Lan Chen
Vatinee Bunya

BASICS

DESCRIPTION

• A bone remodeling disorder resulting in increased bone turnover

• Disorganized bone formation and break down impairs integrity of affected bone.

• Often asymptomatic, however can be associated with pathologic fractures, bone deformity, deafness, and cranial nerve compression due to enlarged bones and secondary osteoarthritis.

• Elevated serum alkaline phosphatase (SAP) and abnormal radiography or bone scan

• Ocular manifestations include angioid streaks, orbital involvement of sarcomas, and compressive optic neuropathy.

EPIDEMIOLOGY

Prevalence

• Paget’s disease is found in 1–2% of Caucasian adults older than 55 years.

• Prevalence increases with age.

• Up to 15% of patients with Paget’s disease have angioid streaks.

RISK FACTORS

• Poorly understood; however, genetic and environmental risk factors – such as viral infection, may have a role.

• Large ethnic and geographic differences in prevalence. It is more common in people of Anglo-Saxon origin.

Genetics

• There appears to be a genetic component.

• Approximately 15% of patients have a positive family history.

• Some families with autosomal dominant inheritance have been described.

GENERAL PREVENTION

No treatment is known to prevent choroidal neovascular (CNV) membranes, which are the most visually significant complications of angioid streaks.

PATHOPHYSIOLOGY

• Focal areas of increased osteoclastic bone resorption with bone marrow fibrosis, increased vascularity of bone, and disorganized bone formation

• Enlarging and abnormally contoured bones that may bow or fracture

• Elevated SAP, normal serum calcium (can be elevated if immobile due to unopposed increased bone resorption)

• Hypercalcemia in an ambulatory patient with Paget’s may be due to another cause such as hyperparathyroidism.

• Angioid streaks in the eye occur due to discontinuities in thickened Bruch’s membrane.

ETIOLOGY

• Cause unknown

• Viral infection may play a role in the etiology.

COMMONLY ASSOCIATED CONDITIONS

• The most common diseases to be associated with angioid streaks can be remembered with the “PEPSI” mnemonic.

– P: Paget’s disease

– E: Ehlers–Danlos

– P: Pseudoxanthoma elasticum (PXE)

– S: Sickle cell hemoglobinopathy

– I: Idiopathic

DIAGNOSIS

HISTORY

• Majority are asymptomatic and diagnosed by routine serum chemistry screen with elevated alkaline phosphatase or radiography performed for another reason.

• Bone pain, bowed tibias, fractures, headache, large head, deafness, warmth over affected areas

• Decreased vision, metamorphopsia, scotoma

• Cardiac disease and abnormalities in calcium and phosphate balance can occur.

• Excessive bleeding during orthopedic surgery may occur.

PHYSICAL EXAM

• Systemic features:

– The most common bones affected by Paget’s disease are the flat and long bones including the spine, femur, pelvis, skull, clavicle, and humerus.

– Bone fractures may occur.

– Increased incidence of bone tumors, which present with pain or an enlarging mass

– Cardiac complications due to widespread severe disease causing heart failure, aortic stenosis, and conduction abnormalities

• Ophthalmic features:

– Angioid streaks: dark red to brown bands irregularly radiating from optic nerves deep to the retina. Usually bilateral

– Atrophic retinal pigment epithelium (RPE) overlying angioid streaks

– RPE clumping with focal hyperpigmentation

– High risk for CNV membranes with RPE detachment or serous and/or hemorrhagic detachments of the retina

– Peau d’ orange is midperipheral RPE mottling sometimes associated with angioid streaks due to Paget’s.

– Compressive optic neuropathy that may cause optic atrophy

– Orbital soft tissue sarcomas

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

• Elevated SAP

• Also check serum calcium, albumin, parathyroid hormone, phosphorus, 25-hydroxy vitamin D, and urinary calcium.

Follow-up & special considerations

• Routinely monitor SAP

• Fundus examination may show angioid streaks or CNV.

Imaging

Initial approach

• Radiography shows dense mosaic bones.

• Bone scans are the most sensitive test and can be used to evaluate the extent and activity of disease. Pagetic bone lesions appear as focal areas of increased uptake.

Follow-up & special considerations

• Repeat imaging with change in symptoms.

• CT or MRI if bone pain increased or refractory to treatment

Diagnostic Procedures/Other

• Please refer to the angioid streaks chapter for more details.

• Ophthalmic diagnostic imaging tests for angioid streaks and CNV may include fundus fluorescein angiography (FA), optical coherence tomography (OCT), or indocyanine angiography (ICG).

Pathological Findings

Mosaic pattern of lamellar bone associated with increases in local bone blood flow and in fibrous tissue in adjacent marrow

DIFFERENTIAL DIAGNOSIS

• Osteomalacia

• Hyperparathyroidism

• Vitamin D deficiency

• Malignancy such as multiple myeloma

TREATMENT

MEDICATION

First Line

• All medications used to treat Paget’s disease of bone are inhibitors of osteoclastic bone resorption.

• Newer-generation nitrogen-containing bisphosphonates are the primary initial agents:

– Zoledronic acid: 5 mg IV single infusion reference (1)[A]

– Risedronate: 30 mg orally daily for 2 months

– Pamidronate: 30 mg IV for 3 days

– Alendronate: 40 mg daily for 6 months

Second Line

• Simple bisphosphonates:

– Tiludronate: 400 mg orally daily for 3 months.

– Etidronate: 200–400 mg orally for 6 months (5 mg/kg of body weight per day)

• Calcitonin (rarely used): Salmon calcitonin 50–100 units subcutaneously daily or 3 times per week.

• Side effects of bisphosphonates at the dosing regimen used in Paget’s disease include but are not limited to

– Influenza-like syndrome

– Musculoskeletal pain

– Osteonecrosis of the jaw

– Dyspepsia or diarrhea

– Esophagitis

– Rarely, uveitis and scleritis

• Contraindications to bisphosphonates include impaired renal function, particularly with IV infusion.

• Common side effects of calcitonin include nausea, vomiting, and flushing. Rarely, tachyphylaxis.

ADDITIONAL TREATMENT

General Measures

• NOTE: Bisphosphonates are poorly absorbed orally. They must be taken with water, first thing in the morning, at least 30 min before any food, beverage, or other oral medications. Patients should not lie down during these 30 min.

• If supplemental calcium is taken, it should be separated by at least 2 h from bisphosphonates because calcium can decrease the absorption of bisphosphonates.

• A normal serum 25-hydroxy vitamin D and calcium levels are generally needed before giving bisphosphonates.

Issues for Referral

• Refer to ophthalmology to monitor and treat ocular complications.

• No treatment for angioid streaks

• Treatment options for ocular CNV include the following:

– Laser coagulation (2)

– Photodynamic therapy (PDT) (3)

– Intravitreal antivascular endothelial growth factor (anti-VEGF) therapy such as bevacizumab (4)

Additional Therapies

• Supplemental calcium with vitamin D for patients with Paget’s disease, particularly if they are receiving bisphosphonate therapy.

– Antiresorptive therapy can improve bone pain; however, analgesics and anti-inflammatory medications may also be necessary.

SURGERY/OTHER PROCEDURES

• Orthopedic surgery to manage bony complications

• For planned surgery at an active pagetic site, preoperative medical treatment may possibly decrease perioperative blood loss.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Depends upon severity of systemic and ophthalmic disease

Patient Monitoring

• Amsler grid monitoring for metamorphopsia

• Safety glasses for patient with angioid streaks because of increased risk of choroidal rupture and subsequent subretinal hemorrhage after trauma

PROGNOSIS

Increased risk of osteosarcomas

COMPLICATIONS

• Fractures and skeletal deformities

• Increased risk of hip and knee replacements

• Osteoarthritis

• Bone pain

• Hearing loss

• Spinal stenosis and nerve compression

• Visual loss

• Hypercalcemia possible with immobilization

• Rarely, osteosarcoma, cardiac failure, hydrocephalus, and paraplegia

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