Paget Disease of Bone

Essentials of Diagnosis

• Often asymptomatic

• Bone pain may be first symptom

• Kyphosis, bowed tibias, large head, deafness

• Frequent fractures

• Serum calcium and phosphate normal; elevated alkaline phosphatase and urinary hydroxyproline

• Dense, expanded bones on radiograph

General Considerations

• Common condition manifested by one or more bony lesions having high bone turnover and disorganized osteoid formation

• Involved bones

  • Have increased osteoclast activity, causing lytic lesions in bone that may progress at about 1 cm/yr

  • Increased osteoblastic activity follows, producing a high rate of disorganized bone formation

  • 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

• Most often discovered incidentally during radiographic imaging or evaluation of serum alkaline phosphatase elevation

• Cause is unknown; about 20% of cases are familial and transmitted as an autosomal dominant trait with incomplete penetrance

Demographics

• Most common in the United Kingdom and in areas of European migration

• Rare in Africa, India, Asia, and Scandinavia

• In the United States, Paget disease is usually diagnosed in patients over age 40 years

• Affects about 1% of whites over age 55 years; prevalence increasing with age

Symptoms and Signs

• Often mild and asymptomatic; only 27% symptomatic at diagnosis

• Involves multiple bones (polyostotic) in 72% and only a single bone (monostotic) in 28%, occurring most commonly in the pelvis, vertebrae, femur, humerus, and skull

• Pain is usual first symptom

  • Usually described as aching and deep

  • Often worse at night

• Bones become soft, leading to bowed tibias, kyphosis, and frequent fractures with slight trauma

• If skull is involved, patient may report headaches, increased hat size, and deafness

• Increased vascularity over involved bones causes increased warmth

• Sarcomatous change suggested by marked increase in bone pain

Differential Diagnosis

• Bone tumor, eg, osteosarcoma

• Plasma cell myeloma (formerly multiple myeloma)

• Metastatic cancer

• Fibrous dysplasia

• Osteitis fibrosa cystica

• Fibrogenesis imperfecta ossium

• Myelofibrosis

• Intramedullary osteosclerosis

• Erdheim-Chester disease

• Langerhans cell histiocytosis

• Sickle cell disease

Laboratory Tests

• Serum alkaline phosphatase markedly elevated

• Other markers of bone turnover are also usually elevated, particularly

  • Serum procollagen type-I N-terminal propeptide (PINP)

  • Urine N-telopeptide of type 1I collagen cross-links (NTx)

• Serum calcium may be elevated, particularly if patient is at bed rest

• A serum 25-OH vitamin D should be obtained to screen for vitamin D deficiency, which

  • Can present with an increased serum alkaline phosphatase and bone pain

  • Should be corrected before prescribing a bisphosphonate

• Sarcomatous change is suggested by sudden rise in serum alkaline phosphatase

Imaging Studies

• Bone radiographs show involved bones as expanded and denser than normal

• Multiple fissure fractures in long bones

• Initial lesion may be destructive and radiolucent, especially in skull ("osteoporosis circumscripta")

• Sarcomatous change suggested by appearance of new lytic lesion

• Technetium pyrophosphate bone scans helpful in delineating activity of bone lesions even before radiographic changes are apparent

Diagnostic Procedures

• Bone biopsy in suspected sarcomatous change

• Asymptomatic patients may require only clinical surveillance and no treatment

• However, treatment should be considered for asymptomatic patients who have extensive involvement of the skull, long bones, or vertebrae

Medications

• Zoledronic acid

  • Treatment of choice

  • Administered intravenously as a single 5-mg dose

  • Normalizes serum alkaline phosphatase in 89% of patients by 6 months and in 98% by 2 years

• Oral bisphosphonates

  • Inferior to intravenous zoledronic acid

  • Patients who do take bisphosphonates should drink 8 oz of plain water and must remain upright afterward to prevent esophageal complications

  • Relative contraindications: history of

    • Esophagitis

    • Esophageal stricture

    • Dysphagia

    • Hiatal hernia

    • Achalasia

  • Patients who cannot tolerate bisphosphonates may be treated with calcitonin

Follow-Up

• Monitor alkaline phosphatase

Complications

• Fractures frequently occur with minimal trauma

• If patient is immobilized and has excessive calcium intake, hypercalcemia and kidney stones may develop

• Vertebral collapse may lead to spinal cord compression

• Osteosarcoma may develop in long-standing lesions (rare)

• Increased vascularity may cause high-output heart failure

• Arthritis frequently develops in joints adjacent to involved bone

• Extensive skull involvement may cause cranial nerve palsies

• Ischemic neurologic events may result from vascular "steal" phenomenon

• In severe forms, marked deformity, intractable pain, and heart failure occur

• Paradoxical increase in pain at sites of disease soon after starting therapy; pain usually subsides with further treatment

• Flu-like symptoms occur fairly frequently

• Following intravenous zoledronate, patients frequently experience fever, fatigue, myalgia, bone pain, and ocular problems

• Serious side effects are rare but include

  • Seizures

  • Uveitis

• Other potential side effects

  • Acute kidney injury

  • Hypocalcemia is common and may be severe; administering calcium and vitamin D supplements, especially during the first 2 weeks following treatment, is advisable

  • Asthma may occur in aspirin-sensitive patients

• Esophageal complications of oral bisphosphonates may be prevented by taking oral bisphosphonates with 8 oz of plain water only

Prognosis

• Prognosis is good but worse the earlier in life the disease starts

• Most patients treated with bisphosphonates have normalization of serum alkaline phosphatase within 6 months, most maintaining this biochemical remission for several years

• Fractures usually heal well

Prevention

• Prompt bisphosphonate treatment markedly reduces occurrence of complications of severe Paget disease