Ophthalmology – Paget Disease of Bone

Basics

Description

Paget disease of bone is a chronic disorder of focal bone remodeling characterized by:

• Excessive osteoclastic bone resorption
• Compensatory but disorganized osteoblastic bone formation
• Structurally enlarged but mechanically abnormal bone

Affected bone may become:

• Thickened
• Deformed
• Hypervascular
• Fragile

Many patients are asymptomatic.

Potential complications include:

• Bone pain
• Pathologic fracture
• Skeletal deformity
• Osteoarthritis
• Hearing loss
• Cranial nerve compression
• Rare malignant transformation

Important ophthalmic manifestations include:

• Angioid streaks
• Secondary choroidal neovascularization (CNV)
• Compressive optic neuropathy from skull involvement
• Rare orbital involvement by sarcomatous transformation

Epidemiology

Paget disease primarily affects:

• Older adults
• Usually patients >50 years

Prevalence rises with age.

It is more common in:

• People of European ancestry
• Historically, populations from the United Kingdom and other regions with British ancestry

Its prevalence has declined in many countries over recent decades.

Risk Factors

The cause is incompletely understood.

Risk factors include:

• Increasing age
• Family history
• Genetic susceptibility
• Geographic and ethnic background

Older hypotheses proposed chronic viral infection as a trigger, but a specific viral cause has not been established.

Genetics

Familial disease occurs in a minority of patients.

The best-known gene association is:

SQSTM1

which may produce autosomal dominant familial Paget disease with variable penetrance.

Other genes affecting osteoclast biology have also been identified.

Pathophysiology

Paget disease usually progresses through phases:

Osteolytic Phase

Excessive osteoclastic bone resorption.

Mixed Phase

Simultaneous increased:

• Osteoclastic resorption
• Osteoblastic bone formation

Sclerotic / Burned-Out Phase

Predominantly disorganized bone formation.

The resulting bone has:

• Abnormal architecture
• Increased vascularity
• Reduced mechanical strength

Histopathology

The classic pathologic finding is:

Mosaic pattern of lamellar bone

with irregular cement lines.

There may also be:

• Marrow fibrosis
• Increased local blood flow
• Increased osteoblastic and osteoclastic activity

Commonly Affected Bones

Paget disease commonly affects:

• Pelvis
• Spine
• Femur
• Skull
• Tibia

Less commonly:

• Humerus
• Clavicle

Disease may be:

• Monostotic
• Polyostotic

Skull Involvement

Pagetic skull disease may cause:

• Enlarged head
• Frontal bossing
• Headache
• Hearing loss
• Cranial neuropathies
• Rare optic nerve compression

Skull involvement is particularly relevant to ophthalmology.

Hearing Loss

Hearing impairment is one of the classic complications of skull Paget disease.

Mechanisms may include:

• Abnormal temporal bone remodeling
• Ossicular dysfunction
• Cochlear or neural involvement

Ocular Manifestations

The major ocular associations include:

• Angioid streaks
• CNV
• Subretinal hemorrhage
• Optic neuropathy
• Rare orbital sarcoma

Angioid Streaks

Angioid streaks are:

Crack-like breaks in an abnormal, calcified, or brittle Bruch membrane

They appear as:

• Irregular
• Reddish-brown to gray
• Radiating lines extending from the optic disc

They are usually:

• Bilateral
• Asymmetric

Pathophysiology of Angioid Streaks

In Paget disease, systemic abnormalities in connective tissue and mineralization can produce:

Thickening and fragility of Bruch membrane

Breaks then develop in Bruch membrane and may extend outward from the optic nerve.

Other Associations of Angioid Streaks

Important associations include:

• Pseudoxanthoma elasticum
• Paget disease
• Sickle cell disease and other hemoglobinopathies
• Occasionally other connective tissue disorders
• Idiopathic cases

The classic mnemonic PEPSI is historically used, but pseudoxanthoma elasticum is the strongest systemic association.

Fundus Appearance

Angioid streaks may appear:

• Dark red
• Brown
• Gray

and radiate outward from the optic nerve.

Associated findings may include:

• RPE mottling
• RPE atrophy
• Focal pigment clumping

Peau d’Orange

Peau d’orange refers to a mottled orange-peel appearance of the temporal or midperipheral fundus.

It is more classically associated with:

Pseudoxanthoma elasticum

and may coexist with angioid streaks.

It is not specific for Paget disease.

Choroidal Neovascularization

The most important vision-threatening complication of angioid streaks is:

Choroidal neovascularization

CNV can develop through breaks in Bruch membrane.

Symptoms include:

• Metamorphopsia
• Central blur
• Central scotoma
• Sudden visual loss

Subretinal Hemorrhage

Because Bruch membrane is fragile, even relatively minor ocular trauma may cause:

• Choroidal rupture
• Subretinal hemorrhage

Patients with angioid streaks should therefore avoid significant ocular trauma.

Compressive Optic Neuropathy

Severe skull involvement may rarely cause:

• Optic canal narrowing
• Optic nerve compression

Clinical findings may include:

• Decreased visual acuity
• Dyschromatopsia
• RAPD
• Visual field loss
• Optic atrophy

This is an uncommon but important neuro-ophthalmic complication.

Orbital Sarcoma

Pagetic bone has an increased risk of malignant transformation.

Rare orbital or craniofacial tumors may include:

• Osteosarcoma
• Other sarcomas

Warning features include:

• New severe bone pain
• Rapidly enlarging mass
• New proptosis
• Cranial neuropathy
• Sudden worsening of previously stable symptoms

Associated Systemic Conditions

Complications of extensive disease may include:

• Secondary osteoarthritis
• Pathologic fractures
• Spinal stenosis
• Nerve compression
• Hearing loss
• High-output cardiac failure in very extensive active disease
• Rare osteosarcoma

History

Many patients are asymptomatic and are diagnosed after:

• Elevated alkaline phosphatase
• Incidental abnormal radiograph

When symptomatic, ask about:

• Bone pain
• Fractures
• Hearing loss
• Headache
• Increased hat size
• Bowing of long bones
• Back pain
• Weakness or numbness

Ophthalmic History

Ask about:

• Decreased central vision
• Metamorphopsia
• Scotoma
• Sudden visual decline
• Previous subretinal hemorrhage
• Ocular trauma

These symptoms raise concern for:

CNV or choroidal rupture

Physical Examination

Systemic findings may include:

• Enlarged skull
• Frontal bossing
• Tibial bowing
• Skeletal deformity
• Warmth over active pagetic bone

Neurologic examination should assess for:

• Hearing impairment
• Cranial neuropathies
• Spinal cord or nerve-root compromise

Ophthalmic Examination

Evaluate:

• Visual acuity
• Pupils
• Color vision
• Amsler grid
• Dilated fundus
• Macula
• Optic nerve

Look for:

• Angioid streaks
• RPE changes
• Subretinal hemorrhage
• CNV
• Optic atrophy

Laboratory Testing

The most useful laboratory marker is:

Serum total alkaline phosphatase (ALP)

It is usually elevated when disease is metabolically active and sufficiently extensive.

Alkaline Phosphatase

ALP is useful for:

• Diagnosis
• Assessing disease activity
• Monitoring response to treatment

However, ALP may be normal in:

• Limited monostotic disease
• Inactive disease

If liver disease may confound interpretation, bone-specific ALP can be helpful.

Calcium and Phosphate

Serum:

• Calcium
• Phosphate

are usually normal.

Hypercalcemia should prompt consideration of:

• Prolonged immobilization
• Hyperparathyroidism
• Another metabolic disorder

rather than being attributed automatically to Paget disease.

Vitamin D

Before bisphosphonate therapy, assess and correct:

• Vitamin D deficiency
• Hypocalcemia

because antiresorptive therapy may precipitate or worsen hypocalcemia.

Renal Function

Check renal function before IV bisphosphonate therapy.

Significant renal impairment may limit use of:

Zoledronic acid

Imaging

Plain Radiography

Typical radiographic findings include:

• Cortical thickening
• Bone enlargement
• Coarse trabeculation
• Mixed lytic and sclerotic change

In the skull, a classic late appearance is:

“Cotton wool” skull

Bone Scan

Radionuclide bone scintigraphy is highly sensitive for determining:

• Extent of skeletal involvement
• Distribution of active disease

Pagetic lesions show:

Increased tracer uptake

CT and MRI

CT or MRI is useful when evaluating:

• Neurologic compression
• Optic canal involvement
• Suspected sarcoma
• Spinal stenosis
• Skull-base disease

They are not routinely needed for uncomplicated disease.

Ophthalmic Imaging

Optical Coherence Tomography

OCT is essential when CNV is suspected.

It can demonstrate:

• Subretinal fluid
• Intraretinal fluid
• Pigment epithelial detachment
• Subretinal hyperreflective material

Fluorescein Angiography

FA may help demonstrate:

• CNV leakage
• Lesion extent

It is less routinely required when OCT clearly establishes active CNV.

OCT Angiography

OCTA may demonstrate:

• Neovascular vascular networks

without dye injection.

It may assist with:

• Diagnosis
• Follow-up

but structural OCT remains essential for activity assessment.

Differential Diagnosis

Important systemic differentials include:

• Osteomalacia
• Hyperparathyroidism
• Vitamin D deficiency
• Bone metastasis
• Multiple myeloma
• Fibrous dysplasia
• Osteosarcoma

Differential Diagnosis of Angioid Streaks

Consider:

• Pseudoxanthoma elasticum
• Sickle cell disease
• Other hemoglobinopathies
• Idiopathic angioid streaks
• Choroidal rupture

Treatment Principles

Treatment of Paget disease is aimed at:

• Suppressing excessive bone turnover
• Relieving bone pain
• Preventing or treating complications

Not every asymptomatic patient requires treatment.

Bisphosphonates

Bisphosphonates are the main treatment.

They inhibit:

Osteoclast-mediated bone resorption

Zoledronic Acid

For most patients requiring treatment, the preferred regimen is:

Zoledronic acid 5 mg IV as a single infusion

It usually produces:

• Rapid biochemical remission
• Prolonged suppression of disease activity
• Durable symptom control

It is generally more effective than older oral regimens.

Indications for Treatment

Treatment is generally considered for:

• Symptomatic active disease
• Significant bone pain attributable to Paget disease
• Neurologic complications
• Active disease at sites where progression could cause complications
• Hypercalcemia related to immobilization in active disease
• Before selected orthopedic procedures involving highly active pagetic bone

Treatment decisions should be individualized.

Oral Bisphosphonates

Alternatives when IV zoledronic acid is unsuitable include:

• Risedronate
• Alendronate

They are effective but generally produce less durable remission than zoledronic acid.

Calcitonin

Calcitonin is now:

Rarely used

It may be considered when bisphosphonates are contraindicated or not tolerated.

Bisphosphonate Adverse Effects

Potential adverse effects include:

• Acute flu-like reaction after IV infusion
• Hypocalcemia
• Renal toxicity
• Musculoskeletal pain
• Esophagitis with oral agents
• Rare osteonecrosis of the jaw
• Rare atypical femoral fracture with prolonged exposure

Ocular inflammatory reactions such as:

• Uveitis
• Episcleritis
• Scleritis

are uncommon but recognized.

Oral Bisphosphonate Administration

Oral agents should usually be taken:

• First thing in the morning
• With plain water
• On an empty stomach

Patients should remain upright and avoid food or other medication for the recommended interval.

This reduces:

• Esophageal irritation
• Impaired absorption

Calcium and Vitamin D

Adequate:

• Calcium
• Vitamin D

should be ensured before and after bisphosphonate therapy unless contraindicated.

Treatment of Angioid Streaks

There is:

No treatment for angioid streaks themselves

Management focuses on preventing and treating complications.

Treatment of CNV

The modern first-line treatment for CNV associated with angioid streaks is:

Intravitreal anti-VEGF therapy

Examples include:

• Bevacizumab
• Ranibizumab
• Aflibercept
• Faricimab in selected settings

Treatment is guided by:

• OCT activity
• Visual response
• Recurrent fluid or hemorrhage

Historical CNV Treatments

Older therapies such as:

• Thermal laser photocoagulation
• Photodynamic therapy

have largely been replaced by anti-VEGF because they generally provide inferior visual outcomes or have more limited indications.

Amsler Grid Monitoring

Patients with angioid streaks can use an:

Amsler grid

to detect:

• New metamorphopsia
• New central scotoma

Any new distortion should prompt urgent retinal evaluation.

Protective Eyewear

Because Bruch membrane is fragile, recommend:

Protective eyewear for activities with risk of ocular trauma

This may reduce the risk of traumatic:

• Choroidal rupture
• Subretinal hemorrhage

Optic Neuropathy Management

If visual loss is suspected to result from optic canal compression:

• Obtain orbital/skull imaging
• Coordinate with neurology/neurosurgery/endocrinology or metabolic bone specialists as appropriate
• Treat active Paget disease

Decompressive surgery is reserved for carefully selected cases.

Orthopedic Surgery

Surgery may be required for:

• Severe osteoarthritis
• Fracture
• Major deformity
• Spinal stenosis

Historically, pretreatment of active Paget disease with bisphosphonate was used to reduce surgical blood loss, but evidence for routine preoperative treatment solely for this purpose is limited.

Referral

Consider referral to:

• Endocrinology or metabolic bone specialist
• Ophthalmology/retina
• Neuro-ophthalmology
• Orthopedics
• Neurosurgery

depending on complications.

Follow-Up

Monitor according to:

• Symptoms
• Disease activity
• Treatment response

Serum ALP is commonly rechecked after therapy to document biochemical response.

Once remission is achieved, monitoring intervals can be lengthened.

Ophthalmic Follow-Up

Patients with angioid streaks should undergo periodic:

• Dilated retinal examination
• OCT when symptoms or macular changes arise

Closer follow-up is required after:

• CNV
• Subretinal hemorrhage
• Anti-VEGF therapy

Prognosis

Most patients with Paget disease have:

Good overall prognosis

when complications are recognized and treated.

Visual prognosis depends primarily on:

• Development of CNV
• Macular scarring
• Subretinal hemorrhage
• Optic nerve compression

Malignant Transformation

Malignant transformation is:

Rare

but most commonly results in:

• Osteosarcoma

It should be suspected with:

• New severe pain
• Rapidly enlarging mass
• Cortical destruction
• Soft tissue extension

Complications

Systemic complications include:

• Bone pain
• Skeletal deformity
• Fracture
• Secondary osteoarthritis
• Hearing loss
• Spinal stenosis
• Nerve compression
• Rare hypercalcemia
• Rare high-output heart failure
• Rare osteosarcoma

Ocular complications include:

• CNV
• Subretinal hemorrhage
• Macular scar
• Optic neuropathy
• Permanent visual loss

Ophthalmology Pearls

• Paget disease is a disorder of excessive, disorganized bone remodeling in older adults.
• The characteristic laboratory abnormality is elevated serum alkaline phosphatase with usually normal calcium and phosphate.
• The classic histologic appearance is mosaic lamellar bone.
• Skull involvement can cause hearing loss and, rarely, compressive optic neuropathy.
• The most important ocular association is angioid streaks, representing breaks in abnormal Bruch membrane.
• Angioid streaks are usually bilateral, irregular, reddish-brown lines radiating from the optic disc.
• The major vision-threatening complication is choroidal neovascularization.
• New metamorphopsia or central blur in a patient with angioid streaks should prompt urgent OCT for CNV.
• Intravitreal anti-VEGF is the modern first-line treatment for CNV associated with angioid streaks.
• Laser and photodynamic therapy are largely historical or highly selective treatments for angioid-streak CNV.
• Patients with angioid streaks should use protective eyewear because relatively minor trauma may cause choroidal rupture and hemorrhage.
• Zoledronic acid 5 mg IV once is generally the preferred systemic treatment when active Paget disease requires therapy.
• Osteosarcoma transformation is rare but should be suspected with new severe bone pain or a rapidly enlarging mass.