Paget's disease may be caused by a slow virus infection (i.e., paramyxoviridae) present for many years before symptoms appear. Associated viral infections include respiratory syncytial virus, canine distemper virus, and the measles virus. However, recent evidence has cast some doubt upon the measles association. Laboratory contamination may have played a role in past studies linking paramyxovirus (e.g. measles) to Paget's disease.

The disease is progressive and slowly worsens with time, although people may remain minimally symptomatic. Treatment is aimed at controlling symptoms, but there is no cure. Any bone or bones can be affected, but Paget's disease occurs most frequently in the spine, skull, pelvis, femur, and lower legs.

Osteogenic sarcoma, a form of bone cancer, is a rare complication of Paget's disease occurring in less than one percent of those affected. The development of osteosarcoma may be suggested by the sudden onset or worsening pain.

The disease has been reported to affect 3 per 1000 infants younger than 6 months in the United States. No predilection by race or sex has been established. Almost all cases occur by the age of 5 months. The familial form is inherited in an autosomal dominant fashion with variable penetrance. The familial form tends to have an earlier onset and is present at birth in 24% of cases, with an average age at onset of 6.8 weeks. The average age at onset for the sporadic form is 9–11 weeks.

Cortical hyperostosis is a potential side effect of long-term use of prostaglandins in neonates.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

Fibrous dysplasia is a disorder where normal bone and marrow is replaced with fibrous tissue, resulting in formation of bone that is weak and prone to expansion. As a result, most complications result from fracture, deformity, functional impairment, and pain. Disease occurs along a broad clinical spectrum ranging from asymptomatic, incidental lesions to severe disabling disease. Disease can affect one bone (monostotic) or multiple (polyostotic), and may occur in isolation or in combination with cafe-au-lait skin macules and hyperfunctioning endocrinopathies, termed McCune-Albright syndrome. More rarely, fibrous dysplasia may be associated with intramuscular myxomas, termed Mazabraud's syndrome. Fibrous dysplasia is very rare, and there is no known cure. Fibrous dysplasia is not a form of cancer.

Approximately eight to 40 children are born in the United States each year with the malignant infantile type of osteopetrosis. One in every 100,000 to 500,000 individuals is born with this form of osteopetrosis. Higher rates have been found in Denmark and Costa Rica. Males and females are affected in equal numbers.

The adult type of osteopetrosis affects about 1,250 individuals in the United States. One in every 200,000 individuals is affected by the adult type of osteopetrosis. Higher rates have been found in Brazil. Males and females are affected in equal numbers.

The odds are greater in the Russian region of Mari El (1 of every 14,000 newborns) and much greater in Chuvashia (1 of every 3,500—4,000 newborns) due to genetic features of the Mari people and Chuvash people, respectively.

While the exact cause of enchondroma is not known, it is believed to occur either as an overgrowth of the cartilage that lines the ends of the bones, or as a persistent growth of original, embryonic cartilage.

An enchondroma may occur as an individual tumor or several tumors. The conditions that involve multiple lesions include the following:

- Ollier disease (enchondromatosis) - when multiple sites in the body develop the tumors. Ollier disease is very rare.

- Maffucci's syndrome - a combination of multiple tumors and angiomas (benign tumors made up of blood vessels).

To date, the specific cause of Gorham's disease remains unknown.

Bone mass and strength are obtained and maintained through a process of bone destruction and replacement that occurs at the cellular level throughout a person's life. Cells called osteoclasts secrete enzymes that dissolve old bone, allowing another type of cells called osteoblasts to form new bone. Except in growing bone, the rate of breakdown equals the rate of building, thereby maintaining bone mass. In Gorham's disease that process is disrupted.

Gorham and Stout found that vascular anomalies always occupied space that normally would be filled with new bone and speculated that the presence of angiomatosis may lead to chemical changes in the bone. Gorham and others speculated that such a change in the bone chemistry might cause an imbalance in the rate of osteoclast activity to osteoblast activity such that more bone is dissolved than is replaced. Beginning in the 1990s there were reports of elevated levels of a protein called interleukin-6 (IL-6) being detected in patients with the disease, leading some to suggest that increased levels of IL-6 and vascular endothelial growth factor (VEGF) may contribute to the chemical changes Gorham and others believed were the cause of this type of osteolysis.

In 1999 Möller and colleagues concluded, "The Gorham-Stout syndrome may be, essentially, a monocentric bone disease with a focally increased bone resorption due to an increased number of paracrine – or autocrine – stimulated hyperactive osteoclasts. The resorbed bone is replaced by a markedly vascularized fibrous tissue. The apparent contradiction concerning the presence or absence or the number of osteoclasts, may be explained by the different phases of the syndrome." They further stated that their histopathological study provided good evidence that osteolytic changes seen in Gorham's disease are the result of hyperactive osteoclastic bone. However, others have concluded that lymphangiomatosis and Gorham's disease should be considered as a spectrum of disease rather than separate diseases.

While there is consensus that Gorham's is caused by deranged osteoclastic activity, there is not yet conclusive evidence as to what causes this deranged behavior to begin.

Fibrous dysplasia is a mosaic disease resulting from post-zygotic activating mutations of the "GNAS" locus at 20q13.2-q13.3, which codes for the α subunit of the G G-coupled protein receptor. In bone, constitutive Gα signaling results in impaired differentiation and proliferation of bone marrow stromal cells. Proliferation of these cells causes replacement of normal bone and marrow with fibrous tissue. The bony trabeculae are abnormally thin and irregular, and often likened to Chinese characters (bony spicules on biopsy).

Fibrous dysplasia is not hereditary, and there has never been a case of transmission from parent to child.

Gorham's disease (pronounced GOR-amz), also known as Gorham vanishing bone disease and phantom bone disease, is a very rare skeletal condition of unknown cause, characterized by the uncontrolled proliferation of distended, thin-walled vascular or lymphatic channels within bone, which leads to resorption and replacement of bone with angiomas and/or fibrosis. Current treatments are experimental only.

As of 2017, approximately 800 cases of FOP have been confirmed worldwide making FOP one of the rarest diseases known. The estimated incidence of FOP is 0.5 cases per million people and affects all races.

Osteogenesis imperfecta is a rare condition in which bones break easily. There are multiple genetic mutations in different genes for collagen that may result in this condition. It can be treated with some drugs to promote bone growth, by surgically implanting metal rods in long bones to strengthen them, and through physical therapy and medical devices to improve mobility.

The only effective line of treatment for malignant infantile osteopetrosis is hematopoietic stem cell transplantation. It has been shown to provide long-term disease-free periods for a significant percentage of those treated; can impact both hematologic and skeletal abnormalities; and has been used successfully to reverse the associated skeletal abnormalities.

Radiographs of at least one case with malignant infantile osteopetrosis have demonstrated bone remodeling and recanalization of medullar canals following hematopoietic stem cell transplantation. This favorable radiographic response could be expected within one year following the procedure - nevertheless, primary graft failure can prove fatal.

Osteitis fibrosa cystica has long been a rare disease. Today, it appears in only 2% of individuals diagnosed with primary hyperparathyroidism, which accounts for 90% of instances of the disease. Primary hyperparathyroidism is three times as common in individuals with diabetes mellitus.

The hospitalization rate for hyperparathyroidism in the United States in 1999 was 8.0 out of 100,000. The disease has a definite tendency to affect younger individuals, typically appearing before the age of 40, with a study in 1922 reporting that 70% of cases display symptoms before the age of 20, and 85% before 35. Primary hyperparathyoidism, as well as OFC, is more common in Asiatic countries. Before treatment for hyperparathyroidism improved in the 1950s, half of those diagnosed with hyperparathyroidism saw it progress into OFC.

Rates of OFC increase alongside cases of unchecked primary hyperparathyroidism. In developing countries, such as India, rates of disease as well as case reports often mirror those published in past decades in the developed world.

The other 10% of cases are primarily caused by primary hyperplasia, or an increase of the number of cells. Parathyroid carcinoma accounts for less than 1% of all cases, occurring most frequently in individuals around 50 years of age (in stark contrast to OFC as a result of primary hyperparathyroidism) and showing no gender preference. Approximately 95% of hyperparatyhroidism caused by genetic factors is attributed to MEN type 1. This mutation also tends to affect younger individuals.

CRMO was once considered strictly a childhood disease, but adults have been diagnosed with it. The affected tends to range from 4 to 14 years old, with 10 as the median age. As stated above, CRMO occurs 1:1,000,000 and primarily in girls with a 5:1 ratio. That means out of six million, there will probably be 5 girls and 1 boy with the condition.

Infantile cortical hyperostosis is a self-limited condition, meaning that the disease resolves on its own without treatment, usually within 6–9 months. Long-term deformities of the involved bones, including bony fusions and limb-length inequalities, are possible but rare.

Age and gender have an effect on the incidence of these lesions; they are more prevalent in women than men (though still common in both genders), and they appear more frequently with age. Due to the standard of medical care and screening in developed countries, it is increasingly rare for primary hyperparathyroidism to present with accompanying bone disease. This is not the case in less developed nations, however, and the two conditions are more often seen together.

PDP occurs more frequently in men than in women (ratio around 7:1). Moreover, men suffer from more severe symptoms (see table 1). African American people are affected to a higher extent.

Table 1. Distribution of different forms of PDP among 201 reported affected men and women (167 men and 34 women).

Osteochondrodysplasia or skeletal dysplasia is a general term for a disorder of the development (dysplasia) of bone ("osteo") and cartilage ("chondro").

Osteochondrodysplasias are rare diseases. About 1 in 5,000 babies are born with some type of skeletal dysplasia.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare connective tissue disease. The disease is caused by a mutation of the body's repair mechanism, which causes fibrous tissue (including muscle, tendon, and ligament) to be ossified spontaneously or when damaged. In many cases, injuries can cause joints to become permanently frozen in place. Surgical removal of the extra bone growths has been shown to cause the body to "repair" the affected area with even more bone.

Osteitis fibrosa cystica is the result of unchecked hyperparathyroidism, or the overactivity of the parathyroid glands, which results in an overproduction of parathyroid hormone (PTH). PTH causes the release of calcium from the bones into the blood, and the reabsorption of calcium in the kidney. Thus, excess PTH in hyperparathyroidism causes elevated blood calcium levels, or hypercalcemia.

There are four major causes of primary hyperparathyroidism that result in OFC:

- Parathyroid adenoma

The vast majority of cases of hyperparathyroidism are the result of the random formation of benign, but metabolically active, parathyroid adenoma swellings. These instances comprise approximately 80–85% of all documented cases of hyperparathyroidism.

- Hereditary factors

Approximately 1 in 10 documented cases of hyperparathyroidism are a result of hereditary factors. Disorders such as familial hyperparathyroidism, multiple endocrine neoplasia type 1 (MEN Type 1) and hyperparathyroidism-jaw tumor syndrome can, if left unchecked, result in OFC. MEN Type 1 is an autosomal dominant disorder and the most common hereditary form of hyperparathyroidism, affecting about 95% of genetic cases of OFC, and also tends to affect younger patients than other forms. Major mutations which can lead to hyperparathyroidism generally involve the parathyroid hormone receptor, G proteins, or adenylate cyclase. Certain genetic mutations have been linked to a higher rate of parathyroid carcinoma occurrence, specifically mutations to the gene HRPT2, which codes for the protein parafibromin.

- Parathyroid carcinoma

Parathyroid carcinoma (cancer of the parathyroid gland) is the rarest cause of OFC, accounting for about 0.5% of all cases of hyperparathyroidism. OFC onset by parathyroid carcinoma is difficult to diagnose.

- Renal complications

OFC is a common presentation of renal osteodystrophy, which is a term used to refer to the skeletal complications of end stage renal disease (ESRD). OFC occurs in approximately 50% of patients with ESRD. ESRD occurs when the kidneys fail to produce calcitriol, a form of Vitamin D, which assists in the absorption of calcium into the bones. When calcitriol levels decrease, parathyroid hormone levels increase, halting the storage of calcium, and instead triggering its removal from the bones. The concept of renal osteodystrophy is currently included into the broader term chronic kidney disease-mineral and bone disorder (CKD-MBD).

The differential diagnosis of malignant infantile osteopetrosis includes other genetic skeletal dysplasias that cause osteosclerosis. They are collectively known as osteosclerosing dysplasias. The differential diagnosis of genetic osteosclerosing dysplasias including infantile osteopetrosis has been tabulated and illustrated in literature citations.

- Neuropathic infantile osteopetrosis

- Infantile osteopetrosis with renal tubular acidosis

- Infantile osteopetrosis with immunodeficiency

- IO with leukocyte adhesion deficiency syndrome (LAD-III)

- Intermediate osteopetrosis

- Autosomal dominant osteopetrosis (Albers-Schonberg)

- Pyknodysostosis (osteopetrosis acro-osteolytica)

- Osteopoikilosis (Buschke–Ollendorff syndrome)

- Osteopathia striata with cranial sclerosis

- Mixed sclerosing bone dysplasia

- Progressive diaphyseal dysplasia (Camurati–Engelmann disease)

- SOST-related sclerosing bone dysplasias

Some parents of children with MHE have observed autism-like social problems in their children. To explore those observations more deeply, a 2012 study by the Sanford-Burnham Medical Research Institute used a mouse model of MHE to observe cognitive function. The findings indicated that the mutant mice endorsed three autistic characteristics: social impairment, impairments in ultrasonic vocalization, and repetitive behavior.

In 25-38% of the cases, patients have a familial history of PDP. It is suggested that the incomplete form and complete form are inherited in different ways: either autosomal dominant inheritance (involving a dominant allele) or autosomal recessive inheritance (involving a recessive allele).

The autosomal dominant model of inheritance with penetrance and variable expression is confirmed in about half of the families, associated with the incomplete form. Of several families, an autosomal recessive model of inheritance is known, associated with the complete form with much more severe symptoms involving joint, bone and skin features. While the male-female ratio in PDP is skewed, this cannot be fully explained by X-linked inheritance.

Two genes have been associated with this condition: hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) and solute carrier organic anion transporter family, member 2A1/prostaglandin transporter (SLCO2A1). The underlying pathophysiology appears to be an abnormality of prostglandin E2 but the details have yet to be elucidated.