A Transiliac Crest Bone Histology and Histomorphometry Study in Postmenopausal Women With Low Bone Mass or Osteoporosis Previously Treated With Denosumab

Study Overview
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Brief Summary
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To characterize the effects of discontinuation of denosumab therapy on variables of bone histology in postmenopausal women with low bone mass or osteoporosis. Patients who have received denosumab and completed study 20050179 (NCT00293813), completed study 20050141 (NCT00330460), completed study 20060237 (NCT00515463), completed study 20030216 (NCT00089791) but did not enroll in study 20060289 (NCT00523341) will be included in this study. Patients who will participate in the off-treatment imaging study for 20080747 (NCT00890981) are also eligible.

Official Title
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A Transiliac Crest Bone Histology and Histomorphometry Study in Postmenopausal Women With Low Bone Mass or Osteoporosis Previously Treated With Denosumab

Conditions
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Low Bone Mass, Low Bone Mineral Density, Osteoporosis, Postmenopausal Osteoporosis

Intervention / Treatment
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* Drug: Previous denosumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ambulatory postmenopausal women Received denosumab and completed study 20050179 (NCT00293813), completed study 20050141 (NCT00330460), completed study 20060237 (NCT00515463), completed study 20030216 (NCT00089791) but did not enroll in study 20060289 (NCT00523341). Patients who will participate in the off-treatment imaging study for 20080747 (NCT00890981) also are eligible. Completed participation in eligible studies ≥ 12 and ≤ 36 months prior to screening Provide signed informed consent Exclusion Criteria: Did not receive denosumab in studies 20050141, 20060237, 20030216, or 20050179. Discontinued investigational product before end of study visit for studies 20050141, 20060237, 20030216, or 20050179. Received > 1 month osteoporosis treatment since having completed studies 20050141, 20060237, 20030216, or 20050179. Received zoledronic acid at any time after ending study participation in parent studies 20050141, 20050179, 20030216, or 20060237. Newly diagnosed with any of the following conditions during the intervening period since completing studies 20050141, 20060237, 20030216, or 20050179: Hyperthyroidism (stable on anti-thyroid therapy or post-ablation is allowed, if the Thyroid Stimulating Hormone is within the normal range) Hypothyroidism (stable on thyroid replacement therapy is allowed, if the Thyroid Stimulating Hormone is within the normal range) Hyper- or hypoparathyroidism Osteomalacia Paget's disease of bone Other bone diseases which affect bone metabolism (eg, osteopetrosis, osteogenesis imperfecta) Malignancy within the last 5 years (except cervical carcinoma in situ or basal cell carcinoma). Self-reported alcohol or drug abuse within the previous 12 months. Permanently non-ambulatory subjects (use of assistive device eg cane, walker is permitted). Has known or suspected sensitivity or contraindication to tetracycline derivatives. Received any investigational product other than denosumab. Current use of the following osteoporosis agents: bisphosphonates, calcitonin, fluoride, parathyroid hormone analogue, selective estrogen receptor modulators, systemic oral or transdermal estrogen (except vaginal preparations and estrogen creams which are acceptable), strontium or tibolone. Has undergone bilateral transiliac crest bone biopsy in the past. Current use of medications that, in the opinion of the investigator, cannot be discontinued and may compromise the safety of the subject when undergoing the bone biopsy procedure (eg, aspirin, warfarin, high-dose heparin). Current use of systemic glucocorticoid therapy (topical or nasal steroids are permitted). Evidence of coagulopathy that in the opinion of the investigator, may compromise patient safety when subjected to the bone biopsy procedure. Any disorder that, in the opinion of the investigator, may compromise the ability of the participant to give written informed consent and/or comply with study procedures.
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: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Previous denosumab<br>Participants who had previously received denosumab received a transiliac crest bone biopsy performed following standard labeling procedures with tetracycline or tetracycline derivative. | Drug: Previous denosumab<br>* Participants who had previously received denosumab received a transiliac crest bone biopsy performed following standard labeling procedures with tetracycline or tetracycline derivative.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Normal/Abnormal Bone Histology | The number of participants with normal/abnormal bone histology as assessed by bone biopsy samples at the central histomorphometric facility. Normal bone histology is characterized by: - normal lamellar bone, - normal mineralization or - osteoid (the organic matrix of bone; young bone that has not undergone calcification). Biopsies with abnormal bone histology are characterized by: - osteomalacia, - marrow fibrosis, - clinically significant marrow abnormality or - woven bone. | 25-34 days post-Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone Histomorphometry: Cancellous Bone Volume | Cancellous (trabecular) bone volume (Tb.V) is the relative volume of total cancellous bone measured (TV), expressed as percentage, that is occupied by trabeculae. Cancellous bone volume was measured using Fluorochrome labeling with tetracyclene and tartrate-resistant acid phosphatase stain (TRAP) staining techniques. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Trabecular Number | Trabecular number (Tb.N) is the number of trabeculae present per lineal mm and is calculated as trabecular bone volume/trabecular thickness. Tb.N is a measure of trabecular connectivity and decreases with bone loss. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Trabecular Separation | Trabecular separation (Tb.Sp) is the mean distance in mm between trabeculae (measured by integrated computer graphics). Tb.Sp increases with trabecular bone loss. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Trabecular Thickness | Mean trabecular thickness (Tb.Th) is a measure of trabecular structure and is calculated as the reciprocal of total bone (trabecular) surfaces. Tb.Th is reduced by aging and osteoporosis. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Cortical Width | Cortical width correlates with dual photon absorptiometric (DPX) measurements of bone density. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Surface Density | Surface density is calculated by total bone (trabecular) surfaces / total tissue volume. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Osteoblast - Osteoid Interface | Osteoblast - osteoid interface is calculated as osteoblast surface / osteoid surface * 100. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Osteoid Surface | Osteoid surface is expressed as a percentage total bone surface. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Osteoid Width | Osteoid thickness (width; O.Th) is the mean thickness of osteoid seams on cancellous surfaces. O.Th is normally <12.5 µm. Increased O.Th suggests abnormal mineralization (osteomalacia). | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Wall Thickness | Wall thickness is the average thickness of trabecular bone structural units (BSU) and is used to assess the overall balance between resorption and formation. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Eroded Surface/Bone Surface | Eroded surface is expressed as a percentage of total bone surface. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Osteoclast Number - Length Based | Osteoclast number expressed per mm of bone. Osteoclast number was measured using fluorochrome labeling with tetracyclene and tartrate-resistant acid phosphatase stain (TRAP) staining techniques. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Osteoclast Number - Surface Based | Osteoclast number expressed per bone surface area. Osteoclast number was measured using fluorochrome labeling with tetracyclene and tartrate-resistant acid phosphatase stain (TRAP) staining techniques. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Single-label Surface | Single-label surface is expressed as a percentage of total bone surface. The presence of a single label indicates that mineralization was occurring during only one labeling period. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Double-label Surface | Double-label surface is expressed as a percentage of total bone surface. The presence of double labels indicates that normal bone mineralization was actively occurring over the labeling interval. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Total Mineralizing Surface | Total mineralizing surfaces (MS) include all double and half of single-labeled surfaces. MS is expressed as a percentage of total bone surface. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Mineral Apposition Rate | The mineral apposition rate (MAR) is the avarage rate at which new bone mineral is being added on any actively forming surface. MAR is calculated as the average distance between visible labels, divided by the labeling interval. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Adjusted Mineral Apposition Rate | The mineral apposition rate (MAR) is the avarage rate at which new bone mineral is being added on any actively forming surface. Adjusted MAR is calculated as: (average distance between visible labels / labeling interval) * (total mineralizing surface/total bone surface). | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Bone Formation Rate - Surface Based | Bone formation rate - surface based (BFR/BS) is the calculated rate at which cancellous bone surface is being replaced annually. BFR/BS is derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface /total bone surface). | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Bone Formation Rate - Volume Based | Bone formation rate - volume based (BFR/BV) is the calculated rate at which cancellous bone volume is being replaced annually. BFR/BV is derived from the Mineral Appositional Rate * 365 * (relative mineralizing surface / total bone volume). | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Formation Period | The formation period is the duration of an interval when a place on the bone surface is actively forming bone. The formation period is calculated as the wall width (thickness of new bone made in one cycle) divided by the mineral apposition rate. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Activation Frequency | The average time that it takes for a new remodeling cycle to begin on any point on a cancellous surface is called the activation frequency (Ac.f). Activation frequency is calculated as the bone formation rate / wall width. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Osteoid Volume | Osteoid volume is expressed as a percentage of total bone volume. | 25-34 days post-Day 1 | 
| Bone Histomorphometry: Mineralization Lag Time | The mineralization lag time is the time interval between osteoid secretion and its subsequent mineralization, in days. | 25-34 days post-Day 1 | 
| C-Telopeptide (CTX-1) | C-Telopeptide is a biochemical marker for bone turnover. Blood samples were drawn for assessment of CTX-1 levels on either Day 3 or Day 20, within 24 hours of the last dose of the respective tetracycline cycle. | Day 3 or Day 20 | 
| Procollagen Type 1 N-terminal Peptide (P1NP) | Procollagen Type 1 N-terminal Peptide is a biochemical marker of bone turnover. Blood samples were drawn for assessment of P1NP levels on either Day 3 or Day 20, within 24 hours of the last dose of the respective tetracycline cycle. | Day 3 or Day 20 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Low Bone Mass, Low Bone Mineral Density, Osteoporosis, Postmenopausal Osteoporosis, Bone Biopsy, Transiliac Crest Bone Histology, Histomorphometry