Paget’s disease of bone has one of the strongest genetic components of any common skeletal disorder, with up to 40% of patients reporting an affected first-degree relative. The disease follows an autosomal dominant inheritance pattern, meaning a single copy of a risk gene inherited from one parent can be enough to set the stage. But “set the stage” is the key phrase here: carrying the gene does not guarantee you will develop the disease. Incomplete penetrance and likely environmental triggers make the genetics of Paget’s disease more interesting, and more unpredictable, than a simple one-gene story.
How Strong Is the Family Connection?
If you have a parent or sibling with Paget’s disease, your risk is substantially higher than that of the general population. Early genetic linkage studies found that up to 40% of patients had affected first-degree relatives, pointing toward a major heritable component long before specific genes were identified.1The American Journal of Human Genetics. Genetic Linkage of Paget Disease of the Bone to Chromosome 18q That family clustering is far higher than you would expect for a disease affecting roughly 1-3% of older adults in populations of European descent.
Yet the picture is not entirely genetic. Even within the same family, disease severity varies widely. One sibling might develop painful, deforming lesions in multiple bones, while another might have a single affected bone discovered incidentally on an X-ray. And over the past several decades, Paget’s disease has become both less common and less severe across entire populations, a trend that genetics alone cannot explain.2PubMed Central. Paget’s disease: a review of the epidemiology, etiology, genetics, and treatment That declining prevalence strongly suggests environmental factors are also in play, interacting with inherited susceptibility in ways researchers are still working out.
The SQSTM1 Gene and Why It Matters Most
The single most important gene in Paget’s disease is SQSTM1, which encodes a protein called p62. Mutations in this gene, particularly one called P392L, are found in a significant minority of patients and are especially common in familial cases. In a study of 737 patients, about 11% carried an SQSTM1 mutation, and those who did tended to be diagnosed younger, have more bones affected, and more frequently need surgery or bisphosphonate treatment than patients without the mutation.3PubMed Central. Mutations of SQSTM1 are associated with severity and clinical outcome in paget disease of bone
The p62 protein acts as a kind of molecular scaffold, helping relay signals that control how bone-resorbing cells called osteoclasts form and behave. When p62 is mutated, it loses part of its ability to bind ubiquitin, a small tag that cells use to mark proteins for recycling. That disruption ramps up a signaling cascade that tells the body to make too many osteoclasts that are too active.4Frontiers in Cell and Developmental Biology. Update on the pathogenesis and genetics of Paget’s disease of bone In practical terms, the affected bone gets chewed up and rebuilt too fast, producing the disorganized, enlarged, and weakened bone that defines Paget’s disease.
Experiments in mice carrying the equivalent mutation confirm this: osteoclast precursors from mutant animals show heightened activation of signals that promote bone breakdown, and the cells are more sensitive to RANKL, a key molecule that drives osteoclast formation.5The Journal of Clinical Investigation. Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget disease Interestingly, though, mice with the P392L mutation alone develop increased osteoclast activity but do not always develop full-blown Paget’s-like bone lesions on their own. That gap between the genetic predisposition and actual disease is one of the most revealing clues about how Paget’s works.
There is also growing evidence that p62 mutations disrupt autophagy, the cellular housekeeping process that clears out damaged proteins and structures. Mice carrying a P394L mutation (the mouse equivalent of P392L) show signs of ramped-up autophagosome formation in their osteoclast precursors.6Human Molecular Genetics. A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget’s disease-like disorder in mice Another mutation in p62 (R321C) has been shown to block autophagy and stimulate the same pro-osteoclast signaling pathway, reinforcing the idea that faulty cellular cleanup is part of the disease process.7PubMed. A mutation in p62 protein (p. R321C), associated to Paget’s disease of bone, causes a blockade of autophagy and an activation of NF-kB pathway A 2025 zebrafish study further demonstrated that deleting the ubiquitin-binding domain of p62 produces a bone phenotype strikingly similar to Paget’s disease, including hyperactive osteoclasts and enlarged osteocyte lacunae.8PubMed. Loss of the Ubiquitin-Associated Domain of sqstm1/p62 in Zebrafish Causes a Phenotype Resembling Paget’s Disease of Bone
Other Genes Linked to Paget’s Disease
SQSTM1 gets the most attention, but it is far from the only gene involved. Genome-wide association studies have identified at least six common loci that raise susceptibility, and family-based studies have pinpointed an additional eight genes that can cause the disease.9PubMed Central. Genetic Determinants of Paget’s Disease of Bone Two of these, OPTN and RIN3, have been confirmed as causal through fine-mapping and functional studies.10PubMed Central. Clinical and Genetic Advances in Paget’s Disease of Bone: a Review Researchers have also found rare variants in candidate genes near these newly identified loci in population studies, including work in the French-Canadian population where Paget’s disease is relatively common.11PubMed. Identification of rare genetic variants in novel loci associated with Paget’s disease of bone
What ties nearly all of these genes together is that they participate in the same broad signaling network that controls osteoclast formation. Most of them feed into the RANK-NF-κB pathway, the central signaling chain that tells osteoclast precursors to mature and start resorbing bone.12PubMed. Pathogenesis of Paget’s disease of bone So even though the mutations are in different genes, they tend to produce the same downstream result: osteoclasts that are too numerous, too active, or both.
A particularly dramatic example is ZNF687. A mutation in this gene was identified in a large Italian family with 14 affected members, four of whom developed giant cell tumors at pagetic bone sites, a rare and serious complication. The same mutation was then found in seven unrelated individuals who also had giant cell tumors arising from Paget’s disease, suggesting a founder effect in that population.13PubMed Central. ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor This is a good reminder that different genetic variants can drive noticeably different clinical pictures, even within the same disease.
Incomplete Penetrance and What It Means for Families
Paget’s disease follows an autosomal dominant pattern of inheritance, which means you only need one copy of a mutated gene (from either parent) to be at risk.14PubMed. Paget’s disease of bone-genetic and environmental factors But dominance here comes with an asterisk: the penetrance is incomplete, meaning not everyone who inherits a disease-causing mutation will actually develop Paget’s disease. Some carriers live their entire lives without symptoms or detectable bone changes.
This incomplete penetrance is why you can have one family member severely affected and another who carries the same mutation without any clinical disease. It also makes genetic counseling more nuanced than for fully penetrant conditions. Finding out you carry an SQSTM1 mutation does not mean Paget’s disease is inevitable. It means you are at elevated risk and would benefit from periodic monitoring, typically a blood test for alkaline phosphatase, a marker of bone turnover.
The Environmental Half of the Equation
If Paget’s disease were purely genetic, its prevalence would stay roughly constant over time, barring some unusual selection pressure. Instead, prevalence has dropped markedly over the past 30 years, and patients who do develop the disease now tend to present later in life with milder symptoms than previous generations.15PubMed. Is the prevalence of Paget’s disease of bone decreasing? Something in the environment has clearly changed.
The most studied environmental candidate is viral exposure, particularly to the measles virus. A landmark mouse study showed that neither the p62 mutation nor expression of measles virus nucleocapsid protein (MVNP) alone was enough to produce full-blown pagetic bone lesions. But mice that expressed both developed dramatic Paget’s-like bone changes strikingly similar to what is seen in human patients.16Cell Metabolism. Contributions of the Measles Virus Nucleocapsid Gene and the SQSTM1/p62P392L Mutation to Paget’s Disease The measles virus component drove osteoclast hypermultinucleation and inflammatory signaling, while the p62 mutation sensitized the cells to stimulation. The two hits together were far worse than either alone.17PubMed Central. Pathobiology of Paget’s Disease of Bone
A more recent hypothesis has linked the decline of Paget’s disease to the decline of domestic coal burning. Across multiple countries, Paget’s disease prevalence has fallen as open-hearth coal use for home heating has disappeared.18PubMed Central. The Decline of Paget’s Disease of Bone and Domestic Coal Use-A Hypothesis The mechanism, if there is one, is unknown, but the geographic and temporal correlation is striking. Whether the link is to airborne particulates, trace metals, or something else entirely remains speculative. Still, the overall message is clear: genetic mutations create vulnerability, but some environmental exposure appears necessary to push many carriers over the threshold into clinical disease.
When Paget’s Disease Is Part of a Larger Genetic Syndrome
In a small number of families, Paget’s disease does not occur in isolation but as one feature of a multi-system disorder. The best-known example involves mutations in the VCP gene, which cause a syndrome combining inclusion body myopathy, Paget’s disease, and frontotemporal dementia. This condition, sometimes called IBMPFD, follows autosomal dominant inheritance, and six distinct missense mutations in VCP were identified across 13 families with the disorder.19Nature Genetics. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein The same VCP mutations can produce widely varying presentations even within a single family: one person might develop Paget’s disease and muscle weakness, while a relative with the same mutation might develop dementia with no bone involvement at all.20PubMed. Three VCP Mutations in Patients with Frontotemporal Dementia
At the other end of the age spectrum, juvenile Paget’s disease is a rare autosomal recessive condition caused by loss-of-function mutations in the TNFRSF11B gene, which encodes a protein called osteoprotegerin. Unlike the adult form, juvenile Paget’s requires two copies of a defective gene (one from each parent) and produces severe, generalized bone disease beginning in childhood.21PubMed. Osteoprotegerin deficiency and juvenile Paget’s disease Most reported cases carry homozygous mutations, though rare compound heterozygous cases (two different mutations in the same gene, one from each parent) have been documented.22PubMed Central. Juvenile Paget disease with unique compound heterozygous sequence variants in the TNFRSF11B gene Despite sharing a name, juvenile Paget’s disease is genetically and clinically distinct from the common adult form.
Genetic Testing and What It Can Do for Families
If Paget’s disease runs in your family, genetic testing for SQSTM1 mutations is available and has been studied as a practical screening tool. The logic is straightforward: test the affected family member first, identify the specific mutation, and then offer targeted testing to first-degree relatives. Those who carry the mutation can be monitored with periodic alkaline phosphatase measurements and imaging, potentially catching the disease early before complications develop.
There is real evidence this approach works. A randomized trial tested the strategy of genetic screening for SQSTM1 mutations in relatives of Paget’s patients, followed by treatment with zoledronic acid (a potent bisphosphonate) for carriers who showed early signs of disease. The intervention was well tolerated and had favorable effects on slowing disease progression.23PubMed. Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget’s disease of bone That study represents the first time a genetics-based preventive strategy for Paget’s disease has been tested in a controlled setting.
There are limitations, though. Genetic testing is most useful when a known SQSTM1 mutation has been identified in the family. For families where the affected member tests negative for SQSTM1 mutations, currently available genetic panels are less informative, since many of the other susceptibility loci involve common variants with small individual effects rather than single high-impact mutations. And the incomplete penetrance of SQSTM1 mutations means a positive test result raises but does not settle the question of whether disease will develop. The value of testing lies in enabling surveillance, not in predicting certainty.24PubMed. Genetic aspects of the Paget’s disease of bone: concerns on the introduction of DNA-based tests in the clinical practice
How Mutation Status Affects Disease Severity and Treatment
Carrying an SQSTM1 mutation does not just increase your risk of getting Paget’s disease; it also shifts the likely clinical course. In the study of 737 patients mentioned earlier, mutation carriers were diagnosed about five years younger on average, had roughly 50% more affected bones, and were more likely to need both orthopedic surgery and bisphosphonate therapy.3PubMed Central. Mutations of SQSTM1 are associated with severity and clinical outcome in paget disease of bone A separate U.S. study of men carrying the P392L mutation found that the majority were diagnosed before age 50, and more than half developed spinal stenosis.25PubMed Central. The implications of the Sequestosome 1 mutation P392L in patients with Paget’s disease in a United States cohort
This means that from a clinical standpoint, knowing a patient’s SQSTM1 status can meaningfully shape expectations and monitoring. A mutation-positive patient may warrant closer follow-up and more aggressive treatment than someone with sporadic, single-site disease and no identifiable genetic driver. The disease is still manageable with bisphosphonates in most cases, but the genetic subtype tends to need management earlier and for longer.
MicroRNAs and the Emerging Epigenetic Layer
Beyond the DNA mutations themselves, researchers are finding that small regulatory molecules called microRNAs may help explain why osteoclasts behave so abnormally in Paget’s disease. MicroRNAs are short stretches of non-coding RNA that act as volume knobs for gene expression, turning certain genes up or down after the DNA has already been read.
One study comparing osteoclasts grown from the blood of 40 Paget’s patients and 30 healthy controls identified six microRNAs that were significantly reduced in pagetic osteoclasts. These molecules normally interact with signaling pathways critical for osteoclast formation and survival, including those controlling programmed cell death.26PubMed. miR profile in pagetic osteoclasts: from large-scale sequencing to gene expression study A separate study homed in on two specific microRNAs, miR-146a-3p and miR-155-5p, that were also reduced in pagetic osteoclasts. In lab experiments, reintroducing these microRNAs dampened osteoclast formation and bone resorption, while a third stable microRNA (miR-133a-3p) had the opposite effect, actually promoting osteoclast activity.27Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. Osteoclast signaling-targeting miR-146a-3p and miR-155-5p are downregulated in Paget’s disease of bone
This work is still at an early stage, but it opens a window onto therapies that go beyond traditional bisphosphonates. If specific microRNAs act as natural brakes on osteoclast overactivity, finding ways to restore their levels could eventually offer a more targeted treatment, particularly for patients whose disease is driven by genetic mutations that feed into those same pathways.
Ancient DNA and What It Tells Us
One curious line of evidence comes from paleopathology. Researchers have found skeletal remains with bone changes that look very much like Paget’s disease dating back centuries. When they extracted and sequenced ancient DNA from one such specimen, they did not find any of the SQSTM1 mutations associated with the disease today.28PubMed Central. Molecular insights into an ancient form of Paget’s disease of bone That finding has a couple of implications. It suggests that Paget’s-like bone pathology can arise through genetic routes that no longer circulate in modern populations, or through environmental causes acting without the specific mutations we currently recognize. It also reinforces the idea that the genetic landscape of this disease is not static. The mutations researchers study today are the ones that happen to be common now, but the disease itself may have had different genetic underpinnings in the past.
For researchers, this makes Paget’s disease a fascinating case study in how genes and environment co-evolve over centuries. For patients and their families, the practical takeaway is more modest but still important: the genetics of Paget’s disease are not fully mapped, and a negative genetic test does not completely rule out hereditary risk. The known mutations account for the largest share of familial cases, but they do not capture every genetic pathway that can lead to the same endpoint.