Bone Histomorphometry in Postmenopausal Men and Women With Osteoarthritis Undergoing Total Hip Replacement

Bone Histomorphometry of the Proximal Femur in Denosumab-treated Subjects Undergoing Total Hip Replacement

The primary objective of this study is to determine the incidence of modeling-based bone formation in the femoral neck in participants who have received denosumab and are undergoing total hip replacement (THR).

Study Overview

• Status: Completed
• Conditions: Osteoporosis
• Intervention / Treatment: Other: Tetracycline; Other: Demeclocycline; Procedure: Total Hip Replacement

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • West Haverstraw, New York, United States, 10993
      • Research Site
    • West Haverstraw, New York, United States, 10993
      • Helen Hayes Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject has provided informed consent/assent prior to initiation of any study-specific activities/procedures
• Ambulatory postmenopausal women and men with osteoporosis
• Scheduled to undergo elective THR due to osteoarthritis of the hip
• Received at least 2 doses of denosumab 60 mg subcutaneously over 18 months
• Last dose of denosumab within 6 months of scheduled THR

Exclusion Criteria:

• Received treatment for osteoporosis other than denosumab in one year prior to THR

• Subjects with current diagnosis of any of the following conditions are excluded

  • Current, uncontrolled hypo- or hyperthyroidism (subjects who have controlled hypo- or hyperthyroidism may be eligible, provided that they have been on a stable therapy for at least 3 months [per subject report])
  • Current, hypo- or hyperparathyroidism
  • Osteomalacia
  • Paget's disease of bone
  • Other bone diseases which affect bone metabolism (eg, osteopetrosis, osteogenesis imperfecta)
  • Severe chronic kidney disease (CKD), defined as CKD stage 4 or greater
• 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
• Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(s)
• Other investigational procedures while participating in this study are excluded
• Subject has known sensitivity to any of the products to be administered (eg, tetracycline, demeclocycline) during study
• Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge
• History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Osteoarthritis Participants; Participants previously treated with denosumab and planning to undergo total hip replacement (THR) received one cycle of tetracycline administered at either 250 mg four times a day or 500 mg twice a day for 3 days and one cycle of demeclocycline administered at either 150 mg four times a day or 300 mg twice a day for 3 days, ten days after last dose of tetracycline in cycle 1. THR surgery was performed 5 to 42 days after the last dose of demeclocycline.

Other: Tetracycline; Treatment during cycle 1 consists of a total oral dose of 1000 mg of tetracycline daily for a total of 3 days.; Other: Demeclocycline; Treatment during cycle 2 consists of a total oral dose of 600 mg of demeclocycline daily for 3 days.; Procedure: Total Hip Replacement; Participants entering this study were prescheduled to undergo elective THR due to osteoarthritis. Surgery was to be performed according to local standard of care. During THR a fragment of femoral bone was acquired for histomorphometry evaluation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Modeling Based Bone Formation in the Femoral Neck	Femoral neck bone samples were prepared according to standard procedures for bone histology and bone histomorphometry at a central bone histomorphometry facility. Modeling based formation units in active bone-forming, tetracycline-labeled surfaces were identified by a smooth cement line. The percentage of participants with fluorochrome labeling present in the cancellous or periosteal, or endocortical surfaces of the femoral neck indicative of modeling-based bone formation is reported.	Days 22-58 (at the time of hip replacement surgery)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modeling Based Formation Units in the Femoral Neck	Femoral neck bone samples were prepared according to standard procedures for bone histology and bone histomorphometry at a central bone histomorphometry facility. Modeling based formation units in active bone-forming, tetracycline-labeled surfaces were identified by a smooth cement line. The number of modeling based formation units was evaluated at the cancellous, periosteal, and endocortical regions and is reported in units per mm of bone surface.	Days 22-58 (at the time of hip replacement surgery)
Overfilled Remodeling-based Formation Units in the Femoral Neck	Femoral neck bone samples were prepared according to standard procedures for bone histology and bone histomorphometry at a central bone histomorphometry facility. Remodeling-based formation units in active bone-forming, tetracycline-labeled surfaces were identified by a scalloped cement line. The number of overfilled remodeling-based formation units was evaluated at the cancellous, periosteal, and endocortical regions and is reported as units per mm of bone surface.	Days 22-58 (at the time of hip replacement surgery)
Remodeling-based Formation Units Including Overfilled Units in the Femoral Neck	Femoral neck bone samples were prepared according to standard procedures for bone histology and bone histomorphometry at a central bone histomorphometry facility. Remodeling based formation units in active bone-forming, tetracycline-labeled surfaces were identified by a scalloped cement line. The number of remodeling based formation units including overfilled units was evaluated at the cancellous, periosteal, and endocortical regions and is reported in units per mm of bone surface.	Days 22-58 (at the time of hip replacement surgery)

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Dempster DW, Chines A, Bostrom MP, Nieves JW, Zhou H, Chen L, Pannacciulli N, Wagman RB, Cosman F. Modeling-Based Bone Formation in the Human Femoral Neck in Subjects Treated With Denosumab. J Bone Miner Res. 2020 Jul;35(7):1282-1288. doi: 10.1002/jbmr.4006. Epub 2020 Apr 2.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2015
• Primary Completion (Actual): December 18, 2017
• Study Completion (Actual): December 18, 2017

Study Registration Dates

• First Submitted: May 26, 2015
• First Submitted That Met QC Criteria: October 13, 2015
• First Posted (Estimate): October 15, 2015

Study Record Updates

• Last Update Posted (Actual): April 26, 2019
• Last Update Submitted That Met QC Criteria: April 8, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: total hip replacement; bone biopsy; tetracycline; demeclocycline
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Tetracycline; Demeclocycline
• Other Study ID Numbers: 20140259