Effect of Denosumab on Inflammatory Osteolytic Lesion Activity in Total Hip Arthroplasty - Full Text View

Purpose

Although hip replacement surgery is a successful way of dealing with the pain and immobility caused by hip arthritis, 10% of the hip replacements carried out in the UK fail within 10 years. The main reason for this is the development periprosthetic osteolysis, that is, loss of bone around the site of the hip replacement. The osteolysis is thought to be due to the small particles of debris worn from the surfaces of the hip implant. These particles cause a reaction in the blood cells around the joint which in turn affects bone cells and leads to a loss of bone around the implant. The joint implant will then eventually become loose and unstable, a condition known as aseptic loosening. At present the only way to treat aseptic loosening is to have another operation to secure the hip joint, known as revision surgery. Revision surgery is not always successful and exposes the patient to the risk of major surgery.

In this study we explore the potential for giving a medication (denosumab) that may prevent the loss of bone around the hip replacement implant. We will recruit patients who have been listed for revision surgery. One group of patients will be given a single dose of denosumab; another group will be given a placebo (dummy drug). At the time of the revision surgery a small sample of the bone from around the hip replacement will be taken and examined under the microscope. Comparisons will be made between the patients having the denosumab and those having placebo to find out whether the denosumab is having a beneficial effect on the bone surfaces. If successful, this study will lead to further studies to develop the use of denosumab to prevent aseptic loosening.

Condition	Intervention	Phase
Revision Surgery of Total Hip Arthroplasty	Drug: Denosumab Other: Placebo	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	Effect of Denosumab on Inflammatory Osteolytic Lesion Activity in Total Hip

Resource links provided by NLM:

MedlinePlus related topics: Hip Replacement

Drug Information available for: Denosumab

U.S. FDA Resources

Further study details as provided by Sheffield Teaching Hospitals NHS Foundation Trust:

Primary Outcome Measures:

Osteoclast number [ Time Frame: 8 weeks after administration ] [ Designated as safety issue: No ]
Absolute difference between study groups in osteoclast number per millimetre at the osteolysis membranebone interface, measured by cell counting in histological sections between the denosumab and placebo groups, 8 weeks after administration of the IMP

Secondary Outcome Measures:

Change in serum or urine levels of βCTXI, NTXI/Cr, TRAcP5b, CTXMMP, PINP, OPG, RANKL [ Time Frame: 8 weeks after administration of the IMP ] [ Designated as safety issue: No ]
Difference between the denosumab and placebo groups in mean absolute change in serum or urine levels of βCTXI, NTXI/Cr, TRAcP5b, CTXMMP, PINP, OPG, RANKL, 8 weeks after administration of the IMP
Difference between the denosumab and placebo groups in mean eroded, quiescent, and osteoblast surfaces at the membrane bone interface [ Time Frame: 8 weeks after administration of the IMP ] [ Designated as safety issue: No ]
Difference between the denosumab and placebo groups in mean eroded, quiescent, and osteoblast surfaces at the membrane bone interface measured using image analysis software, 8 weeks after administration of the IMP (Bioquant Image Analysis Corp, Nashville, TN, USA)
Difference between the denosumab and placebo groups in ratio of viable to apoptotic osteoclast, macrophage fibroblast, and osteoblasts by TUNEL staining and relative number of cells staining positive for apoptosis markers [ Time Frame: 8 weeks after administration of the IMP ] [ Designated as safety issue: No ]
Difference between the denosumab and placebo groups in ratio of viable to apoptotic osteoclast, macrophage fibroblast, and osteoblasts by TUNEL staining and relative number of cells staining positive for apoptosis markers, including but not limited to, Caspase 8, 9, and 3, and proliferation marker Ki67 8 weeks after administration of the IMP

Estimated Enrollment:	30
Study Start Date:	January 2012
Estimated Study Completion Date:	January 2015
Estimated Primary Completion Date:	January 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Denosumab In this study we explore the potential for giving a medication (denosumab) that may prevent the loss of bone around the hip replacement implant	Drug: Denosumab 60mg denosumab by injection as a single dose Other Name: Prolia
Placebo Comparator: Placebo Placebo	Other: Placebo Placebo by injection as a single dose

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Eligibility

Ages Eligible for Study:	30 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Participants must be men or women over 30 years of age undergoing revision THA surgery for periprosthetic osteolysis / aseptic loosening affecting the pelvis and / or femur.
Participants must also be willing and able to give fully informed consent.
Participants must have osteolysis / aseptic loosening affecting fully cementless, hybrid, or fully cemented THA prosthesis

Exclusion Criteria:

Known prosthesis infection
Pregnancy / Breast feeding
Oral bisphosphonate therapy (current use, previous use within the last 12 months, previous 3 or more years cumulative use)
Administration of intravenous bisphosphonate, fluoride or strontium within the last 5 years
Participation in ongoing or previous denosumab clinical trials
Administration of any of the following treatments within the last 12 months
TH or PTH derivatives, eg, teriparatide
anabolic steroids or testosterone
glucocorticosteroids (> 5 mg prednisone equivalent per day for more than 10 days)
systemic hormone replacement therapy
selective estrogen receptor modulators (SERMs), eg, raloxifene tibolone, calcitonin or calcitriol
Any subject in whom denosumab is contraindicated according to the local SmPC of denosumab (SC 60 mg every 6 months in UK)
Current hypocalcemia (albumin adjusted serum calcium below 2.13 mmol/L)
History of rheumatoid arthritis
History of Paget's disease
Malignancy (except basal cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years
Renal insufficiency assessed by eGFR <30
Known sensitivity to mammalian cell derived drug products
Any organic or psychiatric disorder, or laboratory abnormality which, in the opinion of the Investigator, will prevent the subject from completing the study or interfere with the interpretation of the study results
Any disorder that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent and/or comply with study procedures
Evidence of alcohol or substance abuse within the last 12 months that the Investigator believes would interfere with understanding or completing the study
Subject is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug trial(s), or subject is receiving other investigational agent(s).

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01358669

Contacts

Contact: J M Wilkinson, PhD, FRCS (Tr&Orth)

j.m.wilkinson@sheffield.ac.uk

Locations

United Kingdom
Academic Unit of Bone Metabolism	Recruiting
Sheffield, South Yorkshire, United Kingdom, S5 7AU
Contact: Tracey S Higginbottom 01142715238 ext 15238 Tracey.Higginbottom@sth.nhs.uk
Principal Investigator: J M Wilkinson, PhD, FRCS (Tr&Orth)

Sponsors and Collaborators

Sheffield Teaching Hospitals NHS Foundation Trust

Amgen

Sheffield Academic Unit of Bone Metabolism

Investigators

Principal Investigator:

J M Wilkinson, PhD, FRCS (Tr&Orth)

Sheffield Teaching Hospitals NHS Foundation Trust/University of Sheffield

More Information

No publications provided

Responsible Party:	Sheffield Teaching Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier:	NCT01358669 History of Changes
Other Study ID Numbers:	STH15714
Study First Received:	May 11, 2011
Last Updated:	December 14, 2012
Health Authority:	United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Sheffield Teaching Hospitals NHS Foundation Trust:

Denosumab
Total Hip Arthroplasty

ClinicalTrials.gov processed this record on May 19, 2013