Accepted Manuscript

Paget’s Disease of Bone

Natasha M. Appelman-Dijkstra, MD, PhD, Socrates E. Papapoulos, MD, PhD

PII: S1521-690X(18)30073-3
DOI: 10.1016/j.beem.2018.05.005
Reference: YBEEM 1215

To appear in: Best Practice & Research Clinical Endocrinology & Metabolism

Please cite this article as: Appelman-Dijkstra NM, Papapoulos SE, Paget’s Disease of Bone, Best
Practice & Research Clinical Endocrinology & Metabolism (2018), doi: 10.1016/j.beem.2018.05.005.

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 ACCEPTED MANUSCRIPT

Paget’s Disease of Bone

Natasha M Appelman-Dijkstra MD, PhD and Socrates E Papapoulos MD, PhD*

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Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands

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Address for Correspondence: Center for Bone Quality
Leiden University Medical Center
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Albinusdreef 2

2333 ZA Leiden
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The Netherlands
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Tel: +31-71-526 2490

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Fax: +31-71-524 8136

Email: s.e.papapoulos@lumc.nl; n.m.appelman-dijkstra@lumc.nl

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* Corresponding author

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Abstract
Paget’s disease of bone is a focal disorder of bone remodelling that progresses slowly and

leads to changes in the shape and size of affected bones and to skeletal, articular and vascular
complications. In some parts of the world it is the second most common bone disorder after

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osteoporosis though in recent years its prevalence and severity appear to decrease. The disease

is easily diagnosed and effectively treated but its pathogenesis remains incompletely

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understood.

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Key words: bone turnover, genetics, Paget’s disease, SQSTM1, zoledronate

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Introduction
In 1876, Sir James Paget presented to the Surgical and Medical Society of London, UK, an

account of his experience with a previously unrecognized disease of the skeleton which he
termed osteitis deformans and bears his name since. In the full paper published in 1877, he

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summarized his findings as follows: ‘(the disease) begins in the middle age or later, is very

slow in progress, may continue for many years without influence on the general health, and

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may give no other trouble than those which are due to changes of shape, size and direction of

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diseased bones … The bones enlarge and soften, and those bearing weight yield and become

unnaturally curved and misshapen … The disease is attended with pains in the affected bones,

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pains widely various in severity and variously described as rheumatic, gouty or neuralgic …

The bones examined after death show the consequences of an inflammation … The softening is
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associated with enlargement and with imperfectly developed structures, and with increased
blood supply.’ This remarkable description captures all known features of the disease.
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Epidemiology.
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Paget's disease (PDB) affects typically the elderly, slightly more men than women, and seldom
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presents before the age of 35 years. Its prevalence increases with age and it affects 1 to 5% of

those above 50 years of age (Figure 1). The disease affects predominantly people of European
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descent, has a distinct geographical distribution, with highest prevalence in the UK and

lowest in Japan, and there may also be significant variations in the prevalence of the disease in
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regions of the same country (1). However, only a small proportion of individuals with PDB
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comes to clinical attention, most likely these with more severe disease (2,3). In recent years a

decline in the prevalence of the disease has been reported in most, but not all, countries in

which this was estimated and it has been suggested that the clinical severity of the disease has
been attenuated (4-6). These changes in prevalence and possibly severity of the disease

strongly suggest that environmental factors are involved in its pathogenesis.

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Pathophysiology
Paget's disease of bone is characterized by an increase in the number and size of osteoclasts in

affected sites while the rest of the skeleton remains normal. The typically large multinucleated
osteoclasts induce excessive bone resorption associated with increased recruitment of

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osteoblasts to the remodelling sites resulting in increased bone formation (Figure 2). This

accelerated rate of bone turnover is responsible for the deposition of bone with disorganized

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architecture and structural weakness. Osteoclasts, osteoclast precursors and marrow stromal

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cells from patients with the disease express high levels of the bone resorbing factors, IL-6 and

RANKL which contribute to the upregulation of osteoclastogenesis. In addition, bone marrow

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and peripheral cells from patients are hypersensitive to the action of RANKL and calcitriol (7-

12).
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Several, not mutually exclusive, hypotheses have been proposed to explain the pathology of
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the disease, the most relevant being the viral and the genetic. Studies of the distribution of

bone lesions in patients with PDB showed that the probability of a bone being affected is very
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similar to the probability of a bone being affected with haematogenous osteomyelitis

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suggesting a possible contribution of a circulating infectious agent to the pathogenesis of the

disease. An infection of pagetic osteoclasts by a slow virus of the paramyxovirus family (e.g.,
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measles virus, respiratory syncytial virus, canine distemper virus) was supported by some

studies but search for viral presence in Pagetic osteoclasts provided conflicting results (13-16).
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A recent study of a large cohort of patients with PDB found no evidence in support of an
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association between the disease and a persistent infection with measles or other

paramyxoviruses (17). There is good evidence, however, that paramyxoviruses and viral

proteins can promote the formation of osteoclasts with features similar to those of Pagetic
osteoclasts particularly in combination with genetic alterations (18-20) .

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The risk of first degree relatives of patients with PDB to develop the disorder is 7 to 10 times

higher than the risk of age and sex-matched controls and a positive family history has been

reported in up to 40% of patients (21-23). Familial Paget's disease is inherited as an autosomal

dominant trait but initial analyses indicated genetic heterogeneity (23-25). Studies in different

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parts of the world have identified mutations in the SQSTM1 gene, located in chromosome

5q35, in up to 40% of patients with familial PDB and up to 10% of those with sporadic disease

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but these are not disease-causing (26,27). SQSTM1 encodes p62, an adaptor protein that binds

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ubiquitin and is involved in various signaling pathways including the NFκB pathway. The

most common mutation of SQSTM1 reported in studies around the world is P329L that has,

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however, incomplete penetration suggesting that other factors (genetic and/or environmental)

are necessary for the phenotypic expression of the disease (28-30) (Figure 3). In addition,
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genetic studies of patients with PDB and no mutations in the SQSTM1 gene identified 7 loci
that contribute substantially to the risk of developing the disease as well as affecting its
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severity in combination with mutations of SQSTM1. These genetic variants include genes that

are known to play important roles in the differentiation and function of osteoclasts (e.g. CSF1
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and TNFRSF11A) but also genes not previously implicated in the regulation of bone
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metabolism (31-34). The functional significance of these polymorphisms is still unknown.

Interestingly, the P329L mutations has been also found in patients with multisystem
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proteinopathy (inclusion body myopathy, frontotemporal dementia, amyotrophic lateral

sclerosis and PDB) who did not have PDB indicating that the mutation can generate distinct
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phenotypes in different patients (35). The current view is, therefore, that PDB is caused by
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interactions between environmental and genetic factors, the precise nature of which remains to

be determined.

Clinical features
The most commonly affected bones are the pelvis, the spine, the femora and the skull but

practically any bone of the skeleton may be affected. Despite the geographic variation of the
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disease there is remarkable similarity in the frequency of affected bones in large clinical series

from different countries (2,36,37). About one third of patients have only one bone lesion but

the frequency of single lesions varies among series reflecting probably referral patterns and is
higher in asymptomatic patients. Notably the anatomical spread of skeletal lesions in Paget’s

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disease is log normally distributed and the commonly used distinction to monostotic and

polyostotic disease in clinical practice is not pathophysiologically appropriate. The anatomical

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spread of the disease is not related to age or gender, shows no particular symmetry in the body

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and remains largely unchanged throughout life. The disease progresses slowly within an

affected bone but does not generally appear in other bones. Patients with limited bone

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involvement should, therefore, be reassured that the disease will not progress to other bones

with time.
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The majority of patients are asymptomatic and the disease may be diagnosed incidentally by
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skeletal radiographs during investigation of an unrelated complaint or by the finding of an

unexplained elevation of serum alkaline phosphatase (ALP) activity. Prediction of

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development of symptoms in asymptomatic patients is currently not feasible due to the slow
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progression of the disease. Anecdotal evidence indicates, however, that patients with

localizations close to large joints, in weight-bearing bones, the spine and skull or with raised
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serum ALP activity have a higher risk for complications with time (Figure 4). Skeletal

morbidity in PDB is determined by the damage caused and the progression of the disease in
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affected sites as well as by the number and the localization of the lesions. Pain is the
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presenting complaint in the majority of symptomatic patients. It is related to the extent and site

of the disease, it is usually persistent and present at rest, but is not specific. Pain due to

secondary osteoarthritis of the hips, the knees, and the vertebrae, more common in PDB than
in age-matched controls, may hamper assessment of the relative contribution of bone and

joint pains to the patient's disability. The origin of such pain can be assessed only

retrospectively after treatment which reduces mainly the disease-related pain. Back pain may
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be due to disease-affected vertebrae, to osteoarthritis or to compression fractures. Deformities,

mainly of weight-bearing bones, are present in about 15% of patients at the time of diagnosis .

The most common deformity is bowing of the lower limbs. In addition, characteristic
deformities occur in the skull and the jaw. About 9% of patients present with fractures that can

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be complete or fissure fractures (incomplete, pseudofractures) that occur more commonly in

the long bones. Complete fractures are characteristically transverse and are a serious

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complication of the disease. Fissure fractures occur more frequently, may be multiple, cause

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pain, and may develop to complete fractures. Fractures generally heal well but in an older

large series of 182 fractures the incidence of non-union was 40 per cent (38). The skin

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overlying an affected bone may be warm as a result of increased blood flow and bone turnover

locally and hypervascularity of affected bones may cause ischaemia of adjacent structures
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(steal syndrome). This may present as difficulty in walking (mimicking intermittent
claudication) when localized in the lower limbs or dementia when the skull is involved.
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Neurological complications generally occur as a result of ischaemia or are due to mechanical

compression of neural tissues. These include headache, spinal stenosis and rarely brain stem
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and cerebellar compression, hydrocephalus and cranial neuropathies. Irreversible hearing loss
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is the most common neurological complication occurring in about one third of patients with

skull involvement. This is due to structural and/or density changes in the cochlear capsule
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bone rather than to compression of the 8th cranial nerve. Neoplastic transformation of Pagetic

bone is rare (less than 1%) and includes osteosarcoma and giant cell tumours that are
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associated more with familial clustering of the disease (39). A recent study identified
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pathogenic mutations of the ZNF687 gene in a family with PDB with increased prevalence of

giant cell tumours of bone but also in other patients with or without SQSTM1 mutations

(40,41). The ZNF687 gene was further shown to be highly expressed during osteoclast and
osteoblast differentiation and patients with missense mutations of the gene had an earlier

clinical expression and more severe bone disease.

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Investigations
Radiographic changes are characteristic of the pathophysiology of the disease. Increased bone

resorption may be detected as a decrease in the density of affected bones; sometimes a wedge-
or flame-segment of bone resorption may be seen in long bones and extensive osteolytic areas

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in the skull (osteoporosis circumscripta). Older lesions usually have a mixed sclerotic and lytic

appearance and in the last stage of the disease sclerotic lesions predominate. The involved

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parts of the skeleton are enlarged and deformed and the cortex can be thickened and dense.

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Bone scintigraphy is used to assess the extent of the disease but is not specific. Bone

scintigraphy should always be included in the investigation of patients with PDB and

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radiographs of the areas of increased radioisotope uptake should be subsequently made to

confirm the diagnosis.

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The pathology of PDB is reflected in the proportional increase in biochemical markers of bone
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resorption and formation. These can be markedly increased in patients with extensive disease

but can also be within the reference range in about 10% of patients presenting to bone clinics
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with limited bone involvement. Patients with skull localizations tend to have the highest
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values of serum ALP activity. The most sensitive, however, biochemical markers is serum

P1NP for bone formation and peptides of the cross-linking domains of collagen type I, such as
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NTX or CTX for bone resorption . In clinical practice total serum ALP activity in the

presence of normal levels of liver enzymes is still an adequate marker for assessing the
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biochemical activity of the disease. In PDB the increased rate of bone turnover is associated
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with marked changes of calcium turnover which can be doubled even with 10 per cent

involvement of the skeleton. However, despite these changes, extracellular calcium

homeostasis is generally maintained but some disturbances may occur. Hypercalcaemia may
develop in immobilized patients with active, extensive disease or may be due to concurrent

primary hyperparathyroidism, the incidence of which is thought to be higher in PDB.

Hypercalciuria and renal stone disease occur more frequently in patients with PDB.
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Management

The pathology of PDB of Paget's disease provides the rationale for the use of inhibitors of

bone resorption in its management. Bisphosphonates are currently the treatment of choice of

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PDB due to their specific pharmacological properties, i.e. selective uptake at active skeletal

lesions, specific inhibition of bone resorption, and persistence of the effect after stopping

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treatment. Usually symptomatic patients are treated mainly for pain relief. The disease,

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however, is progressive and patients with symptoms were previously asymptomatic and it is

currently impossible to identify patients who will develop symptoms and complications and to

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estimate the risk of symptomatic disease in an individual. On the other hand, currently
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available efficacious treatment does not only relieve symptoms, but also restores abnormal

bone turnover and histology to normal and improves or even normalizes radiographic and
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scintigraphic abnormalities (Figure 5). Moreover, there are indications that complications can

be prevented if bone turnover is adequately suppressed. These considerations led to the

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formulation of the following treatment indications: a. Symptomatic disease to reduce

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complaints and improve the quality of life of patients. b. Preoperative treatment in preparation

for an orthopaedic procedure on Pagetic bone to reduce the increased blood flow and
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excessive bleeding c. Treatment of asymptomatic patients with skeletal localizations at higher

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risk to prevent future complications. Such localizations include those adjacent to large joints,
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the skull, the spine and the weight bearing bones. d. Young patients to prevent the long-term,

slow progression of the disease. It should be noted, however, that for some of these generally

accepted recommendations (6,42,43) firm evidence from prospective, controlled clinical

studies is lacking and treatment only of patients presenting with bone pain has been proposed

(44). With better understanding of the genetic background of familial PDB the question that

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needs to be addressed is whether treatment of younger individuals with a mutation but no

clinically evident disease may arrest its progression (see Figure 4).

Changes of bone turnover of patients with PDB with bisphosphonate treatment follow a

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predictable pattern with an early decrease in the rate of bone resorption followed by a slower

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decrease in the rate of bone formation due to the coupling between these two processes. With

a potent bisphosphonate the decrease of bone resorption occurs within a few days after

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starting treatment. During this initial period bone formation does not change. This will

decrease secondarily, at a slower rate, so that a new equilibrium will be reached after three to

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six months, at a lower rate of bone turnover (45). Thus, adequate suppression of bone
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resorption will be predictably followed by an adequate suppression of the increased rate of

bone formation. Suppression of biochemical indices of bone resorption early during the course
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of treatment provides an indication of the pharmacological efficacy of the bisphosphonate and

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will subsequently determine the adequacy and length of treatment. For example, the
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magnitude and level of decrease of biochemical indices of bone resorption 10–15 days after

the start of treatment, can predict the long-term effect of the bisphosphonate on bone turnover
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(46). On the other hand, inadequate early suppression of bone resorption indicates a need for

additional treatment. It is, therefore, unnecessary to prolong treatment with potent

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bisphosphonates and short courses are sufficient to achieve biochemical remission, assessed in
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practice by measurements of serum ALP activity. Nowadays the efficacy of treatment is

assessed only by its ability to decrease serum ALP activity to the normal range. In clinical

practice there is no need to measure serum ALP activity earlier than 3 months after the start of

treatment, 6 months being the optimal time.

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During the initial phase of bisphosphonate treatment, when bone resorption and bone

formation are still uncoupled, there is increased retention of calcium in the skeleton that leads

to changes in calcium metabolism. There is a fall in serum calcium concentration that

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stimulates the secretion of parathyroid hormone and consequently the renal production of

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calcitriol. These, in turn, increase the renal tubular reabsorption of calcium (parathyroid

hormone) and its intestinal absorption (calcitriol). The result is a marked, but transient,

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increase in calcium balance. The concomitant decrease in serum phosphate concentrations is

due to the renal action of parathyroid hormone. With the attainment of the new equilibrium of

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bone remodelling, calcium balance returns towards pretreatment levels and the values of the
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biochemical indices of calcium metabolism return to normal. These adaptive changes of

calcium metabolism to the marked alterations in bone remodelling, prevent the development
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of symptomatic hypocalcaemia in calcium-replete patients. However, elderly patients in

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various parts of the world commonly have a calcium-deficient diet and/or vitamin D
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insufficiency. For these reasons, calcium and vitamin D supplementations are generally

recommended particularly if the disease is very active.

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Clinical responses to treatment include clear improvement or even disappearance of pain in

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more than 80% of patients with pain complaints. A decrease of bone pain is generally
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observed 1 to 3 months after the start of treatment, the effect is maximal after 6 months and is

maintained for as long as biochemical markers of bone turnover remain within the normal

range. Soon after the start of therapy with a potent bisphosphonate there may be a transient

increase in pain at affected sites and patients should be reassured. Pain due to osteoarthritis is

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unresponsive to treatment in about 75% of patients; NSAIDs can then be used. If the hip joint

is affected, hip arthroplasty may be required to control the symptoms . Back pain resulting

from involvement of lumbar vertebrae is frequently not relieved by treatment. About half of

the patients with pain associated with deformity of the femur or the tibia will respond

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favourably to bisphosphonate therapy but pain may persist and a corrective osteotomy may be

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necessary. Deafness is usually not affected but its progression appears to be arrested and there

have been reports of improvement of spinal cord compression with bisphosphonate therapy.

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Improvement in bone histology and formation of bone with normal lamellar structure has been

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reported with potent bisphosphonates. Radiologically, an arrest of the progression of the
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disease is usually observed. Radiological improvement can be, however, dramatic if lesions

are lytic and are localized in long bones or in the skull. In other areas, improvement is slow
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and sometimes difficult to demonstrate by non-experienced radiologists. Efficacious treatment

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induces further an exponential decrease in radioisotope uptake on bone scintigrams. However,

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with earlier used bisphosphonates only about 10–30 per cent of lesions returned to normal and

residual uptake was detected unless very high bisphosphonate doses were used; such
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scintigraphic changes have not, however, been studied systematically with zoledronate but

case studies have shown normalization of radioisotope uptake in affected bone in most of
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studied patients (47). These clinical, histological and radiological responses emphasize the
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need for an intervention with a bisphosphonate before the development of complications. This

view has been challenged by a study aimed at assessing clinical outcomes in patients with

PDB treated intensively with bisphosphonates compared to patients who received only

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symptomatic treatment (48,49). However, issues related to the design of the study, choice of

patients and treatment regimens used have been criticized (50,51).

All bisphosphonates given to patients with Paget’s disease significantly decrease biochemical

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markers of bone turnover but there are considerable differences in their ability to induce

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remissions of the disease. Generally, potent bisphosphonates induce better responses. Of

these, a single short intravenous infusion of zolendronate 5 mg is currently considered the

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treatment of choice because it induces biochemical remissions in nearly all treated patients, it

improves certain aspects of the quality of life of patients and its effect persists for many years

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(52-54). Oral risedronate 30 mg/d for 2 months is a less effective alternative.
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Biochemical and clinical remissions can be long and recurrences occur slowly; follow-up of
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patients in remission is not, therefore, indicated at intervals shorter than 12 months. The
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duration of remission is determined by the degree of decrease of serum ALP activity and the
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number of affected bones. The lower the serum ALP activity reached with treatment the

longer the period of remission. Suppression of serum ALP activity well within the normal
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range is a prerequisite for long-term remissions and should be an aim of treatment. In a study

of 152 (83% with pain complaints) patients with PDB and median period of biochemical
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remission 78.9 months after short-term treatment with the bisphosphonate olpadronate,
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worsening of pain scores were significantly related to biochemical relapse probability (55).

These observations underscore the relationship of biochemical indices of turnover with pain

and the need to retain them within the normal range. The general principles of potent

bisphosphonate use in patients with Paget’s disease were confirmed in studies with

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zoledronate. Importantly, zoledronate is not only the most potent inhibitor of the molecular

target of bisphosphonate action, the enzyme farnesyl pyrophosphate synthase in osteoclasts,

but has also the strongest binding affinity for bone. Due to these properties and the results

obtained in clinical studies, a single intravenous infusion of zoledronate may even be

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considered curative in some elderly patients with PDB.

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Risks of treatment

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Impaired mineralization of newly formed bone, osteomalacia, is relevant only for etidronate

which is not used any more. Impaired bone mineralization has also been reported in a few

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patients treated with high doses intravenous pamidronate and is reversible. Hypocalcaemia
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may develop, particularly in elderly patients with high rates of bone turnover who are

frequently vitamin D-deficient. Adequate supplementation with vitamin D and calcium should,
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therefore, be given to all patients.

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In some patients treated for the first time with nitrogen-containing bisphosphonates there is a

rise in body temperature and flu-like symptoms during the first 3 days of treatment. These
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symptoms are transient and subside with no specific measures even when treatment is

continued. This response is dose-dependent and is associated more frequently with intravenous
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than oral treatment. Moreover, it does not generally appear upon re-treatment, and if it does, it
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is of lower intensity. Previous exposure to another nitrogen-containing bisphosphonate, but

not to etidronate or clodronate, generally precludes the development of this response.

Laboratory findings are consistent with an acute phase reaction that is related to the

mechanism of action of nitrogen-containing bisphosphonates (56-58). Rarely, high doses of

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such bisphosphonates may induce ophthalmic reactions such as conjunctivitis, iritis or uveitis.

There are case reports of ototoxicity and central nervous toxicity after intravenous

pamidronate. Allergic skin reactions have been occasionally observed with most of the

bisphosphonates. Osteonecrosis of the jaw is extremely rare in patients with Paget’s disease

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treated either with oral or intravenous bisphosphonates. The benefit-risk balance of treatment

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strongly favours the use of bisphosphonates, especially, zoledronate in the pharmacological

management of patients with PDB.

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Future Developments

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Because of the efficacy and tolerability of bisphosphonate treatment and the long-term
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persistence of the effect without need for additional treatment, there is no need for

development of new medications for the treatment of patients with PDB. However,
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bisphosphonates, particularly zoledronate, are not indicated in patients with renal impairment
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(creatinine clearance less than 35 ml/min). In such patients anecdotal evidence suggests that
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treatment with the inhibitor of RANKL, denosumab may be efficacious (59).

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Summary
Paget’s disease of bone is a focal disorder of bone remodelling that progresses slowly and

leads to changes in the shape and size of affected bones and to skeletal, articular and vascular
complications. In some parts of the world it is the second most common bone disorder after

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osteoporosis though in recent years its prevalence and severity appear to decrease. There is a

strong genetic component and mutations of the SQSTM1 gene have reported in up to 40% of

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patients with familial PDB and up to 10% of those with sporadic disease. The current view is

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that PDB is caused by interactions between environmental and genetic factors, the precise

nature of which remains to be determined. The majority of patients are asymptomatic but

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prediction of the likelihood to develop symptoms or complications is not feasible due mainly

to the very slow progression of the disease. Bisphosphonates are currently the treatment of
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choice of PDB due to their specific pharmacological properties and suppression of serum ALP
activity well within the normal range is associated with long-term clinical and biochemical
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remissions. A single intravenous infusion of Zoledronate 5 mg is the preferred treatment that

may even be considered curative in elderly patients with PDB and has a favourable benefit-
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risk balance.
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Acknowlegdment : The authors thank Professor Robert Weinstein, Center for Osteoporosis
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and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, for the bone

biopsy images of Figure 2.

Competing Interests: Dr N Appelman-Dijkstra: none; Dr S Papapoulos has received speaking

and or consulting fees from Amgen, Axsome, Gador, Radius Health and UCB.

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PRACTICE POINTS
• Diagnosis of PDB is made by radiographs

• Bone scintigraphy is recommended in all patients to assess the extent of the disease

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• Serum ALP activity, with normal liver enzymes, is adequate for diagnosis and

treatment follow-up

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• Reduction of serum ALP activity well within the normal range with treatment is a

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prerequisite for long-term remissions

• In patients in remission yearly follow-up is adequate

•
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Single intravenous infusion of zoledronate 5 mg is the treatment of choice of PDB
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RESEARCH AGENDA
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• Which is the optimal pharmacological treatment of patients with PDB and renal
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impairment?
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• What is the reason of the decline in prevalence and severity of the disease in some but

not all countries?

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• Should treatment be offered to all asymptomatic individuals with SQSTM1 mutations?

• Can characterization of the genetic profile of individual patients predict the

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progression of the disease and the development of complications?

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References

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19. Wang FM, Sarmasik A, Hiruma Y, et al. Measles virus nucleocapsid protein, a key

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28. Visconti MR, Langston AL, Alonso N, et al. Mutations of SQSTM1 are associated with

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37. Meunier PJ, Salson C, Mathieu L et al. Skeletal distribution and biochemical parameters of

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LEGENDS TO FIGURES

Figure 1. Prevalence of radiographically confirmed Paget’s disease (PDB) in relation to age

and serum alkaline phosphatase activity (High or Normal AP) in the Netherlands. Note the 10-

fold higher prevalence in individuals with raised serum ALP; however, 86% of men and

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women with PDB had normal serum ALP activity. From reference 3 (own publication).

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Figure 2. A. A large multinucleated osteoclast in a resorption cavity in a bone biopsy

specimen from a patient with PDB. B. Bone biopsy (ultraviolet light) from a patient with PDB

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after two time-spaced administrations of tetracycline (yellow lines) illustrating the high rates

of bone formation; large resorption areas are also seen. Courtesy of Professor Robert

Weinstein.
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Figure 3. Radiograph of the skull and DNA sequence of a women with familial PDB with two

mutations in the same allele of the SQSTM1 gene (P329L and S399P). The patient had the
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most severe phenotype of all subjects with familial PDB of the studied cohort with nearly
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total involvement of the skeleton and pronounced deformities. From reference 23 (own
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publication).

Figure 4. Sequential measurements of serum alkaline phosphatase (AP) activity (U/l) over 25
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years in a 51-year-old woman with familial Paget’s disease of the pelvis and a P329L mutation

of the SQSTM1 gene. Note the slow progressive increase in serum ALP on no treatment and
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the rapid and sustained decrease of serum ALP after short-term treatment with bisphosphonate
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(BP). At the time of intervention the patient had already developed secondary osteoarthritis

and required total hip replacement to control her symptoms. Interrupted line depicts the upper

limit of the reference range of ALP. (Reproduced from Papapoulos SE, Paget’s disease of

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bone, Oxford Textbook of Endocrinology and Diabetes, Wass JA and Stewart PM, eds, 2nd

edition, 2011).

Figure 5. Left panel: Radiographs of the distal femur of a patient with Paget’s disease without

femoral pain before (A) and after (B) 18 months bisphosphonate treatment; the pretreatment

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radiograph shows a large lytic area with thinning or even disappearance of the cortex at

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imminent risk of fractures; these abnormalities were restored with treatment. Right panel

(C,D): Bone biopsies from two patients with Paget’s disease treated with bisphosphonate

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illustrating the formation of normal lamellar bone (L) in the external areas of the trabeculae

with treatment contrasting the disorganized woven bone formed before treatment (W). Bone

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histology images courtesy of the late Dr Pierre Meunier.
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Figure 1

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High AP

PREVALENCE OF PDB

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AGE (yrs)

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PREVALENCE OF PDB

Normal AP
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Figure 2

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Figure 3

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P392L and S399P change in one patient

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Figure 4

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BP

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Figure 5

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