Biochemical Markers of Bone Metabolism and Paget s Disease of Bone
Lead Research Organisation:
University of Liverpool
Department Name: UNLISTED
Abstract
Biochemical markers of bone metabolism are easily measured in either blood or urine samples. Identification of the best of these biomarkers that is able to detect bone disease,correlate with severity of disease and predict response to therapy in metabolic bone disease would be a major advantage to clinicians looking after patients with these diseases. The recently completed PRISM and the ongoing PRISM EZ study have provided a unique clinical data set in the largest population of patients with Paget s disease ever treated as part of a clinical trial. We will measure several new and established biochemical markers of bone metabolism in samples obtained from patients who completed the PRISM study and in those continuing within PRISM EZ and hope to identify which marker(s) best diagnose the condition, correlate with disease severity, predict a good response to treatment, failure of treatment, whether within the symptomatic treatment or intensive treatment arms of the trial patients can be identified by biomarkers that are non responders to treatment and whether these biomarkers correlate better than the currently used marker (ALP) with the clinical outcome. Identifying a biochemical marker(s) that predicts clinical outcome would help the early identification of patients who may respond to specific therapeutic approaches that may prevent unnecessary treatment and waste of valuable clinical resources.
Technical Summary
Measurement of biochemical markers of bone metabolism in plasma/urine, that reflect osteoclast or osteoblast number and function, offers the potential for convenient rapid assessment of:
(1) extent and severity of metabolic bone disease
(2) requirement for therapy
(3) prediction of therapeutic outcomes
(4) requirement for a change of therapy.
Paget s Disease of Bone (PDB) is a model disease to study these biomarkers because both the osteoclast and osteoblast are involved in the pathological process. Newer biomarkers may have advantages in PDB through their cell specificity and reflection of type I collagen metabolism .
We will measure the following bone biomarkers in 9,600 samples obtained from PDB patients who have taken part in the PRISM studies-
Osteoclast Markers
C-terminal cross-linking telopeptide of type I collagen
Tartrate?resistant acid phosphatase type 5b
Urine N-terminal cross-linking telopeptide of type I collagen
Urine pyridinoline and deoxypyridinoline
Osteoblast Markers
Bone Specific Alkaline Phosphatase
Procollagen type I N propeptide (trimer)
Procollagen type I N propeptide (monomer)
Regulatory Molecules
Osteoprotegerin
Soluble Receptor Activitor of NF kappa B Ligand
Each marker will be evaluated using appropriate statistical analysis in terms of:
(1) diagnosis of Paget?s disease at baseline.
(2) correlations with disease extent and activity
(3) changes with treatment
(4) whether clinical changes correlate with alterations in markers
(5) whether markers can predict good or poor response to therapy
(6) the best marker to identify patients relapsing biochemically prior to clinical relapse
(7) outcome related differences between the two treatment groups.
The PRISM trial is a pragmatic, randomised controlled trial in 1331 patients with PDB . Patients were randomised to either the ?intensive? group where the aim was to normalise total ALP with bisphosphonate therapy or ?symptomatic? who were treated only if they had bone pain. Bisphosphonates were given in this group if analgesics/anti-inflammatory drugs were ineffective. PRISM includes 4226 patient years of exposure to treatment and 3 years average follow-up. PRISM has been extended with the ongoing PRISM-EZ trial. The PRISM cohort has been extensively characterised in terms of disease activity,skeletal involvement, bone deformity and other features of the disease providing unique insight into the natural history of the disease. At baseline the PRISM cohort closely reflected the clinical workload for physicians treating PDB. Comprehensive information on disease distribution (isotope bone scan), previous treatment, skeletal complications (joint replacements, fractures, orthopaedic procedures), routine biochemistry,haematology,skeletal radiographs (pelvis, weight bearing lower limbs) and audiograms (where skull involved) is available making this a unique data set for evaluating biomarkers of bone metabolism.
(1) extent and severity of metabolic bone disease
(2) requirement for therapy
(3) prediction of therapeutic outcomes
(4) requirement for a change of therapy.
Paget s Disease of Bone (PDB) is a model disease to study these biomarkers because both the osteoclast and osteoblast are involved in the pathological process. Newer biomarkers may have advantages in PDB through their cell specificity and reflection of type I collagen metabolism .
We will measure the following bone biomarkers in 9,600 samples obtained from PDB patients who have taken part in the PRISM studies-
Osteoclast Markers
C-terminal cross-linking telopeptide of type I collagen
Tartrate?resistant acid phosphatase type 5b
Urine N-terminal cross-linking telopeptide of type I collagen
Urine pyridinoline and deoxypyridinoline
Osteoblast Markers
Bone Specific Alkaline Phosphatase
Procollagen type I N propeptide (trimer)
Procollagen type I N propeptide (monomer)
Regulatory Molecules
Osteoprotegerin
Soluble Receptor Activitor of NF kappa B Ligand
Each marker will be evaluated using appropriate statistical analysis in terms of:
(1) diagnosis of Paget?s disease at baseline.
(2) correlations with disease extent and activity
(3) changes with treatment
(4) whether clinical changes correlate with alterations in markers
(5) whether markers can predict good or poor response to therapy
(6) the best marker to identify patients relapsing biochemically prior to clinical relapse
(7) outcome related differences between the two treatment groups.
The PRISM trial is a pragmatic, randomised controlled trial in 1331 patients with PDB . Patients were randomised to either the ?intensive? group where the aim was to normalise total ALP with bisphosphonate therapy or ?symptomatic? who were treated only if they had bone pain. Bisphosphonates were given in this group if analgesics/anti-inflammatory drugs were ineffective. PRISM includes 4226 patient years of exposure to treatment and 3 years average follow-up. PRISM has been extended with the ongoing PRISM-EZ trial. The PRISM cohort has been extensively characterised in terms of disease activity,skeletal involvement, bone deformity and other features of the disease providing unique insight into the natural history of the disease. At baseline the PRISM cohort closely reflected the clinical workload for physicians treating PDB. Comprehensive information on disease distribution (isotope bone scan), previous treatment, skeletal complications (joint replacements, fractures, orthopaedic procedures), routine biochemistry,haematology,skeletal radiographs (pelvis, weight bearing lower limbs) and audiograms (where skull involved) is available making this a unique data set for evaluating biomarkers of bone metabolism.