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Pathophysiology of Paget's Disease of Bone

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ClinicalTrials.gov Identifier: NCT02802384
Recruitment Status : Recruiting
First Posted : June 16, 2016
Last Update Posted : August 18, 2017
Sponsor:
Information provided by (Responsible Party):
Johns Hopkins University

Brief Summary:

Paget's disease of the bone is a skeletal disorder which results in increased and disorganized bone remodeling, leading to dense but fragile and expanding bones. The identified genetic causes of Paget's disease of bone only explain why bone is destroyed, but not why the bone formed in its place is abnormal.

Current treatment for people with Paget's disease of the bone is limited to patients with bone pain, thought to be related to high rate of bone turnover (breakdown and rebuilding of bone) and works by slowing down the rate of bone breakdown. The current treatment does not address the excess blood vessels and bone formed.

This research is being done to understand factors that may promote blood vessel and bone formation in Paget's disease of the bone.


Condition or disease
Paget's Disease of Bone

Detailed Description:

The genetic mutations found in Paget's disease currently only account for about 15% of cases and are limited to genes that affect osteoclast differentiation and function. These mutations alone are insufficient to explain the full phenotype, particularly hypervascularity and increased bone formation. Through a series of basic science studies, the investigators have recently found that preosteoclasts secrete chemokines to promote migration of various stem cells, which then differentiate into osteoblasts and endothelial cells to support osteogenesis and angiogenesis, respectively.

The investigators will perform a cross sectional study of patients with active Paget's disease of bone compared to similar people without Paget's disease of bone. The goal is to enroll 10 patients with Paget's disease of the bone (cases) and 10 healthy, age- and sex-matched people (controls) whom meet similar exclusion criteria. Participants who consent to the study will undergo a brief history and physical exam, allow review of medical records relevant to their disease, and have one blood (5 tablespoons) sample drawn.

The investigators hypothesize that specific chemokine concentrations are increased in people with Paget's disease of the bone compared to controls. The investigators also hypothesize that these levels correlate with severity of disease. Therefore, the investigators primary objective is to determine if serum chemokine levels are increased in patients with Paget's disease of the bone. The secondary objective is to evaluate if the serum chemokine concentrations correlate with various markers of disease activity. Findings could aid in the clinical monitoring of patients with Paget's disease of the bone and could provide an additional therapeutic target to improve treatment of this painful disease.


Study Type : Observational
Estimated Enrollment : 20 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: Investigation of Pathophysiology of Angiogenesis and Osteogenesis in Paget's Disease of Bone
Study Start Date : April 2016
Estimated Primary Completion Date : April 2018
Estimated Study Completion Date : June 2018


Group/Cohort
Cases
People with active Paget's Disease of Bone
Controls
Age and sex matched people without history of Paget's Disease of Bone



Primary Outcome Measures :
  1. Serum chemokine level [ Time Frame: Day 1 ]
    Compare the serum chemokine concentrations in research participants with Paget's disease of bone to research participants without Paget's disease of bone


Secondary Outcome Measures :
  1. Correlation of chemokine level to Paget's Disease of Bone Pain [ Time Frame: Day 1 ]
    Correlate the serum chemokine concentration in research participants with Paget's disease of bone to burden of disease as assessed clinically by pain utilizing the Likert pain scale.

  2. Correlation of chemokine level to alkaline phosphatase concentration [ Time Frame: Day 1 ]
    Correlate the serum chemokine concentration in research participants with Paget's disease of bone to burden of disease as assessed clinically by serum alkaline phosphatase concentration.

  3. Correlation of chemokine level to proportion of affected skeleton [ Time Frame: Day 1 ]
    Correlate the serum chemokine concentration in research participants with Paget's disease to percent of skeleton affected as assessed radiographically by bone scan and x-ray.

  4. Correlation of chemokine level to number of circulating stem cells [ Time Frame: Day 1 ]
    Correlate the serum chemokine concentration in research participants to number of circulating mesenchymal stem cell and epithelial progenitor cells.


Biospecimen Retention:   Samples With DNA
Human blood samples with be collected. One tube of blood will be utilized to measure specific serum chemokine concentrations. One tube will be utilized to extract DNA for potential future studies if permission is provided. The remainder of the blood sample will be utilized to count the number of stem cells.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Adults with active Paget's Disease of Bone but without other medical conditions or use of medications known to directly affect the bone. Healthy controls similar to age and gender will also be recruited.
Criteria

Inclusion Criteria for Cases:

  • Men and women between the ages of 18-99 years who have evidence of active Paget's disease of bone as clinically and/or radiographically defined by:

    • Increased serum alkaline phosphatase or increased serum collagen type 1 c-telopeptide (CTX) or increase in urinary pyridinoline at diagnosis
    • AND history of at least one of the following signs/symptoms: Pagetoid lesions(s) on x-ray/CT/MRI, increased uptake of radioactive substance by bone scan, bone pain, fracture, hearing loss, headache, hypercalcemia, or bony deformity.

Inclusion criteria for controls:

  • Men and women between the ages of 18-99 years who match age within 5 years of cases and gender who do NOT have evidence of Paget's disease of bone as defined by:

    • No bone pain or bony deformity
    • Normal serum alkaline phosphatase

Exclusion Criteria:

  • Osteosarcoma or other blastic bony metastases alone
  • Fibrous dysplasia of bone
  • Hyperostosis frontalis interna
  • All men and women < 18 years or > 99 years
  • Pregnancy (women) determined by self-report
  • Current use of oral contraceptive tablets or Depo-Provera™ (women)
  • Current use of hormone replacement therapy
  • Creatinine clearance < 60 ml/min./1.73 m2 by Cockcroft-Gault based on most recent serum creatinine level (if greater than 1 year since last assessment, will be measured on collected blood sample to verify eligibility)
  • Current smoking or tobacco use
  • Alcohol use greater than 3 units daily
  • Use of thiazolidinediones within the last year
  • Use of medications known to impact bone and mineral metabolism, including use of a bisphosphonate in the last 11 months; ever use of teriparatide or denosumab; use of calcitonin, selective estrogen receptor modulators (SERMs), or estrogen within the past 6 months, prednisone > 5 mg for over 10 days in the last three months, anti-epileptic medications (e.g. phenytoin, carbamezapine, phenobarbitol, and primidone); current or use within the past year of aromatase inhibitors; leuprolide; histrelin
  • History of a thyroid problem that is currently uncontrolled as defined by most recent thyroid stimulating hormone levels < 0.1 microIU/mL (if greater than 6 months since last assessment, will be measured on collected blood sample to verify eligibility)
  • Other known metabolic or structural bone disease other than low bone density (e.g. hyperparathyroidism, multiple myeloma, sarcoid or other granulomatous disease, celiac disease, osteopetrosis, osteomalacia, osteitis fibrosa cystica)
  • Other significant medical illness (heart disease, pulmonary disease, inflammatory bowel disease, malignancy other than ductal carcinoma in situ (DCIS) or non-melanoma skin cancer, rheumatologic conditions including rheumatoid arthritis, systemic lupus, renal disease requiring dialysis, etc.)
  • Inability to understand and provide informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02802384


Contacts
Contact: Janet Crane, M.D. 410-502-6425 jcrane2@jhmi.edu
Contact: Xiao Wang, Ph.D. 410-502-6425 xwang113@jhmi.edu

Locations
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21205
Contact: Janet Crane, M.D.    410-502-6425    jcrane2@jhmi.edu   
Contact: Xiao Wang, Ph.D.    410-502-6425    xwang113@jhmi.edu   
Sponsors and Collaborators
Johns Hopkins University
Investigators
Principal Investigator: Janet L Crane, M.D. Johns Hopkins University

Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT02802384     History of Changes
Other Study ID Numbers: 00077130
First Posted: June 16, 2016    Key Record Dates
Last Update Posted: August 18, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Johns Hopkins University:
Paget's Disease of Bone
Healthy controls

Additional relevant MeSH terms:
Bone Diseases
Osteitis Deformans
Musculoskeletal Diseases