Table Of ContentADVANCES IN
PATHOBIOLOGY
AND MANAGEMENT
OF PAGET’S DISEASE
OF BONE
ADVANCES IN
PATHOBIOLOGY
AND MANAGEMENT
OF PAGET’S DISEASE
OF BONE
Editedby
SAKAMURI V. REDDY
Darby Children’s Research Institute,
Medical University of South Carolina, SC,
United States
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LIST OF CONTRIBUTORS
OmarM.E.Albagha
CentreforGenomicandExperimentalMedicine,InstituteofGeneticsandMolecular
Medicine,UniversityofEdinburgh,WesternGeneralHospital,Edinburgh,
UnitedKingdom
JacquesP.Brown
DivisionofRheumatology,DepartmentofMedicine,CHUdeQue´bec-Universite´ Laval,
QuebecCity,QC,Canada
JulieC.Crockett
MusculoskeletalResearchProgramme,UniversityofAberdeen,Aberdeen,
UnitedKingdom
TimCundy
DepartmentofMedicine,FacultyofMedical&HealthSciences,UniversityofAuckland,
Auckland,NewZealand
DeborahL.Galson
DepartmentofMedicine,DivisionofHematology-Oncology,UniversityofPittsburgh
CancerInstitute,UniversityofPittsburghSchoolofMedicine,Pittsburgh,PA,
UnitedStates
MarcF.Hansen
CenterforMolecularMedicine,UniversityofConnecticutHealthCenter,Boston,
MA,UnitedStates
MiepH.Helfrich
MusculoskeletalResearchProgramme,UniversityofAberdeen,Aberdeen,
UnitedKingdom
RobLayfield
SchoolofLifeSciences,UniversityofNottingham,Nottingham,UnitedKingdom
Lae¨titiaMichou
DivisionofRheumatology,DepartmentofMedicine,CHUdeQue´bec-Universite´ Laval,
QuebecCity,QC,Canada
StuartH.Ralston
CentreforGenomicandExperimentalMedicine,InstituteofGeneticsandMolecular
Medicine,UniversityofEdinburgh,WesternGeneralHospital,Edinburgh,
UnitedKingdom
ix
x ListofContributors
SarahL.Rea
HarryPerkinsInstituteofMedicalResearch,UniversityofWesternAustralia,Nedlands,
WA,Australia; DepartmentofEndocrinologyandDiabetes,SirCharlesGairdner
Hospital,Nedlands,WA,Australia
SakamuriV.Reddy
DarbyChildren’sResearchInstitute,MedicalUniversityofSouthCarolina,Charleston,
SC,UnitedStates
IanR.Reid
FacultyofMedicalandHealthSciences,UniversityofAuckland,Auckland,
NewZealand; AucklandDistrictHealthBoard,Auckland,NewZealand
G.DavidRoodman
DepartmentofMedicine,DivisionofHematology-Oncology,IndianaUniversity,
Indianapolis,IN,UnitedStates; RichardL.RoudebushVAMedicalCenter,
Indianapolis,IN,UnitedStates
MargaretSeton
DivisionofRheumatology,Brigham&Women’sHospital,Boston,MA,UnitedStates
QuanhongSun
DepartmentofMedicine,DivisionofHematology-Oncology,UniversityofPittsburgh
CancerInstitute,UniversityofPittsburghSchoolofMedicine,Pittsburgh,PA,
UnitedStates
ABOUT THE EDITOR
Sakamuri V. Reddy, PhD is a Professor and
Director of the Osteoclast Center in the Darby
Children’s Research Institute at the Medical
University of South Carolina (MUSC),
Charleston, SC, United States. He is a member
of the American Society for Bone and Mineral
Research (ASBMR). Dr Reddy has over 24 years
of experience in studying skeletal disorders and
bone loss mechanisms. His research is focused on
osteoclast biology, Paget’s disease of bone, cancer
metastasis to bone, and microgravity induced
bone loss. He is very passionate and enthusiastic
in presenting this book with recent developments
in our understanding of the pathogenesis and
treatment of Paget’s disease of bone.
xi
PREFACE
This book represents a comprehensive review of recent advances in our
understanding of pathobiology of the Paget’s disease of bone (PDB), a
chronic focal skeletal disorder in older adults. The disease can occur with
enlarged or deformed bones in one or more regions of the skeleton.
Complications of PDB may include bone pain, osteoarthritis, femoral
fractures, bowing of limbs, hearing loss, and a rare incidence of osteosar-
coma. The disease has variable geographical distribution and is seen most
frequently in people of Western European descent.
PDB is one of the most exaggerated examples of abnormal bone
remodeling and the primary pathologic abnormality resides in the
osteoclasts which resorb bone excessively, followed by osteoblast activity
to form abundant poor quality new bone. Although the etiology of PDB
is unclear, studies have been focused on paramyxo-viral and genetic com-
ponents. A viral etiology for PDB has been suggested based on the pres-
ence of paramyxo-viral nuclear inclusions and detection of measles virus
nucleocapsids (MVNP) containing several sense mutations in pagetic
osteoclasts. Studies also suggest that not only the measles virus (MV), but
other paramyxo-viruses such as respiratory syncytial virus or canine dis-
temper virus, could be responsible for a slow virus infection, although
others have failed to confirm these findings. In recent years, significant
advancement has been made with respect to MVNP expression and
pagetic osteoclast development. Also, recurrent mutations widely occur in
the ubiquitin associated domain of a signaling scaffold protein, sequesto-
some 1 (SQSTM1/p62) in 5(cid:1)10% of patients with PDB. Several other
genetic loci and potential candidate genes associated with PDB are
mapped; however, their contribution to PDB remains unclear. A genetic
defect may favor environmental factors such as MV infection to have a
potential role in pathogenesis of the disease. However, no infectious virus
is isolated and the molecular basis for the persistence of the paramyxo-
viral infection/expression of viral nucleocapsids in osteoclasts from
patients with PDB remains unclear. The focal nature of the disease and
the declining prevalence suggest that environmental factors play an
important role in the pathogenesis of PDB. It is critical to determine a
cause and effect relationship for the persistence of paramyxo-viral
xiii
xiv Preface
infection and genetic predisposition in patients with Paget’s disease.
Although PDB is generally classified as a metabolic bone disorder, it is
essential to define the late onset of disease and underlying molecular
mechanisms to initiate and cause progression of focal lesions. It is also
important to unravel the contribution of paramyxo-viruses and genetic
mutations to induce a pagetic phenotype in osteoclasts and determine
what role genetics plays in marrow stroma/osteoblast function in pagetic
lesions. Such studies would further clarify the etiology of PDB and
advance our knowledge on skeletal biology/diseases. Bisphosphonates are
now considered potent therapeutic agents for the disease; however, the
future awaits new antiresorptive therapies to alleviate the risks of long-
term use.
This book is dedicated in honor of Dr. Frederick R. Singer, MD, a
former long-time Director of the Paget Foundation, New York, United
States. He is truly a blend of science and humanity advancing this
fascinating area of medical science with his noble hearted spirit.
S.V. Reddy
CHAPTER 1
’
Clinical Perspectives of Paget s
Disease of Bone
Tim Cundy
DepartmentofMedicine,FacultyofMedical&HealthSciences,UniversityofAuckland,Auckland,
NewZealand
INTRODUCTION
In London in November 1876 the English surgeon Sir James Paget pre-
sented to the Medical and Chirurgical Society the case of a patient that
he had looked after for almost 20 years, who had an unusual deforming
bone disease. He noted similar cases from the literature (the first from
1801) and suggested they were the same disorder; he published a second
series of cases in 1882.
Paget was particularly struck by the enlargement of affected bones and
reasoned that “only tumour, hypertrophy or chronic inflammation” could
produce this effect. Thinking of parallels with chronic osteomyelitis he
felt the likely pathology was “chronic inflammation” and suggested the
name osteitis deformans. However, even by the late 19th century the epon-
ymous name, Paget’s disease, was already widely used.
We now recognize Paget’s disease of bone as a focal disorder of dysre-
gulated bone turnover that is common amongst older people, particularly
those of western European descent. Although there have been significant
advances in understanding the epidemiology, genetics, and molecular
biology of Paget’s disease, we do not yet have a complete understanding
of its causes and natural history. In this chapter we examine the pathology,
epidemiology, and clinical features of the disorder.
Two excellent monographs on Paget’s disease are those by Ronnie
Hamdy and John Kanis [1,2].
S.V.Reddy(Ed):AdvancesinPathobiologyandManagementofPaget’sDiseaseofBone. ©2016ElsevierInc.
DOI:http://dx.doi.org/10.1016/B978-0-12-805083-5.00001-4 Allrightsreserved. 1
2 AdvancesinPathobiologyandManagementofPaget'sDiseaseofBone
NATURAL HISTORY
There are still gaps in our knowledge of the natural history of Paget’s dis-
ease. It is a lifelong disorder presenting primarily in middle-aged and older
people. It arises apparently simultaneously in one or more skeletal sites. In
longbonesitoriginatesintheproximalepiphysisor metaphysis[3].
A study of 100 patients who had repeated skeletal scintiscans an
average 51/ years after an initial diagnostic scan showed that none had
2
developed new lesions [4], so the disease probably remains restricted to
the bones where it originally arose. An exception to this rule is that the
disease can be transferred to new skeletal sites by the use of pagetic bone
for surgical bone grafting [5].
Once established, the pagetic lesion expands in size. In long bones a
typical “lytic wedge,” reflecting active osteoclastic resorption, can often
be seen at the advancing edge—and is a sign of early disease (Fig. 1.1). In
the skull this appearance is known as “osteoporosis circumscripta.” The
rate of progression of the disease through the skull or long bones, as
estimated from serial radiographs, is in the order of 8mm/year.
Paget’s disease has characteristic radiographic appearances of varying
degrees of lysis and sclerosis that reflect the histological findings of
increases in both bone formation and resorption. Disease activity as
Figure1.1 Lyticbonediseaseofthelowerhumerus.
