 percentage change in PTH |
| Denosumab | Percentage Change From Baseline to 1, 3, and 6 Months in Intact Parathyroid Hormone (PTH) | 6 months (n=27, 33) | 30.40 percentage change in PTH |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Percentage Change From Baseline to 1, 3, and 6 Months in Serum Carboxyterminal Cross-Linking Telopeptide of Type I Collagen (CTX)
CTX is a marker of bone turnover and is a measure of bone resorption. Percentage = (CTX value at specified time points - CTX value at baseline) / (CTX value at baseline) \* 100.
Time frame: Baseline, 1, 3, and 6 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and serum CTX measured at baseline and the specified time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Carboxyterminal Cross-Linking Telopeptide of Type I Collagen (CTX) | 1 month (n=31, 33) | 6.09 percentage change in CTX |
| Teriparatide | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Carboxyterminal Cross-Linking Telopeptide of Type I Collagen (CTX) | 3 months (n=21, 29) | 73.04 percentage change in CTX |
| Teriparatide | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Carboxyterminal Cross-Linking Telopeptide of Type I Collagen (CTX) | 6 months (n=29, 33) | 89.13 percentage change in CTX |
| Denosumab | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Carboxyterminal Cross-Linking Telopeptide of Type I Collagen (CTX) | 1 month (n=31, 33) | -90.70 percentage change in CTX |
| Denosumab | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Carboxyterminal Cross-Linking Telopeptide of Type I Collagen (CTX) | 3 months (n=21, 29) | -90.77 percentage change in CTX |
| Denosumab | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Carboxyterminal Cross-Linking Telopeptide of Type I Collagen (CTX) | 6 months (n=29, 33) | -82.50 percentage change in CTX |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Percentage Change From Baseline to 1, 3, and 6 Months in Serum Osteocalcin
Osteocalcin is a marker of bone turnover and a measure of osteoblast function. Percentage = (osteocalcin value at specified time points - osteocalcin value at baseline) / (osteocalcin value at baseline) \* 100.
Time frame: Baseline, 1, 3, and 6 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had serum osteocalcin measured at baseline and the specified time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Osteocalcin | 1 month (n=31, 33) | 90.53 percentage change in osteocalcin |
| Teriparatide | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Osteocalcin | 3 months (n=20, 29) | 123.66 percentage change in osteocalcin |
| Teriparatide | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Osteocalcin | 6 months (n=29, 31) | 187.29 percentage change in osteocalcin |
| Denosumab | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Osteocalcin | 1 month (n=31, 33) | -6.56 percentage change in osteocalcin |
| Denosumab | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Osteocalcin | 3 months (n=20, 29) | -45.70 percentage change in osteocalcin |
| Denosumab | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Osteocalcin | 6 months (n=29, 31) | -50.53 percentage change in osteocalcin |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Percentage Change From Baseline to 1, 3, and 6 Months in Serum Procollagen Type I N-terminal Propeptide (P1NP)
P1NP is a marker of bone turnover and is a measure of bone formation. Percentage = (P1NP value at specified time points - P1NP value at baseline) / P1NP value at baseline \* 100.
Time frame: Baseline, 1, 3, and 6 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had serum P1NP measurements at baseline and the specified time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Procollagen Type I N-terminal Propeptide (P1NP) | 1 month (n=33, 34) | 134.38 percentage change in P1NP |
| Teriparatide | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Procollagen Type I N-terminal Propeptide (P1NP) | 3 months (n=22, 29) | 213.15 percentage change in P1NP |
| Teriparatide | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Procollagen Type I N-terminal Propeptide (P1NP) | 6 months (n=31, 32) | 284.22 percentage change in P1NP |
| Denosumab | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Procollagen Type I N-terminal Propeptide (P1NP) | 1 month (n=33, 34) | -11.56 percentage change in P1NP |
| Denosumab | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Procollagen Type I N-terminal Propeptide (P1NP) | 3 months (n=22, 29) | -66.64 percentage change in P1NP |
| Denosumab | Percentage Change From Baseline to 1, 3, and 6 Months in Serum Procollagen Type I N-terminal Propeptide (P1NP) | 6 months (n=31, 32) | -68.24 percentage change in P1NP |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies
In this study, post-treatment DLs in the CC, EC, and PC were classified as remodeling-based or modeling-based bone formations which was determined by whether the underlying reversal line was scalloped or smooth and by the collagen fiber orientation. Percentage = (remodeling-based formation units or modeling-based formation units/ total bone formation units) \* 100.
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with the classification of TET DLs as remodeling-based or modeling-based formation in the specified compartments of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | Remodeling-Based Bone Formation in PC (n=29, 5) | 0.00 percentage of the total formation unit |
| Teriparatide | Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | Remodeling-Based Bone Formation in CC (n=31, 32) | 89.02 percentage of the total formation unit |
| Teriparatide | Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | Modeling-Based Bone Formation in CC (n=31, 32) | 10.98 percentage of the total formation unit |
| Teriparatide | Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | Remodeling-Based Bone Formation in EC (n=30, 29) | 83.33 percentage of the total formation unit |
| Teriparatide | Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | Modeling-Based Bone Formation in EC (n=30, 29) | 16.67 percentage of the total formation unit |
| Teriparatide | Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | Modeling-Based Bone Formation in PC (n=29, 5) | 100.0 percentage of the total formation unit |
| Denosumab | Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | Modeling-Based Bone Formation in EC (n=30, 29) | 0.00 percentage of the total formation unit |
| Denosumab | Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | Remodeling-Based Bone Formation in PC (n=29, 5) | 0.00 percentage of the total formation unit |
| Denosumab | Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | Remodeling-Based Bone Formation in EC (n=30, 29) | 100.00 percentage of the total formation unit |
| Denosumab | Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | Remodeling-Based Bone Formation in CC (n=31, 32) | 90.83 percentage of the total formation unit |
| Denosumab | Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | Modeling-Based Bone Formation in PC (n=29, 5) | 100.00 percentage of the total formation unit |
| Denosumab | Percentage of Bone With Remodeling-Based and Modeling-Based Formations in the CC, EC and PC of the Iliac Crest Bone Biopsies | Modeling-Based Bone Formation in CC (n=31, 32) | 9.17 percentage of the total formation unit |
p-value: 0.74Wilcoxon (Mann-Whitney)
p-value: 0.74Wilcoxon (Mann-Whitney)
p-value: 0.008Wilcoxon (Mann-Whitney)
p-value: 0.008Wilcoxon (Mann-Whitney)
p-value: 0.661Wilcoxon (Mann-Whitney)
p-value: 0.661Wilcoxon (Mann-Whitney)
Secondary
Percentage of Eroded Surface/Bone Surface (ES/BS) in the CC, EC and IC of the Iliac Crest
ES/BS is the fraction of the entire trabecular surface occupied by resorption bays, including both those with and without osteoclasts. It is an indicator of bone resorption. Percentage = (ES/BS) \*100.
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with ES/BS assessed in the CC, EC and IC of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Percentage of Eroded Surface/Bone Surface (ES/BS) in the CC, EC and IC of the Iliac Crest | CC (n=31, 35) | 3.73 percentage of BS |
| Teriparatide | Percentage of Eroded Surface/Bone Surface (ES/BS) in the CC, EC and IC of the Iliac Crest | EC (n=30, 35) | 3.79 percentage of BS |
| Teriparatide | Percentage of Eroded Surface/Bone Surface (ES/BS) in the CC, EC and IC of the Iliac Crest | IC (n=30, 35) | 11.19 percentage of BS |
| Denosumab | Percentage of Eroded Surface/Bone Surface (ES/BS) in the CC, EC and IC of the Iliac Crest | CC (n=31, 35) | 1.52 percentage of BS |
| Denosumab | Percentage of Eroded Surface/Bone Surface (ES/BS) in the CC, EC and IC of the Iliac Crest | EC (n=30, 35) | 1.65 percentage of BS |
| Denosumab | Percentage of Eroded Surface/Bone Surface (ES/BS) in the CC, EC and IC of the Iliac Crest | IC (n=30, 35) | 1.27 percentage of BS |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies
The percentage of mineralizing surface where post-treatment DLs in the CC, EC, and PC were classified as remodeling-based or modeling based bone formation based on collagen fiber orientation and whether the underlying reversal line was scalloped or smooth. Percentage = percentage remodeling- or modeling-based formation units \* MS/BS
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with the classification of TET DLs as remodeling- or modeling-based formation in the specified compartments of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | Modeling-Based Bone Formation in PC (n=30, 35) | 4.69 percentage of the total formation unit |
| Teriparatide | Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | Remodeling-Based Bone Formation in CC (n=31, 35) | 16.67 percentage of the total formation unit |
| Teriparatide | Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | Modeling-Based Bone Formation in CC (n=31, 35) | 2.06 percentage of the total formation unit |
| Teriparatide | Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | Remodeling-Based Bone Formation in EC (n=30, 35) | 32.92 percentage of the total formation unit |
| Teriparatide | Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | Modeling-Based Bone Formation in EC (n=30, 35) | 6.58 percentage of the total formation unit |
| Teriparatide | Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | Remodeling-Based Bone Formation in PC (n=30, 35) | 0.00 percentage of the total formation unit |
| Denosumab | Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | Modeling-Based Bone Formation in CC (n=31, 35) | 0.09 percentage of the total formation unit |
| Denosumab | Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | Remodeling-Based Bone Formation in EC (n=30, 35) | 5.42 percentage of the total formation unit |
| Denosumab | Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | Modeling-Based Bone Formation in PC (n=30, 35) | 0.00 percentage of the total formation unit |
| Denosumab | Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | Remodeling-Based Bone Formation in PC (n=30, 35) | 0.00 percentage of the total formation unit |
| Denosumab | Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | Remodeling-Based Bone Formation in CC (n=31, 35) | 0.87 percentage of the total formation unit |
| Denosumab | Percentage of Mineralizing Surface With Remodeling-Based Formation and Modeling-Based Formation in the CC, EC and PC of the Iliac Crest Bone Biopsies | Modeling-Based Bone Formation in EC (n=30, 35) | 0.00 percentage of the total formation unit |
Secondary
Percentage of Osteoid Surface (OS)/Bone Surface (BS) in the CC, EC and IC of the Iliac Crest
OS is the percentage of the entire trabecular BS that is covered by osteoid. Percentage = (OS / BS) \*100.
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with the assessment of OS/BS in the CC, EC and IC of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Percentage of Osteoid Surface (OS)/Bone Surface (BS) in the CC, EC and IC of the Iliac Crest | CC (n=31, 35) | 20.51 percentage of BS |
| Teriparatide | Percentage of Osteoid Surface (OS)/Bone Surface (BS) in the CC, EC and IC of the Iliac Crest | EC (n=30, 35) | 30.85 percentage of BS |
| Teriparatide | Percentage of Osteoid Surface (OS)/Bone Surface (BS) in the CC, EC and IC of the Iliac Crest | IC (n=30, 35) | 17.81 percentage of BS |
| Denosumab | Percentage of Osteoid Surface (OS)/Bone Surface (BS) in the CC, EC and IC of the Iliac Crest | CC (n=31, 35) | 3.46 percentage of BS |
| Denosumab | Percentage of Osteoid Surface (OS)/Bone Surface (BS) in the CC, EC and IC of the Iliac Crest | EC (n=30, 35) | 6.95 percentage of BS |
| Denosumab | Percentage of Osteoid Surface (OS)/Bone Surface (BS) in the CC, EC and IC of the Iliac Crest | IC (n=30, 35) | 4.34 percentage of BS |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Percentage of Osteoid Volume (OV)/Bone Volume (BV) in the CC of the Iliac Crest
OV is the percentage of a given volume of bone tissue that consists of new unmineralized bone matrix (osteoid). Percentage = (OV/BV) \*100.
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with an assessment of OV/BV in the CC of the iliac crest.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Teriparatide | Percentage of Osteoid Volume (OV)/Bone Volume (BV) in the CC of the Iliac Crest | 2.58 percentage of BV |
| Denosumab | Percentage of Osteoid Volume (OV)/Bone Volume (BV) in the CC of the Iliac Crest | 0.39 percentage of BV |
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Percentage of Overfilled Remodeling Sites in the CC, EC and PC of the Iliac Crest Bone Biopsies
The percentage of overfilled remodeling sites in the CC, EC, and PC were defined as the percentage of observed remodeling units in which the second DL (TET) extended beyond the limits of the scalloped reversal line and into the adjacent, previously unresorbed surface of the bone. Percentage = (overfilled remodeling bone formation unit / total bone formation unit) \* 100.
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy evaluated for overfilled remodeling sites in the specified compartments of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Percentage of Overfilled Remodeling Sites in the CC, EC and PC of the Iliac Crest Bone Biopsies | EC (n=30, 29) | 21.98 percentage of overfilled remodeling site |
| Teriparatide | Percentage of Overfilled Remodeling Sites in the CC, EC and PC of the Iliac Crest Bone Biopsies | PC (n=29, 5) | 0.00 percentage of overfilled remodeling site |
| Teriparatide | Percentage of Overfilled Remodeling Sites in the CC, EC and PC of the Iliac Crest Bone Biopsies | CC (n=31, 32) | 17.74 percentage of overfilled remodeling site |
| Denosumab | Percentage of Overfilled Remodeling Sites in the CC, EC and PC of the Iliac Crest Bone Biopsies | CC (n=31, 32) | 0.00 percentage of overfilled remodeling site |
| Denosumab | Percentage of Overfilled Remodeling Sites in the CC, EC and PC of the Iliac Crest Bone Biopsies | EC (n=30, 29) | 0.00 percentage of overfilled remodeling site |
| Denosumab | Percentage of Overfilled Remodeling Sites in the CC, EC and PC of the Iliac Crest Bone Biopsies | PC (n=29, 5) | 0.00 percentage of overfilled remodeling site |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: 0.74Wilcoxon (Mann-Whitney)
Secondary
Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies
At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation and a SL or NL suggested suppression of bone formation. Percentage = (Single or double TET labels / BS) \*100.
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with label surface measured in the specified compartments of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | sLS/BS, in PC (n=30, 35) | 9.37 percentage of TET label |
| Teriparatide | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | dLS/BS, in CC (n=31, 35) | 10.44 percentage of TET label |
| Teriparatide | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | sLS/BS, in EC (n=30, 35) | 24.24 percentage of TET label |
| Teriparatide | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | dLS/BS, in EC (n=30, 35) | 28.84 percentage of TET label |
| Teriparatide | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | sLS/BS, in IC (n=30, 35) | 15.28 percentage of TET label |
| Teriparatide | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | dLS/BS, in IC (n=30, 35) | 14.96 percentage of TET label |
| Teriparatide | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | dLS/BS, in PC (n=30, 35) | 0.00 percentage of TET label |
| Teriparatide | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | sLS/BS, in CC (n=31, 35) | 15.44 percentage of TET label |
| Denosumab | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | sLS/BS, in IC (n=30, 35) | 4.66 percentage of TET label |
| Denosumab | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | sLS/BS, in CC (n=31, 35) | 1.28 percentage of TET label |
| Denosumab | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | dLS/BS, in PC (n=30, 35) | 0.00 percentage of TET label |
| Denosumab | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | dLS/BS, in CC (n=31, 35) | 0.22 percentage of TET label |
| Denosumab | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | dLS/BS, in IC (n=30, 35) | 0.83 percentage of TET label |
| Denosumab | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | sLS/BS, in EC (n=30, 35) | 7.18 percentage of TET label |
| Denosumab | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | sLS/BS, in PC (n=30, 35) | 0.00 percentage of TET label |
| Denosumab | Percentage of Single or Double Tetracycline Labels Per Bone Surface (sLS/BS or dLS/BS) in the CC, EC, IC and PC of the Iliac Crest Bone Biopsies | dLS/BS, in EC (n=30, 35) | 1.68 percentage of TET label |
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: 0.028ANCOVA
Secondary
Wall Thickness (W.Th) in the CC, EC and IC of the Iliac Crest
W.Th is the distance from the cement line to the marrow space of completed trabecular bone packets.
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with a W. Th assessment in the CC, EC and IC of the iliac crest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriparatide | Wall Thickness (W.Th) in the CC, EC and IC of the Iliac Crest | CC (n=31, 35) | 26.29 µm |
| Teriparatide | Wall Thickness (W.Th) in the CC, EC and IC of the Iliac Crest | EC (n=30, 35) | 31.88 µm |
| Teriparatide | Wall Thickness (W.Th) in the CC, EC and IC of the Iliac Crest | IC (n=30, 35) | 38.25 µm |
| Denosumab | Wall Thickness (W.Th) in the CC, EC and IC of the Iliac Crest | CC (n=31, 35) | 24.03 µm |
| Denosumab | Wall Thickness (W.Th) in the CC, EC and IC of the Iliac Crest | EC (n=30, 35) | 30.08 µm |
| Denosumab | Wall Thickness (W.Th) in the CC, EC and IC of the Iliac Crest | IC (n=30, 35) | 37.80 µm |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: 0.042Wilcoxon (Mann-Whitney)
p-value: 0.678Wilcoxon (Mann-Whitney)
Other Pre-specified
Average Length of DLs in the CC, EC, IC and PC of the Iliac Crest
The length of TET DLs is a measure of the extent of bone formation in each compartment within individual remodeling units and is measured in mm. At baseline (18 days prior to randomization / study drug administration), DEM was administered. 22 days prior to the biopsy procedure (biopsy obtained 3 months post first dose of study drug), TET was administered. New bone in the biopsy was seen as the amount of bone between the 2 fluorescently DEM- or TET-labeled lines under a microscope. A DL indicated active bone formation.
Time frame: 3 months post first dose of study drug
Population: Randomized participants who received at least 1 dose of study drug and had an evaluable 3-month bone biopsy with an assessment of DL length in the various compartments of the iliac crest.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Teriparatide | Average Length of DLs in the CC, EC, IC and PC of the Iliac Crest | DL, in CC (n=31, 24) | 0.40 mm | Standard Deviation 0.08 |
| Teriparatide | Average Length of DLs in the CC, EC, IC and PC of the Iliac Crest | DL, in EC (n=30, 25) | 0.48 mm | Standard Deviation 0.15 |
| Teriparatide | Average Length of DLs in the CC, EC, IC and PC of the Iliac Crest | DL, in IC (n=30, 24) | 0.43 mm | Standard Deviation 0.11 |
| Teriparatide | Average Length of DLs in the CC, EC, IC and PC of the Iliac Crest | DL, in PC (n=10, 1) | 0.38 mm | Standard Deviation 0.41 |
| Denosumab | Average Length of DLs in the CC, EC, IC and PC of the Iliac Crest | DL, in PC (n=10, 1) | 0.32 mm | — |
| Denosumab | Average Length of DLs in the CC, EC, IC and PC of the Iliac Crest | DL, in CC (n=31, 24) | 0.31 mm | Standard Deviation 0.1 |
| Denosumab | Average Length of DLs in the CC, EC, IC and PC of the Iliac Crest | DL, in IC (n=30, 24) | 0.27 mm | Standard Deviation 0.12 |
| Denosumab | Average Length of DLs in the CC, EC, IC and PC of the Iliac Crest | DL, in EC (n=30, 25) | 0.35 mm | Standard Deviation 0.2 |
p-value: <0.001ANCOVA
p-value: 0.004ANCOVA
p-value: <0.001ANCOVA
p-value: 0.85ANCOVA