Effects of Teriparatide or Denosumab on Bone in Postmenopausal Women With Osteoporosis

Study Overview
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Brief Summary
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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).

Official Title
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Anabolism Versus Antiresorption: A Quadruple Labeling Histomorphometry Study to Compare the Mechanism of Action of Teriparatide and Denosumab in Postmenopausal Women With Osteoporosis

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: Teriparatide
* Drug: Denosumab
* Drug: Demeclocycline
* Drug: Tetracycline
* Drug: Calcium Supplement
* Drug: Vitamin D


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Teriparatide<br>20 micrograms (µg) teriparatide administered subcutaneously (SC) once every day for 6 months. Demeclocycline (DEM): Beginning 18 days prior to randomization: Days 1, 2, 3 and 16, 17, 18: 150 milligrams (mg) DEM will be taken orally every 6 hours; Days 4 to15: DEM will not be administered. Tetracycline (TET): Beginning 22 days prior to the biopsy procedure: Days 1, 2, 3 and 16, 17, 18: 250 mg TET will be taken orally every 6 hours; Days 4 through 15: TET will not be administered. Calcium: Approximately 1000 milligrams per day (mg/day) administered orally. Vitamin D: Approximately 800 to 1200 International Units per day (IU/day) administered orally. | Drug: Teriparatide<br>* Administered SC<br>* Other names: Forsteo;Drug: Demeclocycline<br>* Administered orally<br>Drug: Tetracycline<br>* Administered orally<br>Drug: Calcium Supplement<br>* Administered orally<br>Drug: Vitamin D<br>* Administered orally<br>|
| Active Comparator: Denosumab<br>60 mg denosumab administered SC once in 6 months. DEM: Beginning 18 days prior to randomization: Days 1, 2, 3 and 16, 17, 18: 150 mg DEM will be taken orally every 6 hours; Days 4 to 15: DEM will not be administered. TET: Beginning 22 days prior to the biopsy procedure: Days 1, 2, 3 and 16, 17, 18: 250 mg TET will be taken orally every 6 hours; Days 4 through 15: TET will not be administered. Calcium: Approximately 1000 mg/day administered orally. Vitamin D: Approximately 800 to 1200 IU/day administered orally. | Drug: Denosumab<br>* Administered SC<br>Drug: Demeclocycline<br>* Administered orally<br>Drug: Tetracycline<br>* Administered orally<br>Drug: Calcium Supplement<br>* Administered orally<br>Drug: Vitamin D<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 3 months post first dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Baseline, 3 months post first dose of study drug | 
| 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. | 3 months post first dose of study drug | 
| 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. | 3 months post first dose of study drug | 
| 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 | 3 months post first dose of study drug | 
| 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. | 3 months post first dose of study drug | 
| 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. | Baseline, 3 months post first dose of study drug | 
| 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. | Baseline, 3 months post first dose of study drug | 
| 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. | Baseline, 3 months post first dose of study drug | 
| 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. | 3 months post first dose of study drug | 
| 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. | Baseline, 1, 3, and 6 months post first dose of study drug | 
| 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. | Baseline, 1, 3, and 6 months post first dose of study drug | 
| 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. | Baseline, 1, 3, and 6 months post first dose of study drug | 
| 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. | Baseline, 1, 3, and 6 months post first dose of study drug | 
| 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. | 3 months post first dose of study drug | 
| 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. | 3 months post first dose of study drug | 
| 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. | 3 months post first dose of study drug | 
| 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. | 3 months post first dose of study drug | 
| 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. | 3 months post first dose of study drug | 
| 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. | 3 months post first dose of study drug | 
| 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. | 3 months post first dose of study drug |