Anabolism Versus Antiresorption: A Quadruple Labeling Histomorphometry Study to Compare the Mechanism of Action of Teriparatide and Denosumab in Postmenopausal Women With Osteoporosis
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 69
- 试验地点
- 1
- 主要终点
- Change From Baseline to 3 Months in Mineralizing Surface (MS) /Bone Surface (BS) in the Cancellous Compartment (CC) of the Iliac Crest Bone Biopsies
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 55 Years 至 89 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Teriparatide
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.
干预措施: Teriparatide (Drug)
Teriparatide
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.
干预措施: Demeclocycline (Drug)
Teriparatide
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.
干预措施: Tetracycline (Drug)
Teriparatide
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.
干预措施: Calcium Supplement (Drug)
Teriparatide
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.
干预措施: Vitamin D (Drug)
Denosumab
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.
干预措施: Denosumab (Drug)
Denosumab
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.
干预措施: Demeclocycline (Drug)
Denosumab
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.
干预措施: Tetracycline (Drug)
Denosumab
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.
干预措施: Calcium Supplement (Drug)
Denosumab
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.
干预措施: Vitamin D (Drug)
结局指标
主要结局
Change From Baseline to 3 Months in Mineralizing Surface (MS) /Bone Surface (BS) in the Cancellous Compartment (CC) of the Iliac Crest Bone Biopsies
时间窗: 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.
次要结局
- 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)
- 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)
- 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)
- 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 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Activation Frequency (Ac.f) in the CC, EC and IC of the Iliac Crest(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(3 months post first dose of study drug)
- Adjusted Apposition Rate (Aj.AR) in the CC, EC and IC of the Iliac Crest(3 months post first dose of study drug)
- Percentage of Osteoid Volume (OV)/Bone Volume (BV) in the CC of the Iliac Crest(3 months post first dose of study drug)
- Osteoid Thickness (O.Th) in the CC, EC and IC of the Iliac Crest(3 months post first dose of study drug)
- Wall Thickness (W.Th) in the CC, EC and IC of the Iliac Crest(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(3 months post first dose of study drug)