Current Allergy and Asthma Reports (2021) 21: 23

https://doi.org/10.1007/s11882-021-01001-2

AUTOIMMUNITY (TK TARRANT, SECTION EDITOR)

Paget’s Disease of Bone: Osteoimmunology

and Osteoclast Pathology
Emily M. Rabjohns 1 & Katlyn Hurst 2 & Arin Ghosh 2 & Maria C. Cuellar 3 & Rishi R. Rampersad 1 & Teresa K. Tarrant 1

Accepted: 23 February 2021 / Published online: 25 March 2021

# The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Abstract
Purpose of Review The purpose of this review is to recognize clinical features of Paget’s disease of bone and to describe how the
osteoclast, a myeloid-derived cell responsible for bone resorption, contributes to the disease.
Recent Findings Recent studies have identified several variants in SQSTM1, OPTN, and other genes that may predispose
individuals to Paget’s disease of bone; studies of these genes and their protein products have elucidated new roles for these
proteins in bone physiology.
Summary Understanding the pathologic mechanisms in the Pagetic osteoclast may lead to the identification of future treatment
targets for other inflammatory and autoimmune diseases characterized by abnormal bone erosion and/or osteoclast activation.

Keywords Paget’s disease of bone . Osteoimmunology . Osteoclast . Chemokines . Chemokine receptor . Optineurin .
Bisphosphonate

Abbreviations M-CSF Macrophage colony-stimulating factor

ALP Alkaline phosphatase NFκB Nuclear Factor Kappa B
BM Bone marrow NFATc1 Nuclear factor of activated T cells, cytoplasmic 1
CTX C-terminal telopeptide of type I collagen NTX N-terminal telopeptide of type I collagen
IFN Interferon PDB Paget’s disease of bone
IL Interleukin OCL Osteoclast
OB Osteoblast
OPG Osteoprotegerin
Key Messages P1NP Procollagen type I amino terminal peptide
1. Paget’s disease of bone is a metabolic bone disorder that occurs with
RANK Receptor activator of NFκB
advanced age; symptoms range from no symptoms to bone pain,
pathologic fracture, bone deformity, and rarely may result in malignancy. RANKL Receptor activator of NFκB ligand
2. Paget’s disease of bone may be hereditary or sporadic; contributing SNP Single nucleotide polymorphisms
factors likely include environmental exposures and specific genetic ZA Zoledronic acid
defects resulting in abnormal bone remodeling driven by changes in the
osteoclast.
3. The primary cell type causing Paget’s disease of bone is the osteoclast,
a cell of hematopoietic origin that resorbs bone matrix.
This article is part of the Topical Collection on Autoimmunity
Introduction
* Teresa K. Tarrant
teresa.tarrant@duke.edu
Paget’s disease of bone (PDB) is a frequently asymptom-
atic disorder of bone remodeling that typically affects peo-
1
Division of Rheumatology and Immunology, Department of ple over the age of 55 and is characterized by discrete
Medicine, Duke University, DUMC #3874, 200 Trent Dr, skeletal lesions with intermixed osteolytic and
Durham, NC 27710, USA osteosclerotic pathology. Pagetic lesions weaken the struc-
2
Duke University, Durham, NC, USA tural integrity of bone, leading to increased risk of fractures
3
Division of Rheumatology, Department of Medicine, Hospital del and deformity and may, in rare instances, give rise to ma-
Salvador, Santiago, Chile lignancy. The exact cause of PDB is unknown, but a
23 Page 2 of 12
combination of environmental, genetic, viral, and inflam-
matory influences is suspected to contribute to disease.
Osteoclasts are the primary cell implicated in PDB and
are derived from immune precursors. The goals of this
review are to describe the clinical and pathologic features
of PDB, to define current diagnostic and treatment algo-
rithms, and to understand disease mechanism in the context
of osteoimmunology.
Body
Paget’s Disease of Bone
Description and History
In 1877, Sir James Paget defined a skeletal disease he
termed osteitis deformans, now commonly known as
Paget’s disease of bone (PDB) [1]. PDB is characterized
by local areas of excessive bone resorption and dysregu-
lated bone remodeling, which leads to lesions described as
osteolytic, mixed osteolytic-osteosclerotic, or
osteosclerotic depending on the stage of disease. Pagetic
lesions are extensively vascularized, disorganized, de-
formed, enlarged, brittle, and prone to fracture. Lesions
most commonly occur in the femur, tibia, pelvis, skull,
and spine [2, 3]. The mechanism by which there is a
preference for lesions to develop in particular bones is
unknown, although some hypothesize weight-bearing or
repetitive biomechanical stress as a potential trigger [4••,
5, 6]. Lesions may occur in a single location (monostotic
disease) or affect multiple bones (polyostotic disease) [2].
Although defined in 1877, PDB-like disease can be seen in
the archaeological record. Skeletons as far back as the Roman
period (first to fourth centuries CE) in Europe have character-
istic pagetic lesions and are more frequently found in the me-
dieval period (1066-1538 CE) [7]. Additionally, there is at
least one report of PDB in a skull from the Middle East dating
between the fourth and seventh centuries [8]. An analysis of
skeletons from Barton on Humber, England, found that the
prevalence before 1500 CE was 1.7% and later increased to
3.1% [9], although later reports contradict this reported in-
crease [10, 11]. Intensive examination of excavated medieval
skeletons in Northwest England reveals pathologic changes
similar to contemporary PDB in 15% of skeletons. Some fea-
tures of this medieval PDB do not align with current defini-
tions such as high disease prevalence, low age at death, and
amount of skeleton affected [12]. It should also be noted that
the life expectancy prior to modern times was drastically low-
er, infections were more prevalent with fewer effective treat-
ments, and diet and lifestyle were different, which may ex-
plain some of these differences in disease presentation.
Curr Allergy Asthma Rep (2021) 21: 23
Clinical Presentation, Laboratory Findings, Imaging,
and Diagnosis
PDB is frequently asymptomatic; a 2008 study found that only
58% of patients experienced symptoms [13]. In symptomatic
cases, bone pain, enlargement, and deformity are commonly
reported [3]. In asymptomatic cases, PDB may be incidentally
found by routine blood work or radiographic studies [14]. One
study found that 22.7% of patients in the cohort were found to
have PDB by incidental finding [15].
Blood work may reveal elevated serum total alkaline phos-
phatase (ALP) levels, which indicates increased bone turnover
and is found in 78–85% of cases [15–17]. However, serum
total ALP levels may not be a suitable diagnostic marker for
patients with comorbidities affecting serum total ALP levels
such as liver disease, or patients with early or monostotic
disease. Other bone markers, such as serum procollagen type
1 amino terminal peptide (P1NP) or bone-specific ALP may
be used. Bone resorption markers such as N-terminal or C-
terminal telopeptides of type 1 collagen (NTX and CTX) can
also substitute as diagnostic tools [18]. In an evaluation of
various biomarkers in 51 PDB patients who had not received
treatment in 6 months, P1NP had the greatest proportion of
elevated values when compared to levels of serum total or
bone-specific ALP. The same study revealed that urinary
NTX was abnormally high in 96% of patients whereas urinary
pyridinoline and osteocalcin were elevated in 69% and 34% of
patients, respectively [19]. In a separate study by the same
group, urinary pyridinoline performed better than other
markers of bone resorption with a higher proportion (73%)
of increased values in PDB patients. Furthermore, 40% of
PDB patients with normal bone-specific ALP levels had ab-
normal urinary pyridinoline [17].
In some cases, a bone biopsy of the affected site is recom-
mended to make the diagnosis when the lesion may appear
malignant, or when the lesion presents in a person suspected
of PDB but in whom it would be unlikely, such as a young
adult or an individual from a country in which PDB is rare
(Fig. 2). Additionally, bone biopsy may be used to rule out
malignancy when a “new” pagetic lesion presents in a patient
with previously stable disease [20].
Histologic examination of pagetic lesions reveals poor dis-
tinction between trabecular and cortical bone. Matrix is disor-
ganized and poorly structured, with randomly oriented colla-
gen fibers indicative of woven bone rather than lamellar min-
eralized bone. On a cellular level, lesions have numerous ab-
normal osteoclasts (OCLs), which exhibit increased size and
nuclear number per cell [21]. OCLs may also contain abnor-
mal nuclear and/or cytoplasmic inclusion bodies [22, 23].
Areas of resorption by OCLs may be irregular and unusually
deep [21]. Pagetic lesions also exhibit increased vasculariza-
tion on histopathologic specimens [24]. Figure 1c shows a
hematoxylin and eosin–stained bone biopsy from a PDB
Curr Allergy Asthma Rep (2021) 21: 23
Fig. 1 Imaging and histology of Paget’s disease of bone. a Plain
radiographs of a PDB patient showing progression of a mixed
osteolytic-osteosclerotic lesion over 9 years. b Nuclear bone scan of a
70-year-old man with polyostotic PDB showing intense radionuclide up-
take indicating excessive OB activity in the thoracic spine, lumbar verte-
bra, pelvis, left femur, and right knee, with expansion and bowing of the
involved femur. c Hematoxylin and eosin stained bone biopsy of a PDB
patient showing several large OCLs lining the trabecular bone
accompanied by osteoblasts (OBs).
X-ray imaging is usually diagnostic, showing the charac-
teristic deformity of bone with thickened cortices marked by
tunneling and accentuated trabeculae [25]. Radiographs may
show focal areas of radiolucency and/or sclerosis, depending
on the stage of disease (Fig. 1a). Early disease, during which
there is increased bone resorption, results in radiolucent
osteolytic lesions. This is followed by a mix of osteolytic-
osteosclerotic areas as OBs attempt to compensate for the
bone loss with bone formation, and the lesions become pro-
gressively sclerotic. Mixed osteolytic-osteosclerotic and
osteosclerotic lesions are associated with enlargement, thick-
ening, or deformity of the bone in X-ray images [14]. In the
absence of therapy, the lytic wedge at the leading edge of the
lesion progresses along the bone at approximately 1 cm/year
[25]. Figure 1a shows the natural history of PDB in the tibia.
Tissue that was previously lytic (Fig. 1a, left panel) becomes
sclerotic (Fig. 1a, right panel) as OCLs are replaced by oste-
oblastic bone formation [25].
A baseline radionuclide bone scan should be obtained in all
patients with PDB to document the extent and locations of
skeletal involvement [28]. Increased radionuclide uptake is
due to excessive OB activity. In Fig. 1b, a nuclear bone scan
demonstrates intense uptake involving several lower thoracic
vertebrae, a lumbar vertebra, pelvis, sacrum, left femur and
right knee, with expansion and bowing of the involved femur.
While useful for assessing the locations of active lesions and
extent of disease, radionuclide bone scans may underestimate
early-stage disease where OCL-dominant lesions are present.
Page 3 of 12 23
patient showing multiple large OCLs (red arrows) accompanied by OBs
(black arrows) along trabecular bone; also shows fibrovascular tissue
replacement of the marrow cavity. FM, fibrovascular marrow; OB, oste-
oblast; OCL, osteoclast; PDB, Paget’s disease of bone; TB, trabecular
bone. Image a reproduced with permission [25]; image b reproduced with
permission case courtesy of Dr. Alexandra Stanislavsky Radiopaedia.org
rID 12871 [26]; image c reproduced with permission [27]
Computed tomography or magnetic resonance imaging scans
may also be used to assess disease burden, although the use of
these scans is not required for diagnosis [29].
Complications within the skeletal system include bone
pain, bone deformity, fractures, and in less than 1% of cases,
malignant sarcomas may develop. A significant portion of
patients have permanent skeletal deformity or damage by the
time diagnosis is made [15]. Neurologic complications, such
as hearing loss, headaches, and peripheral neuropathies may
occur due to bone deformity putting pressure on nearby nerves
[3]. Hearing loss can be caused by cochlear malfunction relat-
ed to a loss of bone mineral density in the cochlear capsule
[30]. Some fibrosing disorders have been associated with
PDB, such as Peyronie’s disease and Dupuytren’s contrac-
tures [31]. Additionally, pagetic lesions develop extensive
vasculature, which increases total cardiac output and can po-
tentially cause cardiovascular complications [3].
Treatment
The presented treatment approach in Fig. 2 and Table 1 is
consistent with both the 2014 clinical practice guidelines of
the Endocrine Society and the 2019 Paget’s Association
guidelines [19, 28]. Treatment is indicated in symptomatic
PDB and in selected asymptomatic patients (Fig. 2). Several
anti-resorptive agents, which target the OCL, are effective in
treating PDB. Of these drugs, bisphosphonates are the first-
line of treatment, but calcitonin is also used. Bisphosphonates
have a very high affinity for the bone surface where they
remain for years. They are phagocytized by OCLs when the
23 Page 4 of 12 Curr Allergy Asthma Rep (2021) 21: 23

Table 1 Recommended treatment regimens for Paget’s disease of bone

Drug Dosage References FDA approved

Zoledronic acid (Zoledronate) 5 mg given as a single intravenous infusion over Reid et al. [32] Yes
15 min. Retreatment is seldom required within 5 years. Seton et al. [33]
Hosking et al. [34]
Alendronate 40 mg/d administered orally for 6 months. Siris et al. [35] Yes
Retreatment may be required between 2 and 6 years. Walsh et al. [36]
Risedronate 30 mg/d administered orally for 2 months. Miller et al. [37] Yes
Retreatment may be required between 1 and 5 years. Rendina et al. [38]
Pamidronate 60 mg/d administered intravenously for 3 days. Wat et al. [39] Yes
Etidronate 5-10 mg/kg/d, not to exceed 6 months, or 11–20 Khairi et. al. [9] Yes
mg/kg/d, not to exceed 3 months.
Calcitonin 100 IU/d administered subcutaneously or Wat et al. [39] Yes
intramuscularly, reduced to maintenance
dose of 50–100 IU 3 times/week. Limit treatment
to 3 months; may be extended to
6 months in exceptional circumstances.

bone is resorbed and inhibit farnesyl pyrophosphate synthase,
a key enzyme in the mevalonate pathway. This results in dis-
ruption of the OCL cytoskeleton and cell death [40]. The
bisphosphonate Zoledronic acid (ZA) is the first-choice treat-
ment for PDB because of its efficacy and ease of administra-
tion [19, 28]. ZA has the advantage of being given once at a
dose of 5 mg by intravenous infusion over 15 min. Many
providers extend the infusion time to 45 minutes, and treat-
ment with acetaminophen pre-infusion and 48 h post-infusion
may lessen the acute phase response. ZA produces the most
sustained response among the bisphosphonates, inducing bio-
chemical remissions lasting 1 to 2 years in most patients after a
single dose. Biochemical remission is defined as a serum total
ALP level that is both 50% above its 6-month value and 1.25
times the upper limit of the normal range [41]. In one report,
only 14% of patients had a biochemical remission within 9
years, which supports a sustained response to therapy [42].
Whether bisphosphonate treatment will prove useful in long-
term outcomes in the lives of patients with PDB is less clear.
In the Paget’s Disease Randomized trial of Intensive versus
Symptomatic Management (PRISM) trial, in which aggres-
sive versus symptomatic treatment of patients with PDB was
studied, no difference was found in outcomes in the two
groups as measured by fracture rate, quality of life, or other
complications of the disease [43].
In patients wishing to avoid intravenous therapy, or if
ZA is not available, a defined course of daily oral therapy
with risedronate or alendronate is a reasonable alternative
(Table 1). If the patient is intolerant of both parenteral and
oral bisphosphonates, treatment with calcitonin is sug-
gested. Calcitonin is also preferred in patients who are
unable to take bisphosphonates due to marginal renal func-
tion and is a reasonable choice in those for whom the goal
of therapy is rapid easing of pain. Calcitonin, a peptide
hormone secreted by the parafollicular cells in the thyroid,
binds directly to a receptor on the OCL surface. Calcitonin
was the first effective medication to come into clinical use
for PDB; however, the requirement for daily injections and
the frequent occurrence of flushing or nausea have limited
its acceptability to patients, and disease relapse occurred
rapidly after treatment cessation [28]. Published evidence
regarding denosumab, a monoclonal antibody that inhibits
receptor activator of NFκB ligand (RANKL), is limited to
case reports, and there is insufficient data to support its use
in routine clinical practice for PDB [44].
In patients presenting with fractures in a pagetic bone,
bisphosphonates may be used once the patient is stable.
Serum calcium, phosphorus, and vitamin D levels should be
measured and appropriate treatment begun to prevent hypo-
calcemia prior to initiating bisphosphonate therapy [45–47].
Orthopedic surgical options that may be considered in selected
patients with PDB include corrective osteotomy for long bone
deformity, fracture fixation, joint arthroplasty, spinal decom-
pression, and resection of bone tumors [48].
If surgery is planned at an active pagetic site, preoperative
medical treatment with a bisphosphonate beginning 3 months
p r i o r to su r g er y m a y b e b e n ef i ci a l by re d u c i n g
hypervascularity and subsequently perioperative blood loss
[49]. Alternatively, calcitonin can also decrease vascularity
of pagetic bone more rapidly than bisphosphonates, with de-
creased skeletal blood flow observed within one week of
starting treatment. Calcitonin is an alternative for untreated
patients unable to take bisphosphonates or for those who re-
quire surgery with insufficient time for bisphosphonates to
take effect [50].
In treated patients with initial increased serum total ALP,
monitoring is recommended 6 months after treatment initia-
tion and every year to detect biochemical relapse [28]. Patients
with osteolytic lesions should have a follow-up radiograph 1
year later [28].
Curr Allergy Asthma Rep (2021) 21: 23 Page 5 of 12 23

Patient presents with symptoms of PDB

• Bone pain Patient presents with raised
Patient presents with abnormal bone
• Symptomatic nerve compression serum total ALP levels and
lesions detected incidentally on imaging
• Bone deformity normal liver function
• Pathological fracture

Plain x-ray initial screening of areas with high

Plain x-ray of the site
incidence of pagetic lesions, including the skull,
of concern
facial bones, abdomen (spine), and tibiae

Are the findings on imaging indicative of PDB?

• Osteolytic and/or osteosclerotic areas
NO • Cortical and/or trabecular thickening YES
• Loss of distinction between cortex and medullary
compartments
• Bone expansion
• Bone deformity

Bone biopsy*

Are the findings on histology indicative of PDB?

• Numerous large OCLs with increased nuclei YES
number/cell Diagnosis of PDB
• Numerous OBs at lesion
• Disorganized woven bone
Once diagnosis is made:
• Assess symptoms
NO • Assess metabolic activity of PDB: check serum total ALP levels and perform
liver function tests; if serum total ALP levels are normal, check bone-specific
ALP, P1NP, NTX levels
Alternative diagnosis • Define extent of PDB: imaging, radionuclide bone scintigraphy

Asymptomatic patient Symptomatic patient

Does the patient have active disease with any of the

NO following conditions? YES Bisphosphonate
• Disease in high risk sites, including the skull, spine,
treatment
weight-bearing bones, abutting joint lines
• Surgery is planned on a bone affected by PDB
• Serum total ALP level is greater than twice the
upper limit of normal Is the patient contraindicated for bisphosphonate
• Hypercalcemia treatment?**
• Congestive heart failure OR
Does the patient have a need for fast-acting
treatment? (planned surgery or rapid pain relief)

No treatment Calcitonin treatment

Fig. 2 Diagnosis and treatment algorithms for Paget’s disease of bone.
*Other indications of bone biopsy include a possible metastatic lesion, a
lesion in a person where PDB is unlikely, or a “new” pagetic lesion.
**Contraindications for all bisphosphonates include hypersensitivity to
any component of the formulation, hypocalcemia, or renal insufficiency
with creatinine clearance <35mL/min; contraindications for oral
bisphosphonates include abnormalities of the esophagus with delayed
esophageal emptying, inability to sit or stand upright for at least 30
min. ALP, alkaline phosphatase; NTX, N-terminal telopeptide of type I
collagen; P1NP, procollagen type I amino terminal peptide; PDB, Paget’s
disease of bone
23 Page 6 of 12
Epidemiology
PDB is the second most common bone remodeling disease
after osteoporosis and affects approximately 1.5 million
persons in the United States [51]. It occurs in 1–2% of
Caucasian adults older than 55 years [52]. The onset of
PDB is typically after the age of 55, with a slight predomi-
nance in men in the US (male:female 1.22:1) [13]. PDB is
decreasing in prevalence and severity, with an increasing
number of monostotic cases as opposed to polyostotic
cases. A British investigation studied the effect of age and
sex on the number and distribution of sites in PDB and
found that younger patients had more monostotic disease,
with a more marked trend in women. Monostotic disease in
females, but not males, showed excess tibial involvement
[53]. Single nucleotide polymorphisms (SNPs) in the gene
encoding osteoprotegerin (OPG), TNFRSF11b, have been
found to be associated with PDB in women, but not in men
[54]. On the other hand, a recent Chinese systematic review
which included a total of 332 patients with PDB found no
significant differences in clinical manifestations or serum
total ALP levels between the sexes [55••].
Estimates vary, but between 15 and 40% of patients with
PDB have a first-degree relative with the disease (termed fa-
milial PDB, as opposed to sporadic PDB, which occurs in
patients without a family history). In familial PDB, the disease
is frequently inherited in an autosomal dominant pattern (al-
though penetrance is incomplete), tends to be diagnosed at a
younger age, and is more likely to be polyostotic [56, 57].
PDB prevalence differs between ethnic groups and geo-
graphic regions. PDB is most common in Great Britain and
Western Europe; however, it is also seen in regions where
British/European emigrants settled, such as Australia, New
Zealand, South Africa, and the Americas. PDB is considered
to be a rare condition in people of non-Caucasian descent and
is especially uncommon in Africa, China, Japan, Southeast
Asia, and India [58]. There are increasing reports of PDB in
regions once thought to be devoid of the disease, but this may
reflect greater awareness of disease rather than an increase in
prevalence [8].
Studies in the 1970s and 1980s indicated that the highest
frequency in England was located in Lancashire, with a re-
ported incidence of 6–8%. However, between 1970 and 1990,
the frequency in this region decreased by 60%. Overall, the
incidence of PDB is decreasing, the prevalence of polyostotic
disease appears to be declining, and age at onset is rising
[59••].
Environmental Factors
Several environmental factors have been investigated as po-
tential contributors to pathogenesis. A study of 147 PDB pa-
tients in Italy found that there was a greater association with
Curr Allergy Asthma Rep (2021) 21: 23
PDB and living in rural areas versus urban areas. Additionally,
the study found an association between animal contact and
PDB [60]. A French-Canadian study found that exposure to
wood-fired heating during youth or adolescence was associat-
ed with an increased incidence of PDB [61]. A French study
associated smoking tobacco with PDB [62], but another study
found this association did not reach significance in their
French-Canadian cohort [61]. Other factors proposed to con-
tribute to PDB include low calcium intake and vitamin D
deficiency during childhood [63, 64], exposure to environ-
mental toxins or contaminants such as arsenic [65], exposure
to cattle, eating bovine meat, living with dogs [66], and infec-
tion with viruses of the Paramyxoviridae family [67]. While
these epidemiological studies reveal an association between
some environmental factors and PDB, the mechanism by
which any of these factors contribute to PDB is unclear and
requires further investigation.
As far back as 1974, it had been noted that OCLs in pagetic
bone specimens contain abnormal nuclear and/or cytoplasmic
inclusion bodies. These inclusions appeared similar to viral
nucleocapsids most closely resembling those of the
Paramyxoviridae family (which includes measles, mumps, re-
spiratory syncytial, canine distemper, and parainfluenza virus-
es), which spawned a theory that PDB may be caused in part
by viral infection [68]. While some early studies confirmed
the presence of paramyxoviral nucleocapsids or mRNA tran-
scripts in pagetic OCLs [51, 68, 69], the theory remains con-
troversial as other studies have reported little to no correlation
between paramyxoviral infection and PDB, or have been un-
able to replicate results finding viral antigens or transcripts in
pagetic samples [57, 64, 70–74].
Proponents of the paramyxoviral infection hypothesis pro-
pose that in individuals predisposed to PDB due to genetic
factors, exposure to non-genetic factors (such as
paramyxoviral proteins) potentiate abnormal OCL signaling
pathways and cytokine secretion, resulting in pagetic OCLs
and lesions [69, 75]. One major flaw in this theory is that
measles infections typically occur in early childhood but
PDB is rarely seen in people younger than 40 years old; to
counter this, Roodman et al. proposed a chronic infection with
measles as a possible mechanism and also proposed that an-
other cell type (such as a hematopoietic stem cell) must be a
reservoir for the virus because OCLs are not self-renewing
[75]. Further investigation is required.
Bone physiology, Osteoimmunology, and Osteoclasts
To understand the pathophysiology of PDB, it is necessary to
understand the normal physiology of bone and its constituent
cell types. Bone is a complex tissue that provides structural
support, protection for tissues and organs, and enables loco-
motion. It is constantly being broken down, remade, and re-
inforced in response to damage, mechanical stress, changes in
Curr Allergy Asthma Rep (2021) 21: 23
serum mineral levels, and hormones. It also is an important
immune organ, as bone marrow (BM) is where hematopoiesis
occurs and where certain hematopoietic stem/progenitor cells
and some lymphocyte subsets reside.
Osteoimmunology
“Osteoimmunology” is a term developed in the 1970s to de-
scribe the relationship between bone and immune cells.
Interestingly, in vertebrate evolution, bone and immune sys-
tems developed in close proximity to each other when aquatic
vertebrates moved to terrestrial environments. Several mole-
cules and receptors that OCLs use were first described in the
context of immune cell function, such as receptor activator of
NFκB signaling (RANK), RANKL, nuclear factor of activat-
ed t cells, cytoplasmic 1 (NFATc1), dendritic cell-specific
transmembrane protein (DC-STAMP), and NFκB signaling.
OCLs are essential for the immune niche during development;
mice without OCLs develop extramedullary hematopoiesis as
there is not enough space in bone for BM without resorption
occurring [76••]. B and T cell–deficient mice are osteoporotic,
suggesting that these immune cell populations are important
for the regulation of OCLs [77]. B cells produce a majority of
OPG (a soluble decoy receptor for RANKL) in the bone mar-
row, but how T cells affect bone remodeling is still unclear
[78]. OCLs are regulated by cytokines and other factors se-
creted by immune cells such as interleukins (ILs), interferons
(IFNs), and tumor necrosis factors (TNFs) [76••, 79]. Several
molecules and enzymes secreted by OCLs, such as IL-8, ma-
trix metallopeptidase 9 (MMP-9), cathepsin K, and osteopon-
tin, have roles in hematopoietic progenitor cell mobilization
from the BM, and thus, the balance of OCL populations in the
BM has implications for hematopoietic progenitor egress [80].
Osteoimmunology is a complex and emerging field and is
further elaborated on in reviews by Tsukasaki et al. and
Okamoto et al. [76••, 81••].
Bone Remodeling
Bone remodeling is the process by which bone is broken
down and new bone is made. This typically occurs in response
to damage or fracture, biomechanical stress, or changes in
serum mineral levels and subsequent hormone signaling.
Cells of mesenchymal origin, OBs and osteocytes, respond
to these conditions by secreting factors that recruit OCL pre-
cursor cells, including monocyte chemoattractant protein 1
(MCP-1, also known as CCL2) and macrophage colony stim-
ulating factor (M-CSF). Once at the site, RANKL expressed
on the cell membrane of OBs and stromal cells induce the
differentiation and fusion of monocyte precursors into mature
multinucleated OCLs. OCLs adhere to the bone surface and
create a local acidic microenvironment between the OCL and
the bone. Enzymes that function in acidic conditions are
Page 7 of 12 23
released by the OCLs into this microenvironment and degrade
the mineralized matrix. Factors secreted by OCLs, such as
sphingosinge-1-phosphate (S1P), and membrane-bound sig-
naling molecules, such as the EphB4:EphrinB2 bidirectional
signaling complex, recruit OB precursor cells which differen-
tiate at the site. Molecules including insulin-like growth fac-
tors (IGFs) and transforming growth factor beta (TGFβ) are
liberated from the bone matrix by resorption and are released
into the BM microenvironment; these factors may act to re-
cruit osteoblastic cells to the site. OBs lay down new matrix
which is mineralized to form new bone [78]. The process of
OCL differentiation for bone remodeling is shown in Fig. 3.
The homeostatic remodeling of bone is an ongoing process of
the human skeleton.
Bone as an Immune Organ
Most long bones contain trabecular bone and BM.
Hematopoietic stem and progenitor cells reside in the BM to
replenish blood cell populations throughout life. The complex
relationship between bone, BM, and the immune system is
beyond the scope of this article and is elaborated in the
highlighted reviews by Mercier et al. and Brozowski et al.
[82, 83••].
Osteoclasts
OCLs are derived from hematopoietic cells of the monocyte
family. OCL precursor cells are typically BM progenitors or
monocytes that express the receptor RANK. When in the
presence of RANKL, the ligation of the receptor triggers a
cascade of changes that results in the fusion of several precur-
sor cells to form large multinucleated cells (mature OCLs).
The rate of osteoclastogenesis is regulated by the RANKL/
RANK/OPG ratio. OPG is a soluble decoy receptor for
RANKL and is secreted by OBs and B cells [78]. OCLs are
highly specialized to dissolve mineralized bone matrix, but
they are also capable of performing other functions character-
istic of monocytic cells such as phagocytosis, antigen presen-
tation, and T cell activation. In pathologic inflammatory con-
ditions, OCLs may form from the fusion of dendritic cells and
may respond to inflammatory signals and cause bone erosion
at abnormal sites, such as in the case of rheumatoid arthritis
and periodontitis [84••]. How OCLs interact with and affect
the immune compartment within bone is shown in Fig. 3.
PDB Pathophysiology
The OCL as the primary pathologic cell type in PDB has long
been suspected due to excessive bone resorption in early
stages of the disease. Several SNPs identified by genetic stud-
ies have known or suspected roles in OCL function. While it is
generally accepted that the OCL harbors the primary defect in
23 Page 8 of 12
M-CSF
CXCL12 Mono
CIRCULATION CSF1R
BONE MARROW
B cell
BM-derived
precursor
RANK
OPG
Other cytokines
(CCL2, ILs, IFNs, TNFs) DC-STAMP
RANKL OPG
OB
ENDOSTEAL BONE SURFACE
Fig. 3 Osteoimmunology: relationships between bone and immune cells.
BM-derived precursor cells or monocytic cells in circulation migrate to
OBs on the bone surface via chemotaxis to M-CSF, CXCL12, and other
cytokines. M-CSF ligation upregulates RANK expression, which binds to
its ligand, RANKL, on the osteoblast surface. OBs and B cells secrete
OPG, a soluble decoy receptor for RANKL, to control osteoclastogenesis
rates. Increased expression of the seven transmembrane protein DC-
STAMP on the pre-OCL surface facilitates the cellular fusion of multiple
precursor cells to form large mature multinucleated OCLs. OCLs form a
tight seal onto the bone matrix upon which they secrete degradation
enzymes. During resorption, factors released from the matrix and secreted
by OCLs recruit pre-OBs to the resorption site to differentiate into OBs
and initiate matrix deposition. OCLs additionally secrete factors that may
PDB, the exact cause for the defect in OCLs or how the OCLs
malfunction is not fully clear.
Genetics
Genetic contribution to the development of PDB has been
suspected as far back as 1883 due to the familial inheritance
patterns; it is estimated that 15–40% of patients with PDB
have a first-degree relative with the disease [56, 57, 60, 85].
Gene variants associated with PDB are frequently involved in
OCL differentiation, ubiquitin-binding, autophagy, vesicular
trafficking, and immune signaling pathways (RANK, IFNs,
TNFs, NFκB). OPTN and SQSTM1 gene variants have been
verified as causative agents in PDB via mouse models repli-
cating a partial pagetic phenotype in vivo [55••, 86]. Gene
variants associated with PDB are elaborated on in Table 2.
DC-STAMP, dendritic cell-specific transmembrane pro-
tein; GWAS, Genome-Wide Association Study; IFNβ, inter-
feron beta; M-CSF, macrophage colony-stimulating factor;
NFκB, nuclear factor kappa B; OB, osteoblast; OCL, osteo-
clast; OPG, osteoprotegerin; PDB, Paget’s disease of bone;
RANK, receptor activator of NFκB signaling; RANKL,
Curr Allergy Asthma Rep (2021) 21: 23
the BM immune Engagement and
compartment activation of T cells
Pre-OB
T cell
Chemokines for
pre-OB recruitment
for bone formation
Antigen
presentation
OCL
Resorption
affect the BM compartment cell composition by inducing or inhibiting
chemotaxis of other cell types, and may act as an antigen-presenting cell
to T cells. Chemotaxis indicated by solid arrow with lined arrowhead;
differentiation indicated by solid arrow with filled arrowhead; secretion of
factors indicated by dashed arrows. BM, bone marrow; CCL2, C-C motif
chemokine ligand 2; CSF1R, macrophage Colony Stimulating Factor 1
Receptor; CXCL12, C-X-C motif chemokine ligand 12; DC-STAMP,
dendritic Cell-specific transmembrane protein; IFN, interferon; IL, inter-
leukin; M-CSF, macrophage colony-stimulating factor; Mono, monocyte;
OB, osteoblast; OCL, osteoclast; OPG, osteoprotegerin; RANK, receptor
activator of NFκB signaling; RANKL, receptor activator of NFκB sig-
naling ligand, TNF, tumor necrosis factor
receptor activator of NFκB signaling ligand; SNP, single nu-
cleotide polymorphism; TNFα, tumor necrosis factor alpha
OCL Pathophysiology
OCL precursor cells isolated from PDB patients and OCLs
generated from these samples exhibit several abnormalities.
Pagetic OCLs are increased in number and size, have in-
creased numbers of nuclei per cell, are hyperresponsive to
osteoclastogenic factors (including RANKL and
1,25-(OH)2D3), have increased resorption capacity, and are
resistant to apoptosis [99, 100]. In addition to intrinsic chang-
es in the OCL, the BM microenvironment may also possess
alterations that potentiate the defects in OCLs. BM samples
from patients with PDB have high levels of IL-6, which are
low or undetectable in healthy controls [101]. IL-6 may be
produced by the pagetic OCLs and act in an autocrine and
paracrine manner [69]. IL-6 induces RANKL expression on
OBs and stromal cells, which may potentiate the
osteoclastogenic microenvironment in PDB [79].
Hyperactive pagetic OCLs secrete coupling factors to recruit
OBs to the resorption site. Pagetic lesions are associated with
Table 2 Genetic variants associated with Paget’s disease of bone

Gene Protein Physiologic role of protein Mutations associated with PDB or PDB-like Familial or Hypothesized pathogenic role of mutation in PDB Refs
syndromes sporadic,
typical or
atypical
presentation
Curr Allergy Asthma Rep (2021) 21: 23

SQSTM1 p62 Contains several functional domains; Several mutations within the ubiquitin-binding Familial, Loss of ubiquitin-binding function affects NFκB [40, 87]
ubiquitin-binding, scaffolding protein, domain identified in PDB; proline 392 to sporadic; signaling, enhanced sensitivity of OCL
autophagy receptor, NFκB signaling pathway leucine (P392L) mutation most common typical precursors to RANKL and TNFα
OPTN Optineurin Contains several functional domains; autophagy Several SNPs have been identified to be Familial; Conflicting reports exist regarding if OPTN [88–91]
receptor, chaperone for ubiquitinated cargoes, associated with PDB; rs1561570, typical variants lead to increased or decreased protein
vesicle transport, NFκB modulation; expression rs3829923, rs2234968 expression or function; changes in OPTN
increases during OCL differentiation and acts as function or expression may lead to enhanced
a negative regulator via modulating NFκB and OCL differentiation via loss of modulation of
IFNβ pathways NFκB and IFNβ signaling pathways
TNFRS11A RANK Receptor for RANKL; required for the Lack of evidence suggesting contribution of Familial; Increased RANK-mediated NFκB signaling, [88,
differentiation of precursor cells into OCLs TNFRS11A mutations to classic PDB; Atypical; increased osteoclastogenesis
insertion mutations affecting exon 1 found in rare
some families with early-onset PDB or PDB-like
PDB-like syndromes syndromes,
early-onset
PDB
92–94]
TNFRS11B OPG Soluble decoy receptor for RANKL secreted by G1181C SNP associated with increased risk of Familial, Functional result of G1181C SNP unknown; [54,
OBs, B cells sporadic and familial PDB; TNFRS11B sporadic; deletion mutations cause reduced OPG which
variants associated with PDB in women, but typical, and results in increased osteoclastogenesis
not men; deletion mutations associated with atypical
Juvenile PDB PDB
95–97]
CSF1 M-CSFCytokine required for the survival and proliferation GWAS identified risk associated loci involving More Increased expression of M-CSF may enhance [88, 98]
of monocytes and OCL precursors; chemotaxis this gene investigation OCL formation
via c-FMS receptor required
DCSTAMP DC-STAMP Cell surface molecule required for the fusion of GWAS identified risk associated loci involving More Increased expression of DC-STAMP may [88, 98]
precursors to form multinucleated OCLs this gene investigation increase OCL formation
required
Page 9 of 12 23
23 Page 10 of 12
increased numbers of immature OBs at the site, which are
known to secrete more RANKL than mature cells [69]. The
mechanism by which the newly formed bone is weak and
poorly structured is unclear. Defects may exist within OBs
in PDB patients, but this requires further investigation.
Conclusion
PDB is a bone disease of aging. While the overall prevalence
of the disease may be decreasing, the study of PDB is still
important. Investigating genetic variants associated with
PDB have elucidated roles for proteins in bone remodeling
that were previously unknown. Given the unique role of
OCLs as cells of bone remodeling and the immune system,
the study of PDB may be important in the emerging field of
osteoimmunology. Understanding the pathologic mechanisms
of OCLs and the bone microenvironment may also provide
important insights into other inflammatory and autoimmune
diseases that involve abnormal bone erosion, such as rheuma-
toid arthritis, periodontitis, and multiple myeloma.
Declarations
Conflict of Interest The authors declare that they have no conflicts of
interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
•• Of major importance
1. Toodayan N. The Paget bicentenary: an Australian perspective. J
Med Biogr. 2018;26(3):164–71.
2. Sabharwal R, Gupta S, Sepolia S, Panigrahi R, Mohanty S,
Subudhi SK, et al. An insight in to Paget’s disease of bone.
Niger J Surg. 2014;20(1):9–15.
3. Singer FR. Paget’s Disease of Bone. In: Feingold KR, Anawalt B,
Boyce A, Chrousos G, de Herder WW, Dungan K, et al., editors.
Endotext. South Dartmouth (MA) 2000.
4.•• Daroszewska A, Rose L, Sarsam N, Charlesworth G, Prior A,
Rose K, et al. Zoledronic acid prevents pagetic-like lesions and
accelerated bone loss in the p62(P394L) mouse model of Paget’s
disease. Dis Model Mech. 2018;11(9):dmm035576 Comment:
primary research of a p62 mutation mouse model of Paget’s
disease.
5. Gasper TM. Paget’s disease in a treadle machine operator. Br Med
J. 1979;1(6172):1217–8.
6. Solomon LR. Billiard-player’s fingers: an unusual case of Paget’s
disease of bone. Br Med J. 1979;1(6168):931.
Curr Allergy Asthma Rep (2021) 21: 23
7. Mays S. Archaeological skeletons support a northwest European
origin for Paget’s disease of bone. J Bone Miner Res. 2010;25(8):
1839–41.
8. Kesterke MJ, Judd MA. A microscopic evaluation of Paget’s dis-
ease of bone from a Byzantine monastic crypt in Jordan. Int J
Paleopathol. 2019;24:293–8.
9. Rogers J, Jeffrey DR, Watt I. Paget’s disease in an archeological
population. J Bone Miner Res. 2002;17(6):1127–34.
10. Waldron HA. Recalculation of secular trends in Paget’s disease. J
Bone Miner Res. 2004;19(3):523.
11. Pusch CM, Czarnetzki A. Archaeology and prevalence of Paget’s
disease. J Bone Miner Res. 2005;20(8):1484 author reply 5.
12. Shaw B, Burrell CL, Green D, Navarro-Martinez A, Scott D,
Daroszewska A, et al. Molecular insights into an ancient form of
Paget’s disease of bone. Proc Natl Acad Sci U S A. 2019;116(21):
10463–72.
13. Wermers RA, Tiegs RD, Atkinson EJ, Achenbach SJ, Melton LJ
3rd. Morbidity and mortality associated with Paget’s disease of
bone: a population-based study. J Bone Miner Res. 2008;23(6):
819–25.
14. Shaker JL. Paget’s disease of bone: a review of epidemiology,
pathophysiology and management. Ther Adv Musculoskelet
Dis. 2009;1(2):107–25.
15. Tan A, Ralston SH. Clinical presentation of Paget’s disease: eval-
uation of a contemporary cohort and systematic review. Calcif
Tissue Int. 2014;95(5):385–92.
16. Winfield J, Stamp TC. Bone and joint symptoms in Paget’s dis-
ease. Ann Rheum Dis. 1984;43(6):769–73.
17. Alvarez L, Guanabens N, Peris P, Monegal A, Bedini JL,
Deulofeu R, et al. Discriminative value of biochemical markers
of bone turnover in assessing the activity of Paget’s disease. J
Bone Miner Res. 1995;10(3):458–65.
18. Gennari L, Rendina D, Falchetti A, Merlotti D. Paget’s disease of
bone. Calcif Tissue Int. 2019;104(5):483–500.
19. Ralston SH, Corral-Gudino L, Cooper C, Francis RM, Fraser WD,
Gennari L, et al. Diagnosis and management of paget’s disease of
bone in adults: a clinical guideline. J Bone Miner Res. 2019;34(4):
579–604.
20. Seton M. Paget disease of bone: diagnosis and drug therapy. Cleve
Clin J Med. 2013;80(7):452–62.
21. Seitz S, Priemel M, Zustin J, Beil FT, Semler J, Minne H, et al.
Paget’s disease of bone: histologic analysis of 754 patients. J Bone
Miner Res. 2009;24(1):62–9.
22. Rebel A, Malkani K, Basle M, Bregeon C. Is Paget’s disease of
bone a viral infection? Calcif Tissue Res. 1977;22(Suppl):283–6.
23. Mills BG, Singer FR. Nuclear inclusions in Paget’s disease of
bone. Science. 1976;194(4261):201–2.
24. Nebot Valenzuela E, Pietschmann P. Epidemiology and pathology
of Paget’s disease of bone - a review. Wien Med Wochenschr.
2017;167(1-2):2–8.
25. Reid IR. Recent advances in understanding and managing Paget’s
disease. F1000Res. 2019;8.
26. Stanislavsky A Polyostotic Paget Disease 2011 [Available from:
https://radiopaedia.org/cases/polyostotic-paget-disease?lang=us.
27. Singer FR. Paget’s disease of bone-genetic and environmental
factors. Nat Rev Endocrinol. 2015;11(11):662–71.
28. Singer FR, Bone HG 3rd, Hosking DJ, Lyles KW, Murad MH,
Reid IR, et al. Paget’s disease of bone: an endocrine society clin-
ical practice guideline. J Clin Endocrinol Metab. 2014;99(12):
4408–22.
29. Winn N, Lalam R, Cassar-Pullicino V. Imaging of Paget’s disease
of bone. Wien Med Wochenschr. 2017;167(1-2):9–17.
30. Monsell EM. The mechanism of hearing loss in Paget’s disease of
bone. Laryngoscope. 2004;114(4):598–606.
Curr Allergy Asthma Rep (2021) 21: 23
31. Lyles KW, Gold DT, Newton RA, Parekh S, Shipp KM, Pieper
CF, et al. Peyronie’s disease is associated with Paget’s disease of
bone. J Bone Miner Res. 1997;12(6):929–34.
32. Reid IR, Miller P, Lyles K, Fraser W, Brown JP, Saidi Y, et al.
Comparison of a single infusion of zoledronic acid with
risedronate for Paget’s disease. N Engl J Med. 2005;353(9):898–
908.
33. Seton M, Krane SM. Use of zoledronic acid in the treatment of
Paget’s disease. Ther Clin Risk Manag. 2007;3(5):913–8.
34. Hosking D, Lyles K, Brown JP, Fraser WD, Miller P, Curiel MD,
et al. Long-term control of bone turnover in Paget’s disease with
zoledronic acid and risedronate. J Bone Miner Res. 2007;22(1):
142–8.
35. Siris E, Weinstein RS, Altman R, Conte JM, Favus M, Lombardi
A, et al. Comparative study of alendronate versus etidronate for
the treatment of Paget’s disease of bone. J Clin Endocrinol Metab.
1996;81(3):961–7.
36. Walsh JP, Ward LC, Stewart GO, Will RK, Criddle RA, Prince
RL, et al. A randomized clinical trial comparing oral alendronate
and intravenous pamidronate for the treatment of Paget’s disease
of bone. Bone. 2004;34(4):747–54.
37. Miller PD, Brown JP, Siris ES, Hoseyni MS, Axelrod DW,
Bekker PJ. A randomized, double-blind comparison of risedronate
and etidronate in the treatment of Paget’s disease of bone. Paget’s
Risedronate/Etidronate Study Group. Am J Med. 1999;106(5):
513–20.
38. Rendina D, Mossetti G, Viceconti R, Sorrentino M, Nunziata V.
Risedronate and pamidronate treatment in the clinical manage-
ment of patients with severe Paget’s disease of bone and acquired
resistance to bisphosphonates. Calcif Tissue Int. 2004;75(3):189–
96.
39. Wat WZ. Current perspectives on bisphosphonate treatment in
Paget’s disease of bone. Ther Clin Risk Manag. 2014;10:977–83.
40. Hocking LJ, Lucas GJ, Daroszewska A, Mangion J, Olavesen M,
Cundy T, et al. Domain-specific mutations in sequestosome 1
(SQSTM1) cause familial and sporadic Paget’s disease. Hum
Mol Genet. 2002;11(22):2735–9.
41. Reid IR, Lyles K, Su G, Brown JP, Walsh JP, del Pino-Montes J,
et al. A single infusion of zoledronic acid produces sustained re-
missions in Paget disease: data to 6.5 years. J Bone Miner Res.
2011;26(9):2261–70.
42. Cundy T, Maslowski K, Grey A, Reid IR. Durability of response
to Zoledronate treatment and competing mortality in Paget’s dis-
ease of bone. J Bone Miner Res. 2017;32(4):753–6.
43. Langston AL, Campbell MK, Fraser WD, MacLennan GS, Selby
PL, Ralston SH, et al. Randomized trial of intensive bisphospho-
nate treatment versus symptomatic management in Paget’s disease
of bone. J Bone Miner Res. 2010;25(1):20–31.
44. Reid IR, Sharma S, Kalluru R, Eagleton C. Treatment of Paget’s
disease of bone with denosumab: case report and literature review.
Calcif Tissue Int. 2016;99(3):322–5.
45. Barry HC. Orthopedic aspects of Paget’s disease of bone. Arthritis
Rheum. 1980;23(10):1128–30.
46. Bidner S, Finnegan M. Femoral fractures in Paget’s disease. J
Orthop Trauma. 1989;3(4):317–22.
47. Whitson HE, Lobaugh B, Lyles KW. Severe hypocalcemia fol-
lowing bisphosphonate treatment in a patient with Paget’s disease
of bone. Bone. 2006;39(4):954–8.
48. Parvizi J, Klein GR, Sim FH. Surgical management of Paget’s
disease of bone. J Bone Miner Res. 2006;21(Suppl 2):P75–82.
49. Calderoni P, Ferruzzi A, Andreoli I, Gualtieri G. Hip arthroplasty
in coxarthrosis secondary to Paget’s disease. Chir Organi Mov.
2002;87(1):43–8.
50. Wootton R, Reeve J, Spellacy E, Tellez-Yudilevich M. Skeletal
blood flow in Paget’s disease of bone and its response to calcitonin
therapy. Clin Sci Mol Med. 1978;54(1):69–74.
Page 11 of 12 23
51. Roodman GD. Insights into the pathogenesis of Paget’s disease.
Ann N Y Acad Sci. 2010;1192:176–80.
52. Numan MS, Jean S, Dessay M, Gagnon E, Amiable N, Brown JP,
et al. Gene-environment interactions in Paget’s disease of bone.
Joint Bone Spine. 2019;86(3):373–80.
53. Haddaway MJ, Davie MW, McCall IW, Howdle S. Effect of age
and gender on the number and distribution of sites in Paget’s
disease of bone. Br J Radiol. 2007;80(955):532–6.
54. Beyens G, Daroszewska A, de Freitas F, Fransen E,
Vanhoenacker F, Verbruggen L, et al. Identification of sex-
specific associations between polymorphisms of the osteoproteg-
erin gene, TNFRSF11B, and Paget’s disease of bone. J Bone
Miner Res. 2007;22(7):1062–71.
55.•• Wong SW, Huang BW, Hu X, Ho Kim E, Kolb JP, Padilla RJ,
et al. Global deletion of Optineurin results in altered type I IFN
signaling and abnormal bone remodeling in a model of Paget’s
disease. Cell Death Differ. 2020;27(1):71–84 Comment: prima-
ry research of an optineurin-deficient mouse model of Paget’s
disease.
56. Morales-Piga AA, Rey-Rey JS, Corres-Gonzalez J, Garcia-
Sagredo JM, Lopez-Abente G. Frequency and characteristics of
familial aggregation of Paget’s disease of bone. J Bone Miner Res.
1995;10(4):663–70.
57. Seton M, Choi HK, Hansen MF, Sebaldt RJ, Cooper C. Analysis
of environmental factors in familial versus sporadic Paget’s dis-
ease of bone–the New England Registry for Paget’s Disease of
Bone. J Bone Miner Res. 2003;18(8):1519–24.
58. Merashli M, Jawad A. Paget’s Disease of Bone among Various
Ethnic Groups. Sultan Qaboos Univ Med J. 2015;15(1):e22–6.
59.•• Cundy T. Paget’s disease of bone. Metabolism. 2018;80:5–14
Comment: recent comprehensive review of Paget’s Disease
of Bone.
60. Merlotti D, Gennari L, Galli B, Martini G, Calabro A, De Paola V,
et al. Characteristics and familial aggregation of Paget’s disease of
bone in Italy. J Bone Miner Res. 2005;20(8):1356–64.
61. Audet MC, Jean S, Beaudoin C, Guay-Belanger S, Dumont J,
Brown JP, et al. Environmental factors associated with familial
or non-familial forms of Paget’s disease of bone. Joint Bone
Spine. 2017;84(6):719–23.
62. Michou L, Collet C, Morissette J, Audran M, Thomas T, Gagnon
E, et al. Epidemiogenetic study of French families with Paget’s
disease of bone. Joint Bone Spine. 2012;79(4):393–8.
63. Siris ES. Epidemiological aspects of Paget’s disease: family his-
tory and relationship to other medical conditions. Semin Arthritis
Rheum. 1994;23(4):222–5.
64. Barker DJ, Gardner MJ. Distribution of Paget’s disease in
England, Wales and Scotland and a possible relationship with
vitamin D deficiency in childhood. Br J Prev Soc Med.
1974;28(4):226–32.
65. Lever JH. Paget’s disease of bone in Lancashire and arsenic pes-
ticide in cotton mill wastewater: a speculative hypothesis. Bone.
2002;31(3):434–6.
66. Lopez-Abente G, Morales-Piga A, Elena-Ibanez A, Rey-Rey JS,
Corres-Gonzalez J. Cattle, pets, and Paget’s disease of bone.
Epidemiology. 1997;8(3):247–51.
67. Ralston SH, Layfield R. Pathogenesis of Paget disease of bone.
Calcif Tissue Int. 2012;91(2):97–113.
68. Singer FR. Update on the viral etiology of Paget’s disease of bone.
J Bone Miner Res. 1999;14(Suppl 2):29–33.
69. Ehrlich LA, Roodman GD. The role of immune cells and inflam-
matory cytokines in Paget’s disease and multiple myeloma.
Immunol Rev. 2005;208:252–66.
70. Matthews BG, Afzal MA, Minor PD, Bava U, Callon KE, Pitto
RP, et al. Failure to detect measles virus ribonucleic acid in bone
cells from patients with Paget’s disease. J Clin Endocrinol Metab.
2008;93(4):1398–401.
23 Page 12 of 12
71. Visconti MR, Usategui-Martin R, Ralston SH. Antibody response
to Paramyxoviruses in Paget’s disease of bone. Calcif Tissue Int.
2017;101(2):141–7.
72. Ralston SH, Afzal MA, Helfrich MH, Fraser WD, Gallagher JA,
Mee A, et al. Multicenter blinded analysis of RT-PCR detection
methods for paramyxoviruses in relation to Paget’s disease of
bone. J Bone Miner Res. 2007;22(4):569–77.
73. Helfrich MH, Hobson RP, Grabowski PS, Zurbriggen A, Cosby
SL, Dickson GR, et al. A negative search for a paramyxoviral
etiology of Paget’s disease of bone: molecular, immunological,
and ultrastructural studies in UK patients. J Bone Miner Res.
2000;15(12):2315–29.
74. Birch MA, Taylor W, Fraser WD, Ralston SH, Hart CA,
Gallagher JA. Absence of paramyxovirus RNA in cultures of
pagetic bone cells and in pagetic bone. J Bone Miner Res.
1994;9(1):11–6.
75. Roodman GD, Windle JJ. Paget disease of bone. J Clin Invest.
2005;115(2):200–8.
76.•• Tsukasaki M, Takayanagi H. Osteoimmunology: evolving con-
cepts in bone-immune interactions in health and disease. Nat
Rev Immunol. 2019;19(10):626–42 Comment: recent review
of osteoimmunology.
77. Li Y, Toraldo G, Li A, Yang X, Zhang H, Qian WP, et al. B cells and
T cells are critical for the preservation of bone homeostasis and
attainment of peak bone mass in vivo. Blood. 2007;109(9):3839–48.
78. Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of
bone remodeling. J Biol Chem. 2010;285(33):25103–8.
79. Amarasekara DS, Yun H, Kim S, Lee N, Kim H, Rho J.
Regulation of osteoclast differentiation by cytokine networks.
Immune Netw. 2018;18(1):e8.
80. Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg
Y, et al. Osteoclasts degrade endosteal components and promote
mobilization of hematopoietic progenitor cells. Nat Med.
2006;12(6):657–64.
81.•• Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T,
Komatsu N, Terashima A, et al. Osteoimmunology: the concep-
tual framework unifying the immune and skeletal systems.
Physiol Rev. 2017;97(4):1295–349 Comment: recent reivew
of osteoimmunology.
82. Mercier FE, Ragu C, Scadden DT. The bone marrow at the cross-
roads of blood and immunity. Nat Rev Immunol. 2011;12(1):49–60.
83.•• Brozowski JM, Billard MJ, Tarrant TK. Targeting the molecular
and cellular interactions of the bone marrow niche in immunologic
disease. Curr Allergy Asthma Rep. 2014;14(2):402 Comment:
review of the bone marrow niche components.
84.•• Madel MB, Ibanez L, Wakkach A, de Vries TJ, Teti A, Apparailly
F, et al. Immune Function and Diversity of Osteoclasts in Normal
and Pathological Conditions. Front Immunol. 2019;10:1408
Comment: recent review on osteoclast physiology and roles
in immunology.
85. Ralston SH, Taylor JP. Rare Inherited forms of Paget’s Disease
and Related Syndromes. Calcif Tissue Int. 2019;104(5):501–16.
86. Daroszewska A, van’t Hof RJ, Rojas JA, Layfield R, Landao-
Basonga E, Rose L, et al. A point mutation in the ubiquitin-
associated domain of SQSMT1 is sufficient to cause a Paget’s
disease-like disorder in mice. Hum Mol Genet. 2011;20(14):
2734–44.
Curr Allergy Asthma Rep (2021) 21: 23
87. Laurin N, Brown JP, Morissette J, Raymond V. Recurrent
mutation of the gene encoding sequestosome 1 (SQSTM1/
p62) in Paget disease of bone. Am J Hum Genet.
2002;70(6):1582–8.
88. Albagha OM, Visconti MR, Alonso N, Langston AL,
Cundy T, Dargie R, et al. Genome-wide association study
identifies variants at CSF1, OPTN and TNFRSF11A as
genetic risk factors for Paget’s disease of bone. Nat
Genet. 2010;42(6):520–4.
89. Obaid R, Wani SE, Azfer A, Hurd T, Jones R, Cohen P, et al.
Optineurin negatively regulates osteoclast differentiation by mod-
ulating NF-kappaB and interferon signaling: implications for
Paget’s disease. Cell Rep. 2015;13(6):1096–102.
90. Zhu G, Wu CJ, Zhao Y, Ashwell JD. Optineurin negatively reg-
ulates TNFalpha- induced NF-kappaB activation by competing
with NEMO for ubiquitinated RIP. Curr Biol. 2007;17(16):
1438–43.
91. Silva IAL, Conceicao N, Gagnon E, Caiado H, Brown JP,
Gianfrancesco F, et al. Effect of genetic variants of OPTN in the
pathophysiology of Paget’s disease of bone. Biochim Biophys
Acta Mol basis Dis. 2018;1864(1):143–51.
92. Nakatsuka K, Nishizawa Y, Ralston SH. Phenotypic characteriza-
tion of early onset Paget’s disease of bone caused by a 27-bp
duplication in the TNFRSF11A gene. J Bone Miner Res.
2003;18(8):1381–5.
93. Iwamoto SJ, Rothman MS, Duan S, Baker JC, Mumm S, Whyte
MP. Early-onset Paget’s disease of bone in a Mexican family
caused by a novel tandem duplication (77dup27) in
TNFRSF11A that encodes RANK. Bone. 2020;133:115224.
94. Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H,
Wallace RG, et al. Mutations in TNFRSF11A, affecting the signal
peptide of RANK, cause familial expansile osteolysis. Nat Genet.
2000;24(1):45–8.
95. Whyte MP, Obrecht SE, Finnegan PM, Jones JL, Podgornik MN,
McAlister WH, et al. Osteoprotegerin deficiency and juvenile
Paget’s disease. N Engl J Med. 2002;347(3):175–84.
96. Daroszewska A, Hocking LJ, McGuigan FE, Langdahl B, Stone
MD, Cundy T, et al. Susceptibility to Paget’s disease of bone is
influenced by a common polymorphic variant of osteoprotegerin.
J Bone Miner Res. 2004;19(9):1506–11.
97. Daroszewska A, Ralston SH. Genetics of Paget’s disease of bone.
Clin Sci (Lond). 2005;109(3):257–63.
98. Albagha OM. Genetics of Paget’s disease of bone. Bonekey Rep.
2015;4:756.
99. Galson DL, Roodman GD. Pathobiology of Paget’s Disease of
Bone. J Bone Metab. 2014;21(2):85–98.
100. Chamoux E, Couture J, Bisson M, Morissette J, Brown JP, Roux
S. The p62 P392L mutation linked to Paget’s disease induces
activation of human osteoclasts. Mol Endocrinol. 2009;23(10):
1668–80.
101. Roodman GD, Kurihara N, Ohsaki Y, Kukita A, Hosking D,
Demulder A, et al. Interleukin 6. A potential autocrine/paracrine
factor in Paget’s disease of bone. J Clin Invest. 1992;89(1):46–52.
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