26-20: Paget Disease of Bone (Osteitis Deformans)

Paget disease of bone is manifested by one (monostotic) or more (polyostotic) bony lesions having high bone turnover and disorganized osteoid formation. The involved bone first has increased osteoclast activity, causing lytic lesions in bone that may progress at about 1 cm/year. Increased osteoblastic activity follows, producing a high rate of disorganized bone formation. Involved bones become vascular, weak, and deformed. Eventually, there appears to be a final burned-out phase with markedly reduced bone cell activity and abnormal bones that may be enlarged with skeletal deformity.

The prevalence of Paget disease has declined by about 36% over the past 20 years, yet it is the second most common bone disease after osteoporosis. It is most common in the United Kingdom and in areas of European migration, and it is rare in Africa, India, Asia, and Scandinavia. In the United States, Paget disease is usually diagnosed in patients over age 40 years and affects about 1% of whites over age 55 years, with its prevalence increasing with age. About 20% of cases are symptomatic, but most cases are discovered incidentally during radiology imaging or because of incidentally discovered elevations in serum alkaline phosphatase.

Paget disease of bone is hypothesized to be due to a viral infection in genetically susceptible individuals, but the precise cause is unknown. About 20% of cases are familial and transmitted as an autosomal dominant trait with incomplete penetrance. Mutations in the SQSTM1 gene have been discovered in about 35% of patients with familial Paget disease and in 7% of patients with apparently sporadic Paget disease.

A. Symptoms and Signs

Paget disease is often mild and asymptomatic. Only 27% of affected individuals are symptomatic at the time of diagnosis. Paget disease involves multiple bones (polyostotic) in 72% and only a single bone (monostotic) in 28%. It occurs most commonly in the pelvis, vertebrae, femur, humerus, and skull. The affected bones are typically involved simultaneously, and the disease tends not to involve additional bones during its course. Pain, often described as aching and deep and often worse at night, is the usual first symptom. It may occur in the involved bone or in an adjacent joint, which can be involved with degenerative arthritis. Paget disease typically first affects long bones proximally and then advances distally, with bone pain at the osteolytic front being aggravated by weight bearing. Joint surfaces (such as the knee) can be involved and cause arthritic pain. The bones can become soft, leading to bowed tibias, kyphosis, and frequent “chalkstick” fractures with slight trauma. If the skull is involved, the patient may report headaches and an increased hat size; the finding of dilated scalp veins, present in half such patients, is known as the “scalp vein sign.” Involvement of the petrous temporal bone frequently damages the cochlea and causes hearing loss (mixed sensorineural and conductive) and occasionally tinnitus or vertigo. Increased vascularity over the involved bones causes increased warmth and can cause vascular “steal” syndromes.

B. Laboratory Findings

Serum alkaline phosphatase is often markedly elevated. However, about 40% of patients with Paget disease of bone have normal serum alkaline phosphatase levels, particularly patients with monostotic involvement. A serum bone-specific alkaline phosphatase is usually high and is useful for patients with a normal serum alkaline phosphatase and to distinguish the source of an elevated alkaline phosphatase as being from bone (rather than liver). However, bone alkaline phosphatase is less useful for following the effectiveness of therapy. Other useful measures for bone turnover are serum N-terminal propeptide of type 1 collagen (NTx) and serum beta C-terminal propeptide of type 1 collagen (betaCTx). However, such bone turnover markers may overestimate or underestimate the response to treatment. Serum calcium may be elevated, particularly if the patient is at bed rest. A serum 25-OH vitamin D determination should be obtained to screen for vitamin D deficiency, which can also present with an increased serum alkaline phosphatase and bone pain.

C. Imaging

On radiographs, the initial lesions are typically osteolytic, with focal radiolucencies (“osteoporosis circumscripta”) in the skull or advancing flame-shaped lytic lesions in long bones (eFigure 26–21). In vertebrae, the lesions of Paget disease may display a “clover” or “heart” appearance, helping distinguish them from bone metastases. Bone lesions may subsequently become sclerotic and have a mixed lytic and sclerotic appearance. The affected bones eventually become thickened and deformed. Technetium-99m pyrophosphate bone scans are helpful in delineating activity of bone lesions and finding additional lesions in other locations (eFigure 26–22).

Certain rare familial types of sclerosing bone dysplasias share phenotypic homologies with Paget disease of bone. Familial expansile osteolysis, familial early-onset Paget disease, and familial skeletal hyperphosphatasia are autosomal dominant disorders caused by different tandem duplications of the gene encoding RANK, resulting in its constitutive activation. Juvenile Paget disease is an autosomal recessive disorder caused by an inactivating mutation in the gene encoding osteoprotegerin. The syndrome of Paget disease, inclusion body myopathy, and frontotemporal dementia is caused by a mutation in the gene that encodes valosin-containing protein. The differential diagnosis also includes myelofibrosis, intramedullary osteosclerosis, Erdheim-Chester disease, Langerhans cell histiocytosis, and sickle cell disease.

Paget disease must be differentiated from primary bone lesions such as osteogenic sarcoma, plasma cell myeloma, and fibrous dysplasia and from secondary bone lesions such as osteitis fibrosa cystica and metastatic carcinoma to bone. Fibrogenesis imperfecta ossium is a rare symmetric disorder that can mimic the features of Paget disease; serum alkaline phosphatase is likewise elevated. This condition may be associated with paraproteinemias.

If immobilization occurs, hypercalcemia and renal calculi may develop. With severe polyostotic disease, the increased vascularity may give rise to high-output heart failure. Arthritis frequently develops in joints adjacent to involved bone.

Extensive skull involvement may cause cranial nerve palsies from impingement of the neural foramina. Skull involvement can also cause a vascular steal syndrome with somnolence or ischemic neurologic events; the optic nerve may be affected, resulting in loss of vision. Jaw involvement can cause the teeth to spread intraorally and become misaligned. Vertebral collapse can cause compression of spinal cord or spinal nerves, resulting in radiculopathy or paralysis. Vertebral involvement can also cause a vascular steal syndrome with paralysis. Surgery for fractured long bones is often complicated by excessive blood loss from these vascular lytic lesions.

A sarcoma or giant cell tumor may develop in long-standing lesions but is rare (less than 1%). Sarcomatous change is suggested by a marked increase in bone pain, sudden rise in alkaline phosphatase, and appearance of a new lytic lesion.

Asymptomatic patients may require only clinical surveillance and no treatment. However, treatment with bisphosphonates should be considered for asymptomatic patients who have significant involvement of the skull, long bones, or vertebrae. Patients must be monitored carefully before, during, and after treatment with clinical examinations and serial serum alkaline phosphatase determinations.

Zoledronic acid is the treatment of choice. Administered intravenously as a single 5-mg dose, it normalizes the serum alkaline phosphatase in 89% of patients by 6 months and in 98% by 2 years.

Zoledronic acid should be administered prior to total arthroplasty for a Paget-involved joint in order to reduce the risk of intraoperative hemorrhaging and loosening of the prosthesis postoperatively. Zoledronic acid should also be administered before osteotomy for severe bowing of a lower extremity caused by Paget disease. For patients with paraplegia due to vertebral involvement, intravenous zoledronic acid should be given while neurosurgical consultation is obtained.

Patients frequently experience a paradoxical increase in pain at sites of disease soon after commencing bisphosphonate therapy; this is the “first dose effect” and the pain usually subsides with further treatment. Following intravenous zoledronic acid, patients frequently experience fever, fatigue, myalgia, bone pain, and ocular problems. Serious side effects are rare but include seizures, uveitis, and acute kidney disease. Asthma may occur in aspirin-sensitive patients. Hypocalcemia is common and may be severe, especially if intravenous bisphosphonates are given along with loop diuretics. Therefore, it is advisable to administer calcium and vitamin D supplements, especially during the first 2 weeks following treatment. Any vitamin D deficiency should be corrected before prescribing a bisphosphonate.

Oral bisphosphonate regimens are inferior to intravenous zoledronic acid for therapy of Paget disease. However, if they are given, to prevent esophageal complications, oral bisphosphonates should be taken with 8 oz of plain water only, and the patient must remain upright afterward. Oral bisphosphonates are relatively contraindicated in patients with a history of esophagitis, esophageal stricture, dysphagia, hiatal hernia, or achalasia. Patients who cannot tolerate bisphosphonates may be treated with calcitonin.

The prognosis is good, but relapse can occur after an initial successful treatment with bisphosphonate. By 6.5 years after initial therapy, the recurrence rate is 12.5% after treatment with zoledronic acid and 62% after risedronate. Therefore, patients must be monitored long term, measuring serum alkaline phosphatase at least yearly. In general, the prognosis is worse the earlier in life the disease starts. Fractures usually heal well. In the severe forms, marked deformity, intractable pain, and high-output heart failure occur if not treated with bisphosphonates. Osteosarcoma that arises at sites of Paget disease results in a 2-year survival of only 25%.