Genetic Adult Paget Disease of Bone and Multisystem Proteinopathy

Familial and monogenic forms of Paget disease of bone (SQSTM1, ZNF687, PFN1, TNFRSF11A) and multisystem proteinopathy with inclusion body myopathy, Paget disease of bone and frontotemporal dementia (VCP, HNRNPA2B1, HNRNPA1, SQSTM1)

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. From osteitis deformans to a disease of bone remodelling

Paget disease of bone (PDB) was described by Sir James Paget, who presented it in 1876 and published it in 1877 under the name osteitis deformans, interpreting it as a chronic inflammation of the bones [1, 18]. It is known today that it is not an inflammatory disease, but a focal disturbance of bone remodelling in which increased osteoclastic resorption is coupled to likewise increased and disorganised bone formation, in one (monostotic form) or several bones (polyostotic form), with a predilection for the pelvis, femur, lumbar spine, skull and tibia [8, 18]. The woven bone thus produced is bulkier, more vascularised and mechanically weaker, and the marrow undergoes fibrosis [8, 10].

Familial aggregation was recorded early on: a 1960 review gathered 35 pedigrees published up to 1956, and later studies in Spain and in the United States (USA) showed that 12–40% of index cases have an affected first-degree relative [1]. The hypothesis of a slow viral infection, fed by the observation of nuclear inclusions in osteoclasts resembling paramyxovirus nucleocapsids, gave contradictory results; more recent work interprets those inclusions as aggregates of p62 with proteins not degraded because of defective autophagy [8, 18].

1.2. Milestones of molecular discovery

A linkage to the HLA complex at 6p (PDB1), proposed in 1977, was not confirmed [1]. In 2000, duplications in the signal peptide of TNFRSF11A, which encodes the RANK receptor, were described in familial expansile osteolysis (FEO) and in a Japanese family with early-onset PDB (PDB2) [4, 5]. In 2001, analysis of 24 French-Canadian families identified two loci, 5q35 (PDB3) and 5q31 (PDB4), and in 2002 Laurin and colleagues described the recurrent SQSTM1 variant p.(Pro392Leu), which encodes the p62 protein, present on two haplotypes and at a hypermutable CpG dinucleotide [1]. In the same year, other SQSTM1 variants were described in British and Australian families [1].

The genome-wide association studies (GWAS) of 2010 and 2011 added common risk loci near CSF1, OPTN, TNFRSF11A, TM7SF4, PML, RIN3 and NUP205, which explain a substantial fraction of the population risk without being causal in themselves [1, 8, 9]. In 2016, Divisato and colleagues identified ZNF687 in a family from Campania with severe PDB and GCT (PDB6) [20], and in 2020 two Italian teams associated loss-of-function variants of PFN1 with an early-onset polyostotic PDB, today classified as PDB7 (MIM 621600) [3, 22].

On the neuromuscular side, Tucker and colleagues described in 1982 a large family with lower motor neuron degeneration and skeletal changes resembling PDB, and Kimonis and colleagues described in 2000 a family with autosomal dominant limb-girdle dystrophy, early PDB and cardiomyopathy [24]. The locus was mapped to 9p13.3-p12 in 2001, and in 2004 Watts and colleagues identified six missense variants of VCP in 13 North American and Canadian families with inclusion body myopathy, PDB and FTD, with two ancestral haplotypes of northern European origin [24]. In 2013, Kim and colleagues described variants in the prion-like domains of HNRNPA2B1 and HNRNPA1 in families with the same picture [25, 26].

1.3. Nomenclature and reclassifications

The term multisystem proteinopathy (MSP) replaced the acronym IBMPFD (inclusion body myopathy with early-onset Paget disease of bone and/or frontotemporal dementia) because the spectrum goes beyond the original triad and includes amyotrophic lateral sclerosis (ALS), parkinsonism, cardiomyopathy, peripheral neuropathy and respiratory failure [6]. The 2022 consensus numbers the forms by gene: MSP1 (VCP), MSP2 (HNRNPA2B1), MSP3 (HNRNPA1) and MSP4 (SQSTM1), and proposes MSP5 for MATR3, MSP6 for ANXA11 and MSP7 for PFN1 [7]. The 2026 GeneReviews keeps only the first four genes as classical MSP and designates as «MSP-like» the diseases with clinical and pathological overlap due to ANXA11, HSPB8, MATR3, OPTN, PFN1, TARDBP, TBK1, TFG and TIA1 [6]. MSP is not classified as a limb-girdle muscular dystrophy (LGMD) because the biopsy is non-specific in most patients [6].

In OMIM, PDB is divided into PDB2 (TNFRSF11A, classified as a susceptibility), PDB3 (SQSTM1), PDB4 (5q31, no gene), juvenile PDB5 (TNFRSF11B), PDB6 (ZNF687) and PDB7 (PFN1) [1]. Juvenile PDB due to osteoprotegerin deficiency is an autosomal recessive disease of childhood [27, 28].

1.4. Definition of the entities in this article

The entities covered form three groups. The first is classical adult PDB, a common disease in populations of European origin, with a polygenic basis, an environmental component and familial forms of autosomal dominant inheritance with incomplete penetrance, in which SQSTM1 is the most important susceptibility gene [8]. The second comprises the severe or early-onset monogenic forms (ZNF687, PFN1, TNFRSF11A), with more sites involved, a lower age at onset or a risk of GCT [4, 20, 22]. The third is MSP, in which PDB arises as one of the manifestations of a proteinopathy that affects muscle, brain, motor neuron and heart [6]. The allelic diseases of VCP without PDB (Adams-Oliver syndrome, neurodevelopmental disorder) and of SQSTM1 (recessive childhood neurodegeneration) are relevant to the differential diagnosis and to counselling [6].

2. Molecular Genetics and Pathophysiology

2.1. The pagetic lesion and the RANKL–RANK–NF-κB axis

The PDB lesion begins with a focal increase in the number and activity of osteoclasts, which are larger and contain many more nuclei than normal, besides characteristic inclusions; there follows increased osteoblastic activity, with deposition of woven bone, marrow fibrosis and increased blood flow [8, 18]. A final phase of reduced cellular activity, with a chaotic mosaic of lamellar and woven bone, has been described in biopsies and autopsies [19]. Most of the predisposing genes act on osteoclast differentiation and function and converge on the nuclear factor kappa B (NF-κB) signalling pathway downstream of the RANK receptor, activated by its ligand RANKL and restrained by the decoy receptor osteoprotegerin (OPG) [10, 18]. Many of these genes also take part in autophagy, which explains why the same variants may cause isolated PDB or neurological and muscle disease [18, 29]. Saudubray classifies SQSTM1-associated PDB among the diseases of vesicular trafficking and autophagy [29].

Macrophage colony-stimulating factor (M-CSF), encoded by CSF1, is essential for osteoclast differentiation; its serum level is raised in PDB and associated with musculoskeletal pain, and regulatory variants upstream of CSF1 are genetic risk factors [18]. Interleukin 6 has been proposed as a mediator, but recent studies have not confirmed raised serum levels [18]. The focal nature of the disease remains unexplained: somatic SQSTM1 variants have given contradictory results and the hypothesis of targeted biomechanical loading rests on anecdotal observations [18].

2.2. SQSTM1: the most important susceptibility gene

SQSTM1 (5q35.3; MANE transcript NM_003900.5) encodes p62/sequestosome-1, an autophagy receptor that links polyubiquitinated cargo to the LC3 of the autophagosome and serves as a platform for the NF-κB and KEAP1–NRF2 pathways [10, 30]. The variants associated with PDB cluster in the C-terminal ubiquitin-binding (UBA) domain and reduce that binding, which intensifies RANKL-induced NF-κB signalling and osteoclast activity [8, 10]. More than 30 variants have been described, found in 40–50% of cases with a family history and in 5–10% of cases without a known family history (up to 15% in the screening programme of the ZiPP trial) [8, 11, 31]. The commonest is NM_003900.5:c.1175C>T p.(Pro392Leu), present in about two thirds of the carriers included in ZiPP; it was identified in French-Canadian families on two haplotypes, at a hypermutable CpG dinucleotide, and in ClinVar it has conflicting classifications of pathogenicity, consistent with an allele of incomplete penetrance [1, 31, 32]. Other described variants include truncating ones (e.g. E396X) and p.(Gly411Ser) [11].

Carriers of SQSTM1 variants have more extensive and earlier disease than non-carriers [31]. In a Turkish national study of 105 patients, the 10 carriers (9.5%) had polyostotic disease in 90% (against 45%), a family history in 30% (against 5%) and a median bone alkaline phosphatase of 206 U/L (against 58 U/L) [23].

2.3. Common risk loci and polygenic architecture

The 2010 GWAS, in 750 patients without SQSTM1 variants and 1002 controls with independent replication, identified signals near CSF1 (1p13; P = 5.38 × 10⁻²⁴), in OPTN (10p13) and near TNFRSF11A (18q21), with a cumulative population attributable risk of 70% and an odds ratio (OR) of 1.34 per risk allele [9]. The 2011 study (2215 cases and 4370 controls from 7 populations) added PML (OR 1.34), RIN3 (OR 1.44) and NUP205/7q33 (OR 1.45) and confirmed TM7SF4 (OR 1.40) [1]. The proposed mechanisms are increased M-CSF expression (CSF1), fusion of osteoclast precursors (TM7SF4), early endosome function (RIN3, a Rab5 activator), NF-κB signalling (PML, OPTN) and a mitochondrial protein (STMP1, at the 7q33 locus) [18]. Common TNFRSF11A variants predispose to classical PDB, whereas rare exon 1 variants cause FEO and related syndromes [18]. Epigenetic influences also modulate occurrence and severity, at loci different from those identified by GWAS [18].

2.4. ZNF687 and PDB with giant cell tumour

ZNF687 (1q21.3; MANE NM_020832.3) encodes a C2H2 zinc finger protein of the Z3 transcriptional regulatory complex, highly expressed during osteoclastogenesis and osteoblastogenesis and a target of NF-κB [10, 20]. The variant NM_020832.3:c.2810C>G p.(Pro937Arg) co-segregates with the disease in a family with 14 affected members from Campania, four of whom developed GCT at multiple pagetic sites, and it was found in all seven unrelated patients tested with PDB-associated GCT (four from southern Italy and three North Americans of European origin), on a common ancestral haplotype, which indicates a founder effect [20, 30]. A second variant, c.725G>T p.(Ser242Ile), co-segregates in an Italian family [20, 30]. p.(Pro937Arg) strengthens a nuclear localisation signal and increases the nuclear fraction of the protein, which suggests gain of function; the osteoclasts of carriers are larger and have more nuclei [20]. In a series from Avellino, 33% of 30 patients with PDB had ZNF687 variants, against 2 carriers of SQSTM1 p.(Pro392Leu) [10]. ZNF687 expression is increased in the peripheral blood of patients with PDB with and without SQSTM1 variants (3× and 2×) and still more in ZNF687 carriers (5×) [20].

2.5. PFN1 and early-onset PDB (PDB7)

PFN1 (17p13.2; MANE NM_005022.4) encodes profilin-1, an actin-binding protein that regulates cytoskeletal polymerisation [10]. The deletion NM_005022.4:c.318_321del p.(Asp107ArgfsTer3) was identified in five members of an Italian family and in one patient from a cohort of 41 with early PDB without a molecular cause, and later in a large Chinese family with PDB and GCT; also described are NM_005022.4:c.324del p.(Thr109ArgfsTer2) and the missense c.335T>C p.(Leu112Pro) [3, 22, 30]. Loss of function or haploinsufficiency of PFN1 causes early-onset polyostotic PDB, whereas other missense variants (A20T, C71G, T109M, M114T, E117G, G118V, R136W, Q139L) cause ALS type 18; despite the proximity to the ALS variants, carriers of p.(Leu112Pro) did not develop motor neuron disease, and the heterozygous mouse reproduces PDB with giant osteoclasts without an ALS phenotype [7, 22]. In the osteoclast, the variant strengthens the actin ring structures on the bone surface without altering NF-κB activation [22].

2.6. TNFRSF11A: FEO, PDB2 and expansile skeletal hyperphosphatasia

TNFRSF11A (18q21.33; MANE NM_003839.4) encodes RANK [10, 30]. In-frame duplications in exon 1, which alter the signal peptide, prevent the normal cleavage of RANK, which accumulates and activates NF-κB without RANKL: the 18 bp duplication causes FEO, the 27 bp one causes PDB2 and the 15 bp one causes expansile skeletal hyperphosphatasia (ESH) [5, 10]. The historical duplication «84dup18» corresponds to NM_003839.4:c.84_101dup p.(Pro33_Cys34insTrpGlnIleAlaProPro) in VariantValidator; the description of the 27 bp duplication generates a warning about crossing an intron, so the historical nomenclature is retained [30]. Biallelic loss of function of the same gene causes osteoclast-poor autosomal recessive osteopetrosis (osteopetrosis B7, OPTB7), a disease of opposite mechanism [10, 33]. This form accounts for about 5% of cases of autosomal recessive osteopetrosis, has a severe skeletal phenotype (hydrocephalus, visual impairment, fractures) with milder haematological involvement, and early haematopoietic stem cell transplantation is recommended for consideration, because of the skeletal severity; after transplantation, severe and prolonged hypercalcaemia may arise [33, 34]. A case of dysosteosclerosis with a splicing variant in TNFRSF11A has been described [35].

2.7. VCP and MSP1

VCP (9p13.3; MANE NM_007126.5) encodes p97, a homohexameric AAA ATPase which, with the cofactors UFD1 and NPLOC4, extracts ubiquitinated proteins from membranes and complexes and directs them to the proteasome; it takes part in endoplasmic reticulum-associated degradation (ERAD), in the reorganisation of the Golgi and of the nuclear envelope in mitosis, in the clearance of stress granules, in autophagy and in the DNA damage response [6, 10]. This is a defect of proteostasis and not an enzyme deficiency, which explains the joint involvement of muscle, bone and brain [10]. The pathogenic variants of MSP cluster in the N-terminal domain (double ψ barrel, amino acids 25–106; β barrel, 112–186; linker segment, 107–111) and act by gain of function: they increase the ATPase activity and the binding to the cofactors [6]. A 2025 review describes them as loss-of-function variants, but GeneReviews, the functional studies and the 2022 consensus describe a gain of function, and for that reason deletions and duplications are not an expected cause of MSP [6, 7, 18]. The variants associated with early onset or with early loss of ambulation have greater ATPase activity [36].

More than 50 missense variants have been described [7]. The most cited, validated on transcript NM_007126.5, are c.464G>A p.(Arg155His), the commonest in the international biopsy series (18.8%) and classified as pathogenic in ClinVar, c.463C>T p.(Arg155Cys), c.277C>T p.(Arg93Cys), c.475C>T p.(Arg159Cys), c.572G>A p.(Arg191Gln) and c.695C>A p.(Ala232Glu) [30, 32, 37]. Watts and colleagues found two northern European ancestral haplotypes that account for half of the initial North American families [24]. In a Brazilian family, the variant NM_007126.5:c.271A>T p.(Asn91Tyr) manifested as myopathy in one brother, ALS in another and late-onset neurological disease in the father [24].

Genotype-phenotype correlations are weak: in the cohort of 231 individuals from 36 families with 15 variants, no correlation was statistically significant [6]. Some observations suggest variant effects: p.(Arg155Cys) was associated with earlier onset and shorter survival than p.(Arg155His); carriers of p.(Arg159Cys) have later myopathy and did not develop PDB in one family and in the CoRDS registry; and the biopsies of the 12 patients with p.(Arg93Cys) showed no foci of degeneration [21, 37–39].

2.8. HNRNPA2B1 and HNRNPA1 (MSP2 and MSP3)

HNRNPA2B1 and HNRNPA1 encode heterogeneous nuclear ribonucleoproteins that bind RNA and take part in pre-mRNA processing, in alternative splicing and in nucleocytoplasmic transport; both have low-complexity prion-like domains [6]. The MSP variants lie in those homologous domains and increase the tendency to form self-seeding fibrils and toxic cytoplasmic aggregates [6]. The reference variants are NM_002137.4:c.869A>T p.(Asp290Val) in HNRNPA2B1 and NM_031157.4:c.941A>T p.(Asp314Val) in HNRNPA1, the latter known historically as p.D262V in the short A1 isoform; the variant NM_031157.4:c.940G>A p.(Asp314Asn) caused isolated inclusion body myopathy in two families [10, 30]. The two proteins share regions of homology that may interfere with sequencing [6]. HNRNPA2B1 also causes an early-onset oculopharyngeal muscular dystrophy (OPMD2), through variants that alter the stop codon, and HNRNPA1 causes ALS type 20 [10].

2.9. SQSTM1 beyond bone

Besides PDB3, SQSTM1 causes FTD and/or ALS type 3 (FTDALS3; variants in 15 of 546 patients with ALS, 2.8%), distal myopathy with rimmed vacuoles (DMRV, through a splicing variant) and, in homozygosity for loss-of-function variants, a recessive childhood neurodegeneration with ataxia, dystonia and gaze palsy (NADGP) [40–42]. The bone disease and the neurodegenerative diseases are distinct entities that may coexist in the same family, and in the Mayo Clinic series five patients had simultaneous SQSTM1 and TIA1 variants [10, 43]. Heterozygotes for the NADGP variants have no skeletal or neurological changes [42].

2.10. Table of the class: types and genes

2.11. Penetrance and expressivity

In MSP, penetrance is almost complete and age-dependent, with great intra- and interfamilial variability: 10% of affected individuals have all three major manifestations, 50% have two, and the apparently isolated forms correspond to myopathy in 37%, PDB in 5% and FTD in 3% [6]. An unaffected carrier of a pathogenic VCP variant has a 90% probability of developing one or more manifestations by 45 years of age [7].

In SQSTM1-associated PDB, old cross-sectional estimates attributed a penetrance of 79–87% from 60 years of age, or about 80% by the seventh decade [11, 31]. Recent longitudinal studies diverge: in carriers followed with scintigraphy, the rate of new cases was 2–15 per 1000 patient-years, with mostly monostotic and asymptomatic disease, and in the placebo arm of ZiPP the rate was one eighth of that predicted [11, 31]. In New Zealand, carrier offspring developed PDB about 20 years later than their parents, with a mean alkaline phosphatase of 121 IU/L against 1250 IU/L and 1 bone involved against 11 [11].

2.12. Allelic diseases of VCP

Reduced-function VCP variants cause a childhood-onset neurodevelopmental disorder (13 patients aged 2 to 22 years, 12 with a de novo variant), with developmental delay, intellectual disability, hypotonia and macrocephaly [6]. Hypermorphic variants, with increased ATP hydrolysis, cause Adams-Oliver syndrome with or without pulmonary hypertension, mainly from pulmonary veno-occlusive disease, described in seven families in 2026 [6]. VCP also causes CMT2Y, an autosomal dominant sensorimotor axonal neuropathy, an adult-onset distal myopathy with foot drop and a complex spastic paraplegia with PDB described in one family [15, 17, 44].

2.13. Environment and modifiers

The prevalence and severity of PDB have decreased in recent decades in the United Kingdom, in continental Europe and in New Zealand, faster than could be explained by genetic factors, which points to a gene–environment interaction with reduced exposure to an environmental factor [8, 11]. The proposed factors include low calcium intake, vitamin D deficiency, tobacco, wood or coal stoves, lead, pollution, contact with animals and paramyxoviruses [18]. In Castile and León, the incidence correlated moderately with the density of breeding cows (R² = 0.236) [45]. In the mouse, overexpression of the measles virus nucleocapsid in osteoclasts increases remodelling, and the combination with the p.(Pro392Leu) variant produces the animal model closest to the disease [8, 19].

3. Clinical Spectrum and Manifestations by System

3.1. Classical adult PDB: presentation

PDB rarely manifests clinically before 40–50 years, but it is likely to be silently present in many people from the third decade; the clinically diagnosed prevalence doubles with each decade after the fifth [18, 19]. It is estimated that fewer than 10% of people with radiographic PDB come to medical attention and that about 5% have symptoms requiring treatment [1, 8]. In about 20% of patients, the disease is discovered incidentally on a blood test or on imaging performed for another reason [18]. The bones most often involved are the pelvis, the vertebrae, the skull, the femur and the tibia; in long bones, the disease usually begins at the proximal end and advances towards the diaphysis [8, 19].

Musculoskeletal pain is the commonest complaint, present in 73–75% of patients who reach the clinic [8, 18]. The pain does not always result from metabolic activity: in a study of the causes of pain, the commonest origin was osteoarthritis of joints distant from the affected bones (44%), followed by metabolically active PDB (14.7%), deformity (11.4%) and osteoarthritis of a neighbouring joint (9%) [18]. The correlation between pain and alkaline phosphatase is weak: in the alendronate trial, 23 of 55 patients (41.8%) with raised ALP had no pain, and in PRISM 295 of 635 (46.4%) [8]. Local warmth over the affected bone, especially the tibia, reflects the increased blood flow [19].

3.2. Complications of classical PDB

In a systematic review, deformity was present in 21.5% of patients at presentation, deafness in 8.9% and pathological fracture in 8.5% [8]. Deformity becomes apparent when the disease involves the skull, the mandible, the clavicle, the femur or the tibia, with bowing of the weight-bearing long bones [19]. Most pathological fractures involve the femur or the tibia; those of the femoral neck have high rates of non-union [8]. Deafness, when the skull base is involved, results mainly from cochlear dysfunction associated with the increased bone density, rather than from compression of the auditory nerve [18]. Secondary osteoarthritis is frequent: patients in the British General Practice Research Database had an OR of 3.1 (95% CI 2.4–4.1) for hip arthroplasty compared with controls of the same age [8].

The increased bone volume may cause basilar invagination, obstructive hydrocephalus, spinal canal stenosis and paraplegia, at times through a vascular «steal» phenomenon; high-output heart failure and hypercalcaemia on immobilisation are rare [8, 18]. Heart disease is more frequent than was supposed: in an Italian study of 69 patients treated with zoledronic acid and 115 matched controls, PDB was associated with aortic and mitral valve calcification or sclerosis, a lower ejection fraction, a greater left ventricular mass and a lower global longitudinal strain, with no relationship to disease activity [46]. In the CARTaGENE cohort from Quebec, the 101 participants with PDB among 19,990 had a hazard ratio (HR) of 2.06 (95% CI 1.06–4.04) for major cardiovascular events of five components [47]. Autopsy series have described aortic stenosis in 24% of patients with PDB against 4% of controls [48].

Osteosarcoma complicates about 0.3% of cases (less than 0.5%), presents as increasing pain and swelling at an affected site, at times with fracture, and has a poor prognosis; its prevalence has fallen in parallel with that of PDB [8, 18]. Pagetic sarcoma predominates in men, with a mean age of 66 years, and in the pelvis [48]. GCT is very rare (117 cases published worldwide), with over-representation of patients of Campanian ancestry, and it is estimated to complicate about 0.8% of cases of PDB in Italy [8]. About half of the patients with PDB die within five years of the diagnosis of GCT, and 80% by ten years [20].

3.3. Severe or early-onset monogenic forms

In PDB6, the disease is polyostotic and predominantly axial, with onset between 26 and 61 years and many sites involved (up to 12 in one family); four of the 14 affected members of the founder family developed multifocal GCT, always with skull involvement, and a subgroup has coronary disease [12, 20]. In the Avellino series, the patients with ZNF687 had severe disease with many sites involved and giant osteoclasts, with up to 150 nuclei [10].

In PDB7, the disease arises in adolescence or in the young adult, is extensively polyostotic and may be complicated by malignant GCT; in a Chinese family, the proband's mother died at 39 years with multiple mandibular tumours [3, 22]. The response to zoledronic acid and to denosumab was worse than in typical PDB [22]. A 2026 review groups ZNF687 and PFN1 as causes of more aggressive variants of PDB, with possible progression to GCT and osteosarcoma, and associates VCP and TNFRSF11A with syndromic forms [49].

In FEO and PDB2, conductive deafness arises in the first decade (generally before 10 years), from damage to the ossicles, followed by sensorineural deafness; there is early tooth loss from root resorption and, from the second decade, metadiaphyseal osteolytic lesions that evolve into medullary expansion with a lace-like pattern, with pain, deformity and fractures after minimal trauma; the tibia is the bone most often involved and the expansion may reach several times the original diameter [5, 10]. In Japanese PDB2, the symptoms began in adolescence and in the early third decade, with deformity of the lower limbs, enlargement of the interphalangeal joints of the hands and mandibular deformity; a Brazilian girl with severe PDB2 had a bowed femur on prenatal ultrasound, dento-osseous disease at 3 years and deafness with absent ossicles and eroded cochleae [4].

3.4. PDB in carriers of SQSTM1 variants: current natural history

In asymptomatic carriers identified by family screening, the disease is today later and less extensive than in their parents. In ZiPP, with a mean age at entry of 50 years, 9% of the carriers already had lesions on scintigraphy, were on average three years older than the rest, and only two participants in the placebo arm developed new lesions over 84 months [31]. In the New Zealand cohort, the two new cases detected after 13.5 years were asymptomatic, monostotic or with two bones involved, and with normal ALP [11]. These data describe carriers with affected parents recruited in research centres and do not apply directly to other genetic forms.

3.5. MSP: myopathy

Myopathy is the commonest manifestation and the one most often presenting first: about 90% of affected individuals, with a mean age at diagnosis of 43 years (3–61; typically between 20 and 40 years) [6]. The weakness is mainly proximal, of the pelvic and shoulder girdles, with a waddling gait, lordotic posture, difficulty climbing stairs and raising the arms; the commonest presentation is symmetrical lower limb weakness (50%), but distal onset in the hands and feet is not rare, and there is asymmetry in 10–20% [6, 21]. Foot drop, winged scapula, scapuloperoneal weakness, camptocormia and falls may arise; facial weakness is rare, and presentations resembling facioscapulohumeral dystrophy (FSHD), oculopharyngeal dystrophy and the distal myopathies have been described [7, 21]. Loss of ambulation occurs 13 ± 7 years after onset [7, 21].

In the assessment of 82 affected individuals from 48 families, the functional score of the inclusion body myositis scale (IBMFRS) decreased by 1.9% a year, fatigue increased by 4.4% and the six-minute walk distance decreased by 6% a year; women declined faster on the IBMFRS and more slowly in walking [38]. In the CoRDS registry (79 participants, three years), lower limb function decreased by 1.6% per year of disease [39]. In the Mayo Clinic series, the median onset was 52 years and, 11.5 years later, 15 of 31 patients walked without aids [43].

3.6. MSP: Paget disease of bone

PDB occurs in about 42% of affected individuals, with a mean age at diagnosis of 41 years (31–61), and it may be the initial manifestation [6]. It is often asymptomatic and detected through alkaline phosphatase and scintigraphy, so that it is probably underdiagnosed [6]. When symptomatic, it manifests as spinal or hip pain, bone tenderness, loss of height, deformity of the long bones or of the skull, rare pathological fractures and deafness [6]. In MSP1, the preferential sites are the spine, the hip, the pelvis, the skull and the scapulae, with relative sparing of the extremities; in MSP2, PDB may be more severe and involve the extremities more [6]. Depending on the variant, PDB arises in 18–44% of patients with VCP myopathy; about 77% of those who have it show radiographic lesions, 48% have bone pain and 55% have raised ALP [21].

3.7. MSP: frontotemporal dementia

FTD affects about 30% of affected individuals, with a mean age at diagnosis of 56 years (30–86) in a cross-sectional study in which several individuals were not yet old enough to develop it [6]. The behavioural variant predominates, but there are primary progressive aphasias; in the early phases dysnomia, dyscalculia, comprehension deficits and paraphasias arise, with relatively preserved episodic memory, and the course leads to mutism, inability to understand simple commands, alexia and agraphia [6, 7]. FTD is frequently associated with parkinsonian signs (dystonia, tremor, gait disturbance) [7]. Neuropathologically, MSP1 is a TDP-43 proteinopathy, with ubiquitin-positive intranuclear neuronal inclusions and dystrophic neurites abundant in the neocortex and absent from the dentate gyrus [6]. Alzheimer disease has been described in 2% of VCP patients [7].

3.8. MSP: motor neuron, parkinsonism and peripheral nerve

About 10% of the affected individuals in the cohort of 231 had a previous diagnosis of ALS, and GeneReviews estimates the overall frequency of ALS in MSP at about 10–15% [6]. In a systematic electromyographic assessment of 17 patients from eight families, electromyography (EMG) was abnormal in all, purely neurogenic in four and mixed in seven, with motor neuron involvement in 11 of 17 (65%) [6]. VCP variants were found in 5 of 289 families with familial ALS (1–2%) [6]. The ALS of MSP is clinically indistinguishable from other forms and progresses faster than the myopathic presentations, even with the same variant [7, 50]. Parkinsonism or Parkinson disease occurs in 3.8–4% of the patients in the cohorts (about 3–5% in the overall GeneReviews estimate), usually with a response to levodopa and associated with other manifestations [6, 7]. Sensorimotor axonal neuropathy (CMT2Y) and spastic paraplegia are rare [7].

3.9. MSP: heart and respiratory function

Cardiomyopathy is probably under-recognised [6, 36]. In the first family with p.(Arg155His), 3 of 11 affected individuals (27%) had cardiac manifestations; in another family, 4 of 18 (22%) had dilated cardiomyopathy; in a large international cohort, 17 of 234 patients had a cardiac abnormality, but among the 28 with an echocardiogram the proportion reached 12 of 28 (43%), with seven hypertrophic patterns, five dilated ones and four patients with conduction disease (atrial fibrillation, bundle branch blocks) [36]. Another multicentre cohort reports cardiac involvement in less than 10% and autonomic dysfunction in 21.4% [21]. Diastolic dysfunction may be an early sign [7]. In the Mayo Clinic series, cardiac involvement occurred only in the VCP form [43].

Respiratory weakness affects at least 40–50% of patients, with recurrent respiratory infections from an ineffective cough, nocturnal hypoventilation, aspiration in bulbar patients and, finally, hypercapnic respiratory failure; forced vital capacity (FVC) is reduced in about half [7, 21].

3.10. MSP: other manifestations and non-VCP forms

Hepatic steatosis, cataracts, pyramidal dysfunction, sphincter disturbance, urinary and anal incontinence and sensorineural deafness have been described [6, 7]. In SQSTM1-associated MSP, the presentation may be isolated PDB, FTD, ALS, distal myopathy with rimmed vacuoles or a combination [6]. In a family with an HNRNPA1 variant, five siblings had proximal weakness with onset in the lower limbs, mildly raised creatine kinase (CK) and PDB, without motor neuron disease or cognitive impairment [26]. In a Chinese cohort of 953 patients with ALS, inclusion body myopathy or dementia, 29 (3.0%) had variants in MSP genes, and only one had PDB [50].

3.11. Natural history and treated disease

The natural history data for PDB come mainly from old cohorts, predating the potent bisphosphonates, and from patients with extensive disease; the treated-disease data come from trials with short-term biochemical outcomes [8]. In MSP there is no disease-modifying therapy, and the series describe the natural history under supportive care [6]. Death typically occurs in the sixth decade, mainly from respiratory failure, with cardiac and neurodegenerative contributions [6, 36].

4. Clinical Recognition and Warning Signs

4.1. When to suspect PDB

PDB should be considered in the face of localised bone pain in an adult over 50 years, deformity or increased volume of a long bone or of the skull, local warmth over the tibia, pathological fracture, deafness with skull base involvement, or a raised alkaline phosphatase with normal liver function tests on a routine blood test [8, 19]. Incidental discovery on a radiograph or on a scintigram performed for another reason is frequent [18].

4.2. When to suspect a genetic form

Suspicion of a genetic basis increases with the family history (an affected first-degree relative increases the risk about sevenfold, and about 20-fold if the proband has severe or early disease), with onset before 50 years, with extensive polyostotic disease, with GCT or Campanian ancestry (ZNF687), with onset in adolescence or in the young adult (PFN1), and with conductive deafness and tooth loss in childhood associated with expansile lytic lesions (TNFRSF11A) [5, 18, 20, 22]. A negative family history does not exclude predisposition, because the disease is often asymptomatic in the parents [18].

4.3. When to suspect MSP

The combination is the most useful sign: adult-onset girdle weakness with early PDB, or either of these with early FTD in the family [10]. As only 10% of affected individuals have all three manifestations and 37% have apparently isolated myopathy, VCP should be considered in the face of a limb-girdle dystrophy phenotype, any autosomal dominantly transmitted myopathy, hereditary inclusion body myopathy, familial or sporadic ALS, FTD with raised alkaline phosphatase, early-onset Parkinson disease with other MSP manifestations, axonal CMT or spastic paraplegia with PDB [6, 7, 21]. The family history must include dementia, parkinsonism, neuropathy and PDB, and not only weakness [21]. Patients are frequently diagnosed as having LGMD, FSHD, myofibrillar myopathy, distal myopathy (tibial, GNE), sporadic inclusion body myositis or ALS, after an odyssey of several years through neurology, rheumatology, endocrinology and pain medicine [6, 21].

4.4. Warning signs and emergencies

Increasing pain and swelling at a pagetic site, especially with fracture, must raise the suspicion of osteosarcoma or of GCT [18]. Signs of spinal cord or root compression, hydrocephalus or basilar invagination require urgent imaging and neurosurgical assessment [8, 19]. In MSP, acceleration of weakness, bulbar signs, upper motor neuron signs or respiratory dysfunction suggest ALS; exertional dyspnoea, orthopnoea and oedema suggest cardiomyopathy; hypercapnia and recurrent respiratory infections indicate respiratory weakness that requires respiratory medicine assessment [7]. There is no newborn screening for these diseases.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnosis of PDB

There is no single reference test: radiography and scintigraphy provide different information and either may be diagnostic [8]. The radiographic findings — osteolytic areas, cortical thickening, loss of the cortico-medullary distinction, trabecular thickening, osteosclerosis, bone expansion and deformity — are individually non-specific, but together they are usually diagnostic [8].

The 2014 Endocrine Society guideline recommends radiographs of the suspected regions (1|⊕⊕⊕⊕), suggests scintigraphy for the extent and the asymptomatic sites (2|⊕⊕⊕○), recommends total ALP or a more specific formation marker (1|⊕⊕⊕⊕) and a specific formation or resorption marker in hepatic or biliary disease (1|⊕⊕⊕○) [19]. In untreated monostotic disease, it suggests PINP or bone ALP together with C-terminal telopeptide (βCTX) or NTX, which may be normal despite scintigraphic activity [19]. In PDB, calcium, phosphate and parathyroid hormone are usually normal [7]. Scintigraphy is indispensable in the screening of SQSTM1 carriers, because the markers have poor sensitivity and specificity for early lesions: in ZiPP, only 3.6% of the carriers had raised ALP at entry, against 8–11% with scintigraphic lesions [31].

5.2. Diagnosis of MSP

There are no published consensus clinical criteria [6]. The diagnosis is established in a proband with a typical clinical picture and a heterozygous pathogenic or likely pathogenic variant in VCP (more than 99% of cases), HNRNPA1 (less than 1%), HNRNPA2B1 (less than 1%) or SQSTM1 (rare) [6]. The identification of a variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [6].

5.3. Genetic testing strategy

In suspected MSP with a known familial variant, only that variant is tested, unless atypical features suggest a second diagnosis [21]. In undifferentiated cases, a multigene panel including VCP, HNRNPA2B1, HNRNPA1, SQSTM1, MATR3, TIA1 and OPTN is recommended, and it is advisable to confirm that the chosen panel includes VCP, because older myopathy, dementia, ALS, neuropathy or Parkinson disease panels may not contain it [7, 21]. Exome or genome sequencing is justified in the face of atypical phenotypes [6]. As the described variants of VCP, HNRNPA1 and HNRNPA2B1 are gain-of-function, testing for deletions and duplications is not indicated for these genes; in SQSTM1, about 10% of the pathogenic variants are deletions or duplications detectable by targeted methods [6]. The homology between HNRNPA1 and HNRNPA2B1 may interfere with sequencing [6].

In PDB, genetic testing has been used mainly in research; the guidelines do not recommend routine genetic profiling and the 2019 guideline lists its role in diagnosis and in the prediction of complications among the research priorities [8, 18]. In ZiPP, Sanger sequencing of exons 7 and 8 of SQSTM1, with classification according to the Association for Clinical Genomic Science (ACGS) and the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), was used to identify carriers among first-degree relatives [31]. In the Turkish study, two-stage screening (SQSTM1, then a panel with TNFRSF11A, TNFRSF11B, VCP, PFN1, OPTN, COL1A1/2, SP7 and CSF1) identified rare variants of VCP, TNFRSF11A and TNFRSF11B in the patients without SQSTM1 variants [23]. A negative panel test does not exclude a genetic basis, given the existence of loci without an identified gene (PDB4) and the polygenic component [1, 9].

5.4. Content of the report, VUS and segregation

The report must state the gene, the transcript and its version (for example NM_007126.5 for VCP), the HGVS description at the coding DNA and protein levels, the zygosity and the ACMG/AMP class [6, 30]. In the face of a VUS in VCP, family segregation, a muscle biopsy with characteristic findings and review by reference groups help with reclassification; the author of the GeneReviews chapter offers to review VCP VUS [6, 21]. The SQSTM1 variant p.(Pro392Leu) has conflicting classifications in ClinVar, consistent with an allele of incomplete penetrance, and must be interpreted in the family context [11, 32].

5.5. Prenatal and preimplantation diagnosis

Once the pathogenic variant has been identified in an affected relative, prenatal diagnosis and preimplantation genetic testing are possible in MSP [6]. For SQSTM1-associated PDB, the incomplete penetrance, the late age at onset and the generational attenuation of the disease make the discussion of these tests particularly individual [11].

5.6. Practical algorithm

6. Differential Diagnosis

6.1. Differential diagnosis of PDB

Adult PDB is distinguished from the dysplasias with hyperphosphatasia by the age at onset, by the asymmetrical distribution and by the absence of generalised involvement: PDB manifests after childhood and rarely involves the whole skeleton symmetrically [27, 51]. FEO mainly involves the metadiaphyses of the appendicular skeleton and rarely the subarticular area, and it combines early deafness and dental resorption, absent in PDB [5]. Fibrous dysplasia has expansile «ground glass» lesions, onset in the first two decades and a cranial form described as «pagetoid», and it is caused by GNAS mosaicism [8, 52]. Osteosclerotic metastases, hyperostosis frontalis interna and chronic non-bacterial osteomyelitis enter the differential, which in practice is resolved by the clinical picture and by the radiographic and scintigraphic appearance; the «heart» vertebral scintigraphic sign helps in the differential with metastases, with described false positives [8].

6.2. Differential diagnosis of MSP

The differential diagnosis of MSP includes the «MSP-like» diseases and the myopathies that are confused with it. Sporadic inclusion body myositis is distinguished by the inflammation on biopsy, absent in MSP; the LGMDs, FSHD, myofibrillar myopathy and the distal myopathies (tibial, GNE) are distinguished by genetics [10, 21]. Hereditary inclusion body myopathy due to GNE (distal myopathy with rimmed vacuoles, or Nonaka myopathy) is autosomal recessive, generally begins after 20 years, progresses over 10–20 years with sparing of the quadriceps until the advanced stages and shows rimmed vacuoles, grouped small fibres and tubulofilaments without inflammation; it results from a defect of sialic acid biosynthesis and is not accompanied by PDB or FTD [53]. FTD and ALS due to C9orf72 expansion, GRN, MAPT or TARDBP do not cause PDB or inclusion body myopathy and enter only the differential diagnosis [6, 54].

The relationship between some of these diseases and MSP is one of overlap and not of identity: in the Chinese cohort, ANXA11 variants were the commonest among the patients with variants in MSP genes, with upper limb or bulbar onset, and those of OPTN had a later onset [50].

7. Treatments and Risk Management Strategies

7.1. Objectives and indications of PDB treatment

The medical management of PDB has two strands: suppressing the increased bone remodelling of active disease and controlling musculoskeletal pain [18]. Bisphosphonates are the treatment of choice and the only drugs assessed in randomised trials; drugs such as glucagon, mithramycin, actinomycin D and gallium nitrate are only of historical interest [8]. Bisphosphonates bind to hydroxyapatite, are taken up by osteoclasts during resorption and inhibit farnesyl pyrophosphate synthase of the mevalonate pathway, which disorganises the osteoclast cytoskeleton and may induce apoptosis; zoledronic acid is the most potent inhibitor and the one with the greatest affinity for bone mineral, which explains its long duration of action [19].

The two main guidelines diverge in the indications. The 2019 international guideline, developed by the Paget's Association with the European Calcified Tissues Society (ECTS) and the International Osteoporosis Foundation (IOF), endorsed by the American Society for Bone and Mineral Research (ASBMR), by the Bone Research Society and by the British Geriatrics Society, and based on the GRADE methodology, recommends bisphosphonates for PDB-associated bone pain (moderate evidence), with zoledronic acid as the bisphosphonate with the highest probability of a pain response [8]. It considers the evidence insufficient to recommend bisphosphonates with the aim of improving quality of life, preventing fractures, halting the progression of osteoarthritis or of deafness, preventing deformity, reducing blood loss in elective surgery or preventing neoplastic transformation; in asymptomatic patients with increased metabolic activity, bisphosphonates may be considered, but the clinical benefit is uncertain [8]. The 2014 Endocrine Society guideline recommends treating with a bisphosphonate most patients with active PDB at risk of future complications (1|⊕⊕⊕○), suggests treating to prevent worsening of deafness, before elective arthroplasty or osteotomy and in heart failure, and suggests reducing remodelling below the midpoint of the reference range to prolong remission [19]. The 2019 guideline is more recent and incorporates the results of PRISM and PRISM-EZ, which showed no clinical benefit from the strategy of ALP normalisation; symptom-guided treatment is therefore the reference adopted, and the 2014 position constitutes a divergence [8, 19].

7.2. Dosing of bisphosphonates and of other antiresorptives

The PDB regimens apply to adults; zoledronic acid is not indicated in paediatric age and the EMA waived paediatric studies in PDB [57, 58]. The Endocrine Society guideline states that retreatment is rarely necessary within the 5 years following zoledronic acid, whereas after alendronate it may be needed between 2 and 6 years and after risedronate between 1 and 5 years [19].

7.3. Calcium, vitamin D and prevention of hypocalcaemia

Before an antiresorptive, especially an intravenous one, an adequate calcium intake and a replete vitamin D status must be ensured, because rapid suppression of remodelling may cause hypocalcaemia [7, 18]. With marked vitamin D deficiency (25-hydroxyvitamin D below 25 nmol/L), potent bisphosphonates may cause symptomatic hypocalcaemia; a single oral dose of 100,000 IU of calciferol before treatment is considered adequate by the 2014 guideline and was used in ZiPP [19, 31]. The labels differ in the supplementation after zoledronic acid: the FDA label indicates 1500 mg of elemental calcium a day in divided doses (750 mg twice or 500 mg three times a day) and 800 IU of vitamin D a day, especially in the two weeks after the infusion; the EMA and the Portuguese SmPC recommend at least 500 mg of elemental calcium twice a day for at least 10 days, and measurement of serum calcium before the infusion [57–59]. In the PDB trials, symptomatic hypocalcaemia occurred in about 1% and calcium fell below 2.10 mmol/L in 21%, more than in the osteoporosis trials (2.3%) [58].

7.4. Adverse effects and their management

In the trials of oral bisphosphonates in PDB, adverse effects did not differ from placebo, but zoledronic acid increased them (relative risk 2.57; 95% CI 1.21–5.44), mainly through a transient influenza-like syndrome [8]. The 2014 guideline estimates this reaction at about 25%, halved by prophylactic paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs); in the PDB trials, the influenza-like syndrome occurred in 11% and fever in 9%, and in osteoporosis the acute phase reactions after the first infusion included fever (17–18%), myalgia (7.8–9%) and headache (7%), generally in the first three days and milder with subsequent infusions [8, 19, 57, 58]. Dexamethasone 4 mg immediately before and for two days after zoledronic acid significantly reduced the severity of the symptoms [18]. Uveitis and other ocular inflammation occur in about 1% and require prompt ophthalmological review; they resolve with a topical corticosteroid [19]. Osteonecrosis of the jaw with oral bisphosphonates in PDB has been estimated at between 0.0004% and 0.06%, far below osteoporosis, and up to 2017 the EMA had received a single report of an atypical femoral fracture in a patient with PDB, probably because the courses are short or intermittent [8]. The labels also describe osteonecrosis of the external auditory canal, occasional disabling musculoskeletal pain and caution in aspirin-sensitive asthma [57, 58]. Oral bisphosphonates cause upper gastrointestinal discomfort [18]. The 2019 guideline recommends informing patients of the favourable adverse effect profile and of the frequency of the influenza-like syndrome with zoledronic acid [8].

7.5. Strategy: symptoms or normalisation of alkaline phosphatase

The PRISM trial compared, in 1324 patients (mean age about 74 years, mean duration 8 years, 70% already treated with bisphosphonates), an intensive strategy of maintaining ALP within the reference range with a strategy directed at pain control [8]. At the end of the study, 78.8% of the intensive arm and 61.2% of the symptomatic arm had normal ALP, but clinical fractures (7.0% against 7.3%), fractures in pagetic bone (1.2% against 2.0%), orthopaedic surgery (7.2% against 8.2%), pain at 2 years (73.7% against 69.7%), quality of life and progression of deafness did not differ [8]. In the PRISM-EZ extension, with zoledronic acid as first choice in the intensive arm and a mean total follow-up of 7.3 years, clinical fractures (8.1% against 5.2%) and arthroplasties (4.1% against 1.7%) were not fewer in the intensive arm, and serious adverse events were 32.2% against 28.4% [8]. The 2019 guideline therefore recommends symptom-directed treatment rather than ALP normalisation [8].

Monitoring after treatment is carried out with total ALP or another baseline marker at 6–12 weeks, with maximum suppression at 6 months; after zoledronic acid, once normalisation has been demonstrated, reassessment every 1–2 years is sufficient, and with less effective drugs every 6–12 months [19]. A PINP below 40 µg/L or an ALP below 80 IU/L at 6 months after zoledronic acid was associated with a probability above 90% of no relapse [19]. PINP is recommended for predicting the extent of the lesions on scintigraphy after treatment, but the markers do not predict the pain response [8]. Clinical relapse (pain) and biochemical relapse are distinct entities: in the extension of the pivotal trial, pain recurred in 9.2% of the patients on zoledronic acid and in 25.2% on risedronate, whereas biochemical relapse was 0.7% and 20% [8]. The 2014 guideline recommends that biochemical follow-up be used as a more objective indicator of relapse than symptoms (1|⊕⊕⊕○), a position that diverges from the symptom-directed approach of 2019 [8, 19]. In patients with osteolytic lesions, it suggests a radiograph about one year after diagnosis [19].

7.6. Analgesia and non-pharmacological measures

The pain response to bisphosphonates is often incomplete, and most patients need analgesics, NSAIDs or drugs for neuropathic pain; in PRISM, all the patients used at least one of these drugs [8, 18]. No trial has assessed these drugs specifically in PDB, and no study has assessed physiotherapy, occupational therapy or other non-pharmacological interventions [8]. In mild to moderate joint pain from adjacent osteoarthritis, the 2014 guideline suggests analgesics as adjuvant therapy [19].

7.7. Surgery

Surgery is recommended for the fixation of fractures in pagetic bone, but the results in femoral neck and subtrochanteric fractures are poor: in British series, non-union occurred in 8 of 11 (72.2%) and in 11 of 11 femoral neck fractures; no technique is preferable [8]. Total hip or knee arthroplasty is recommended in osteoarthritis with insufficient medical treatment [8]. In a series of 91 cemented hip arthroplasties, heterotopic ossification occurred in 37% (against 4.7% without PDB), radiographic loosening in 41.7% and revision in 15.3%, with more revisions after 10 years (about 40% against 5%); in uncemented arthroplasties with normal ALP in 94%, the result was excellent in 84.2% with no revisions at 7 years [8]. Mean blood losses were 744 mL in hip arthroplasties (against 200–450 mL without PDB) [8]. A recent systematic review showed implant longevity similar to that of the general population, with more medical and surgical complications (blood loss, operating time, fixation, positioning, heterotopic ossification, periprosthetic fractures) [18]. Osteotomy may be considered in osteoarthritis with deformity, with union in 23 of 25 procedures (mean of 6 months, slower in metaphyseal ones), and spinal surgery in stenosis and cord compression, with improvement in 14 of 17 published cases [8]. In PRISM, about 8% of the patients needed elective surgery and 7% had fractures [18].

Administration of a bisphosphonate before elective surgery to reduce blood loss is suggested by the Endocrine Society (before arthroplasty, osteotomy and surgery for osteosarcoma or GCT), but the 2019 guideline considers the data contradictory and does not recommend it [8, 19].

7.8. Neurological complications, deafness and tumours

In neurological dysfunction, the 2019 guideline suggests that a trial of calcitonin be considered as part of treatment and that bisphosphonates may also be considered; in a series of 49 patients treated with calcitonin (100 IU SC, then 50 IU three times a week, for 7–31 months), there was objective improvement in 40% of cranial nerve lesions, 33% of radicular ones and 50% of spinal cord ones [8]. In paraplegia from vertebral PDB, the Endocrine Society suggests immediate potent IV bisphosphonate with neurosurgical assessment, surgery possibly becoming unnecessary after effective medical treatment [19]. For deafness, the 2019 guideline found no evidence of benefit (an observational study of 25 patients with no change in thresholds at 12 months), whereas the 2014 guideline suggests a potent bisphosphonate to prevent worsening [8, 19]. Osteosarcoma and GCT require assessment by an orthopaedic surgeon; denosumab may be considered in unresectable GCT (three published cases with pain improvement and tumour reduction) [8, 19]. Bisphosphonates have not been proven to prevent neoplastic transformation [8].

7.9. Particular features of the genetic forms of PDB

No guideline is genotype-specific, and the treatment of the genetic forms follows the general guideline [8, 10]. In PDB6, the risk of GCT justifies attention to new pain, swelling or increased volume at pagetic sites, especially in the skull, although the sources consulted do not define an oncological surveillance protocol [12, 20]. In PDB7, two Chinese patients with p.(Leu112Pro) maintained raised ALP and pain despite annual zoledronic acid for six years and denosumab 120 mg every 2 months, a regimen outside the conditions of the label; the authors suggest that inhibition of the RANKL–RANK axis alone may be insufficient in this form [22]. In FEO, PDB2 and ESH, osteoclast inhibitors are used: IV pamidronate gave sustained clinical and biochemical improvement in FEO, calcitonin a short-lived effect; the FDA labels cover PDB, so that use in FEO and ESH is off-label, with evidence limited to series and case reports [5, 10].

7.10. Asymptomatic carriers of SQSTM1 variants

The ZiPP trial randomised 222 asymptomatic carriers aged 30 years or more, without a previous diagnosis of PDB, to a single infusion of zoledronic acid 5 mg or placebo [31]. The primary outcome (new lesions on scintigraphy) was not met (0 against 2; OR 0.41; 95% CI 0.00–3.43; p = 0.25), because the rate of new lesions was far lower than predicted; the unfavourable outcome (new, unchanged or progressing lesions) occurred in 0 against 8 participants (OR 0.08; 95% CI 0.00–0.42; p = 0.003), and 13 of the 15 lesions present at entry disappeared with zoledronic acid, against 1 of 29 with placebo [31]. The authors argue for a genetic testing programme in relatives with the offer of prophylactic zoledronic acid to carriers [18, 31]. This intervention is not an approved indication and does not appear in the guidelines; it remains undefined whether all carriers should be treated or only those with lesions, and the recent penetrance data have led other authors to question the value of screening and of regular surveillance [11, 31]. The results do not transfer to carriers of ZNF687, PFN1 or VCP [10].

7.11. Treatment of MSP

There is no disease-modifying therapy for MSP; care rests on a multidisciplinary team with a neuromuscular neurologist, an endocrinologist or rheumatologist experienced in PDB, specialist nursing, respiratory medicine, cardiology, speech and language therapy, physiotherapy, occupational therapy, respiratory physiotherapy, nutrition, psychology, social work and genetics [6, 7]. The 2022 international consensus, promoted by the patient association Cure VCP Disease with more than 40 experts and based on level III evidence, and the 2023 provisional recommendation for the myopathy, guide the management of the VCP form; for the other genes, management is individualised according to the systems involved [6, 7, 21].

In the myopathy, the measures are weight control, physiotherapy with regular, monitored, low to moderate intensity aerobic exercise (inactivity worsens the weakness), stretching to prevent contractures, occupational therapy, assistive devices (ankle-foot orthoses, walking sticks, walking frames, wheelchair, hoists), adaptations at home and at work, surgery for orthopaedic deformities (foot, scoliosis), respiratory training and, when necessary, assisted living [6, 7, 21]. No supplement has demonstrated benefit [21]. The 2022 consensus suggested an anti-inflammatory or Mediterranean-type diet and mentioned a lipid-rich diet that had improved a murine model, but the murine study of the lipid diet and a study of rapamycin and chloroquine in the same model were retracted in 2026 [7, 66, 67].

In the PDB of MSP, potent bisphosphonates lower ALP and relieve pain and disability; it is the only effective pharmacological treatment available in the disease, which justifies actively seeking the bone disease [6, 10]. The recommendation extrapolates from the treatment of classical PDB and has not been demonstrated specifically in MSP; courses may be repeated when pain recurs with raised ALP or uptake on scintigraphy, and the benefit of early intervention in VCP carriers without bone symptoms is unknown [7, 10].

In FTD, the measures are supportive: education and support for the carer (at high risk of burnout), a daily routine, redirection techniques, removal of triggers of risky behaviours, supervision in driving, in the kitchen, with medication, with finances and in the use of tools, exercise and cognitive activity, speech and language therapy with augmentative and alternative communication [6, 7]. Selective serotonin reuptake inhibitors may help with compulsions and hyperphagia; antipsychotics (quetiapine, risperidone) or valproate for agitation and aggression must be prescribed by experts, given the risk of serious effects; the Alzheimer disease drugs (rivastigmine, galantamine, donepezil, memantine, aducanumab) have not been studied or were ineffective in FTD [7].

In presentation as ALS, follow-up in a multidisciplinary clinic every 3 months is recommended, with management of sialorrhoea, cramps, spasticity, pseudobulbar affect, dysphagia (percutaneous endoscopic gastrostomy) and respiratory failure (non-invasive ventilation and, rarely, tracheostomy), and with palliative care [7]. Riluzole and edaravone are approved by the FDA for ALS irrespective of the genotype, but there is no evidence in the VCP form and the consensus did not reach agreement on their prescription; tofersen is specific to SOD1 ALS and does not apply [7, 10]. In parkinsonism, a trial of carbidopa-levodopa is recommended; there are no published cases of deep brain stimulation in VCP [7]. In CMT2Y, physiotherapy, occupational therapy, orthoses and foot surgery [7].

In cardiomyopathy, referral to cardiology is made and treatment follows the guidelines for non-ischaemic heart failure, as there are no specific trials: the 2022 consensus mentions angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), beta blockers and mineralocorticoid receptor antagonists (MRAs), and the 2025 review, following the 2022 and 2024 North American guidelines, the four pillars for a symptomatic ejection fraction ≤40%: an angiotensin receptor-neprilysin inhibitor (preferable to an ACEI or ARB), a beta blocker (carvedilol, extended-release metoprolol or bisoprolol), an MRA and a sodium-glucose cotransporter 2 inhibitor (SGLT2i) [7, 36]. Late gadolinium enhancement on MRI should not, by itself, decide the initiation of therapy; on progression, an implantable cardioverter-defibrillator with or without resynchronisation, left ventricular assist device or transplantation are considered, without data on benefit in VCP [36].

In respiratory dysfunction, up-to-date vaccination, lung volume recruitment with a manual insufflator, mechanical insufflation-exsufflation, suction of secretions, early treatment of infections and non-invasive ventilation (bilevel positive pressure or volume-assured pressure support) at the onset of nocturnal hypoventilation or with an arterial CO2 pressure above 45 mmHg, FVC below 50% of predicted or maximum inspiratory pressure below −60 cmH2O are recommended; continuous positive pressure is reserved for obstructive apnoea without hypoventilation, and oxygen alone and respiratory depressants must be avoided [7]. Mental health must be screened and followed, and urinary and anal incontinence must be sought annually [7].

7.12. Baseline assessment in MSP

7.13. Regulatory situation

7.14. Main clinical trials

The PDB trials used mainly short-term biochemical outcomes, and there are no trials powered for outcomes such as joint replacement [8, 19]. The results of different trials must not be compared indirectly, and the relative differences must be read together with the absolute rates: in PRISM, fractures in pagetic bone were 1–2% in both arms [8]. PRISM and PRISM-EZ are negative trials for the strategy of ALP normalisation, and ZiPP failed its primary outcome, the described benefit being based on secondary outcomes [8, 31]. In MSP there are no registered interventional clinical trials; the natural history study NCT04823143 (44 patients, one year) ended in August 2025 [71].

7.15. Developments of the last 12 months and research

7.16. Pregnancy, lactation, perioperative period and transition

Zoledronic acid is contraindicated in pregnancy and breastfeeding according to the EMA, and the FDA label indicates discontinuation when pregnancy is recognised [57, 58]. Classical PDB is rare before 40 years, but in the early forms (PDB2, PDB7) and in MSP the childbearing years may coincide with the disease; the sources consulted do not describe the specific management of pregnancy in these forms. In the perioperative period, the increased vascularity of pagetic bone raises blood losses and arthroplasty is technically more difficult [8, 18]. In MSP with respiratory weakness, respiratory assessment and the avoidance of respiratory depressants are relevant before any sedation [7]. Hydration before zoledronic acid is particularly important in older people and in patients on diuretics, and renal function must be assessed before each dose [57, 59]. In the forms with onset in childhood or adolescence (FEO, PDB2), transition to adult services follows the bone disease and the deafness [5].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

MSP associated with VCP, HNRNPA1, HNRNPA2B1 or SQSTM1 has autosomal dominant inheritance: each child of an affected individual has a 50% probability of inheriting the variant [6]. Most patients have an affected parent, and about 5% will have a de novo variant, an estimate based mainly on the VCP form [6]. When the proband appears to be the only affected individual, the variant must be tested in the parents and neurological assessment, CK and ALP performed, because the disease may not have been recognised, the parent may have died before onset or may have late onset [6]. If the variant is not detected in the leucocytes of either parent, the risk to siblings is estimated at about 1% because of the possibility of gonadal mosaicism, not yet described in MSP; if the parents are clinically unaffected but of unknown genetic status, the risk is low but higher than in the population [6]. The age at onset, the severity, the rate of progression and the combination of manifestations are not predictable from the familial variant: in the same family, some carriers have apparently isolated myopathy, PDB or FTD and others combinations that include ALS, parkinsonism, cardiomyopathy or neuropathy [6]. In VCP, the myopathy and the PDB typically begin in the third decade, possibly delayed to the fifth, and the FTD in the fifth or sixth decade [6].

In familial PDB associated with SQSTM1, ZNF687 or PFN1, inheritance is also autosomal dominant, but the penetrance of the SQSTM1 form is incomplete and age-dependent, and expression is today later and attenuated in the younger generations [8, 11]. The relative risk of PDB in the first-degree relatives of a patient is about seven times that of the population, and the cumulative risk up to 90 years was estimated at 9% against 2% in a North American study; the relative risk rises to about 20 times in the relatives of patients with severe or early disease [1, 18]. In NADGP due to SQSTM1, inheritance is autosomal recessive and heterozygotes are healthy, while juvenile PDB due to TNFRSF11B is likewise recessive [27, 42].

8.2. Cascade testing and predictive testing

Once the variant has been identified in an affected individual, predictive testing of at-risk relatives is possible, under a counselling protocol similar to that used in other adult-onset diseases, with prior discussion of the socioeconomic consequences, of the need for follow-up and of the limitations of the test [6]. In the 2022 consensus, presymptomatic VCP testing may be justified by early cardiac and respiratory screening and by career, lifestyle and reproductive decisions; counselling must precede and follow the test, with psychological support available for carriers and non-carriers, and legislation on genetic non-discrimination varies between countries [7]. A study of the psychological impact of predictive testing in VCP underpinned the protocol in use [6].

In SQSTM1-associated PDB, ZiPP demonstrated that it is feasible and acceptable to test the first-degree relatives of patients with a variant and to offer scintigraphy to carriers: of the 1307 relatives invited, 750 accepted testing and 350 were carriers [31]. The clinical utility of such a programme depends on the benefit of prophylactic intervention, not yet incorporated into the guidelines, and on current penetrance, which longitudinal studies show to be lower than the old estimates [8, 11].

8.3. Minors, family planning and prenatal diagnosis

Predictive testing of asymptomatic minors for adult-onset diseases without beneficial early treatment must be discussed in formal counselling, favouring autonomy and deferral until the capacity for informed decision-making; symptomatic relatives may be tested at any age [6]. The ideal time to discuss genetic risk and the options of prenatal diagnosis and preimplantation genetic testing is before pregnancy, and counselling should be offered to young affected or at-risk adults [6]. Decisions about prenatal and preimplantation diagnosis rest with the parents, but discussion of the different perspectives is appropriate [6].

9. Special Considerations: Population Diversity and Epidemiology

9.1. PDB: what each figure measures

PDB is commonest in the United Kingdom, which has the highest incidence in the world, in Spain, Italy and France, and in the countries of European immigration (Australia, New Zealand, USA, Canada); it is rare in Scandinavia, in the Indian subcontinent, in China and in the Far East [8, 18]. In the United Kingdom, it is about 20% commoner in people who identify as Black British and about 50% less common in those who identify as British Asian [18]. Archaeological studies suggest that the predisposing variants arose in north-western Europe centuries ago and spread by emigration [8]. The Lancashire focus and the prevalence in British migrants in Australia have been interpreted as a sign of an environmental factor [1]. Prevalence and severity have fallen over the last 25 years in the United Kingdom, in continental Europe and in New Zealand, especially in the previously most affected regions, with a parallel reduction in adult osteosarcoma; in Quebec, the prevalence is stable, but the incidence and severity have fallen [8, 48]. The Portuguese series is hospital-based and does not measure the national prevalence; the sources consulted do not provide a population estimate for Portugal or for Brazil.

9.2. Founder populations and genetic variation

The proportion of cases with a family history varies: 5–15% in most series, but up to 50% in Quebec, where the SQSTM1 variant p.(Pro392Leu) was identified in French-Canadian families on a founder haplotype [1, 18]. In Spain, 40% of index cases had an affected first-degree relative [1]. The ZNF687 variant p.(Pro937Arg) is a founder variant in Campania (Avellino), with carriers among descendants of Italians in the USA and also in French-Canadian patients [20]. PFN1 variants have been described in Italian and Han Chinese families, and PDB2 in a Japanese family and in a Brazilian patient [3, 4, 22]. In VCP, two ancestral haplotypes of northern European origin account for about half of the initial North American families; the cohort of 231 individuals included patients of European, Brazilian, Hispanic and Apache origin, and a Brazilian family with p.(Asn91Tyr) illustrates the intrafamilial variability [24].

9.3. MSP

The true prevalence is unknown. GeneReviews cites a British estimate of about 1:300,000, which does not come from a population-based ascertainment; another British estimate is 0.66 per million; Orphanet assigns the class below 1 per million and 26 validated families, drawn from GeneReviews itself [6, 14, 21]. The disease is considered underdiagnosed, given the diagnostic odyssey [6]. VCP variants account for 1–2% of familial ALS in a cohort of 289 families and for about 21% of the patients with variants in MSP genes in a Chinese cohort [6, 50]. Very few families have MSP due to HNRNPA1 or HNRNPA2B1, and MSP due to SQSTM1 is rare [6].

9.4. Special populations

Scintigraphy and ALP lose their usefulness in patients with liver disease, in whom the 2014 guideline recommends specific formation or resorption markers [19]. In renal failure with CrCl below 35 mL/min, zoledronic acid is contraindicated and oral bisphosphonates are a safer alternative [19, 58]. Patients with MSP and kyphosis or scoliosis have limited echocardiographic windows, which favours cardiac MRI [7, 36].

9.5. European networks and patient associations

The relevant European reference networks are ERN BOND for rare bone diseases (https://ernbond.eu), EURO-NMD for neuromuscular diseases (https://ern-euro-nmd.eu), whose members took part in the 2023 recommendation for VCP myopathy, and ERN-RND for rare neurological diseases (https://www.ern-rnd.eu) [21]. The patient associations include the Paget's Association (United Kingdom; https://paget.org.uk), which coordinated the 2019 guideline and publicised ZiPP, Cure VCP Disease (https://www.curevcp.org), which maintains the CoRDS patient registry, the Association for Frontotemporal Degeneration (https://www.theaftd.org), the Muscular Dystrophy Association, Muscular Dystrophy UK and the Myositis Association [6, 8, 31, 39].

10. Illustrative Clinical Case

10.1. Early-onset PDB with giant cell tumour due to a PFN1 variant

Weng and colleagues described in 2025 a Han Chinese family from Shaanxi province [22]. The proband, a man, suffered a fracture of the left forearm at 26 years and subsequently developed progressive deformities of the limbs and of the skull, with bone pain [22]. The radiographs showed lytic lesions and deformities of the humeri, tibiae, femora and pelvis, with coarse and disorganised trabeculation, and a deformed skull with thickened diploe and sclerotic foci; scintigraphy showed uptake in 21 bones, about 10.2% of the skeleton, including skull, clavicles, spine, humeri, ulnae, pelvis, femora and tibiae, with confirmation by CT, MRI and radiography (figure 1, panels B and C: https://pmc.ncbi.nlm.nih.gov/articles/PMC12712971/figure/dgaf314-F1/) [22]. At 33 years, tumours appeared in the right parietal region of the calvarium and were resected, their histology showing numerous multinucleated giant cells, compatible with GCT (figure 1, panel D) [22]. His mother had suffered a fracture of the left humerus at 35 years after a fall, had developed multiple mandibular tumours and had died at 39 years [22].

Sequencing of PFN1 identified the heterozygous variant c.335T>C p.(Leu112Pro), absent in 500 Chinese controls and already described in another family with PDB and GCT; on the MANE transcript it corresponds to NM_005022.4:c.335T>C [22, 30]. Despite the proximity to variants associated with ALS, no carrier had motor neuron disease [22]. The proband received zoledronic acid 5 mg intravenously once a year between 2013 and 2019, without normalisation of ALP or relief of pain, and from the end of 2020 denosumab 120 mg subcutaneously every 2 months: ALP fell but remained above 1200 U/L, and the pain did not improve; CTX and PINP also did not improve significantly [22]. In the other family, a patient treated with denosumab had only a slight reduction in scintigraphic uptake after 5 years (figure 1, panel E) [22].

The case illustrates three points. First, PDB with onset before 30 years, polyostotic and with GCT in the family, must lead to testing of PFN1 and ZNF687 [20, 22]. Second, annual repetition of zoledronic acid and denosumab every 2 months do not correspond to the recommendations or to the labels: the 2019 guideline uses zoledronic acid as a single dose with retreatment for relapse, does not recommend denosumab for PDB and reserves it for unresectable GCT, for which the label provides for 120 mg every 4 weeks with loading doses on days 8 and 15 [8, 58, 65]. Third, the poor response to antiresorptives in this form is an observation in two patients, without controlled comparison [22].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis of PDB

Most people with radiographic PDB never come to medical attention, and the more recent generations have later and less extensive disease [8, 11]. Zoledronic acid produces prolonged biochemical remissions: in the extension of the pivotal trial, 88% maintained a normal ALP at 5 years, against 47% with risedronate, and the mean time to the need for retreatment was 7.7 years against 5.1 years [8, 58]. In the Portuguese cohort, 22.1% of the patients needed retreatment, and the mean survival of the first-line drug was 16.0 years with zoledronic acid against 11.7 years with other drugs [77]. The structural complications (deformity, osteoarthritis, deafness) do not regress with treatment, and intensive treatment did not reduce fractures or surgery in PRISM [8].

The associated mortality is modest and variable: in the British General Practice Research Database, 5-year mortality was 33% in patients with PDB (n = 2465) against 28% in controls (n = 7395), with circulatory causes (38%), cancer (22%) and respiratory diseases (21%); in Olmsted County (Minnesota, diagnoses from 1950–1994), the standardised mortality ratios were not increased [48]. In Quebec, between 2000/2001 and 2020/2021, the standardised mortality of patients aged 55 years or more rose from 47.1 to 54.2 per 1000 while that of the general population fell from 27.6 to 22.3 per 1000, and the adjusted relative risk went from 1.06 (99% CI 0.95–1.19) to 1.16 (99% CI 1.06–1.27), possibly because of the ageing of the cohort and vascular calcifications [48]. Osteosarcoma has a poor prognosis even with aggressive treatment, and about half of the patients with PDB die within 5 years of a GCT [8, 20].

11.2. Prognosis of MSP

MSP is progressive: loss of ambulation occurs 13 ± 7 years after the onset of the myopathy, and death typically occurs in the sixth decade, mainly from respiratory failure, with cardiac and neurodegenerative contributions [6, 7]. ALS and dementia are associated with rapid decline, whereas survival after onset with myopathy or with PDB is longer and offers a window for preventive and supportive interventions [38]. p.(Arg155Cys) was associated with earlier onset and shorter survival than p.(Arg155His) [38]. In the Mayo Clinic series, loss of ambulation (5 patients) and death (3 patients) occurred only in the VCP form [43].

11.3. Surveillance table

The MSP intervals diverge between the 2026 GeneReviews and the 2022 consensus in alkaline phosphatase (annual against 6–12 months), in cardiac assessment (echocardiogram and ECG every 2–3 years against baseline cardiac MRI repeated according to symptoms or every 2 years if abnormal) and in cognitive assessment (every 2–3 years against annual); both sources are expert-based and the choice depends on resources and on the phenotype [6, 7]. The cardiac MRI proposals derive from Duchenne muscular dystrophy and have not been validated in VCP [36].

12. Summary and Final Considerations

PDB is a focal disturbance of bone remodelling that affects mainly people over 50 years of European origin, with a prevalence that has been falling for decades for environmental reasons that remain unclear. Its genetic basis combines common risk alleles, identified by genome-wide association studies, with SQSTM1 variants in 40–50% of families and in 5–10% of sporadic cases, and with rare and severe forms due to ZNF687, with a risk of giant cell tumour, due to PFN1, of early onset, and due to TNFRSF11A, with deafness and tooth loss in childhood. The diagnosis is made by targeted radiographs, scintigraphy and alkaline phosphatase with normal liver function tests. Zoledronic acid 5 mg as a single dose is the treatment of choice for bone pain, with biochemical remissions lasting several years; the 2019 guideline directs treatment by symptoms and not by normalisation of alkaline phosphatase, after PRISM failed to show a clinical benefit from the intensive strategy, whereas the 2014 guideline proposed treating most active patients at risk of complications.

In asymptomatic carriers of SQSTM1 variants, the ZiPP trial showed that zoledronic acid makes early lesions regress, without meeting the primary outcome, and longitudinal studies indicate that current penetrance is much lower than was estimated; genetic testing of relatives and prophylaxis remain outside the guidelines. Multisystem proteinopathy, caused mainly by gain-of-function VCP variants, combines inclusion body myopathy, Paget disease of bone, frontotemporal dementia, amyotrophic lateral sclerosis, parkinsonism and cardiomyopathy, with great variability within families. PDB is the only manifestation with an effective pharmacological treatment, and it must therefore be actively sought with alkaline phosphatase and scintigraphy; the remainder require multidisciplinary care and respiratory, cardiac and cognitive surveillance, with intervals that diverge between GeneReviews and the international consensus. Research into antisense oligonucleotides and VCP modulators remains preclinical, and genetic counselling, predictive testing and reproductive options follow the model of autosomal dominant adult-onset diseases.

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