Paget's disease

What is Paget's Disease of Bone?

Paget's disease of bone (also known as osteitis deformans) is a chronic skeletal disorder characterized by excessive and disorganized bone remodeling. In affected areas, the normal process of bone breakdown (resorption by osteoclasts) and formation (by osteoblasts) becomes chaotic and accelerated (1, 3).

Initially, there is often a phase of increased osteoclastic activity (bone resorption), followed by a compensatory but disorganized increase in osteoblastic activity (bone formation). This results in bone that is enlarged, structurally abnormal, less compact, more vascular, and weaker than normal bone, making it prone to deformities and fractures (1, 2).

The exact cause of Paget's disease is unknown, but genetic factors (mutations in the SQSTM1 gene are found in some familial cases) and potential environmental triggers (possibly viral infections like paramyxoviruses) are thought to play a role (1, 3).

It typically affects individuals over the age of 40-50 and is more common in people of Northern European descent. Many people with Paget's disease are asymptomatic and diagnosed incidentally (1, 5).

Bone Composition and Remodeling

To understand Paget's disease, it's helpful to know about normal bone structure and the remodeling process.

Bone is a specialized connective tissue composed of cells and an extracellular matrix. The matrix has two main components:

• Organic Matrix (Osteoid): Primarily consists of Type I collagen fibers (providing tensile strength) along with non-collagenous proteins like osteocalcin and osteonectin.
• Inorganic Material: Mainly composed of calcium phosphate crystals in the form of hydroxyapatite, which provides rigidity and compressive strength. Magnesium and other minerals are also present.

Bone is constantly undergoing a process called remodeling or "bone turnover." This involves the coordinated action of bone cells:

• Osteoclasts: Cells responsible for resorbing (breaking down) old or damaged bone.
• Osteoblasts: Cells responsible for forming new bone tissue (osteoid), which then mineralizes.
• Osteocytes: Mature osteoblasts embedded within the bone matrix, thought to sense mechanical stress and regulate remodeling.

In healthy bone, resorption and formation are tightly coupled, maintaining bone mass and strength. Disruptions in this cycle lead to metabolic bone diseases. In Paget's disease, this coupling is lost, leading to chaotic and excessive remodeling (3).

Phases of Paget's Disease

Paget's disease typically progresses through three overlapping phases within the affected bone (1, 3):

1. Lytic Phase: Dominated by intense osteoclastic activity, leading to rapid bone resorption and the formation of lytic lesions (areas where bone has been destroyed).
2. Mixed Phase: Characterized by both increased osteoclastic resorption and increased, but disorganized, osteoblastic formation. The newly formed bone is woven and structurally unsound.
3. Sclerotic Phase (Blastic Phase): Osteoblastic activity predominates, leading to the formation of dense, thickened, but brittle and disorganized bone. This phase often results in bone enlargement and deformity.

Symptoms

Many individuals with Paget's disease (up to 70-80%) have no symptoms, and the condition is often discovered through routine blood tests (elevated alkaline phosphatase) or X-rays taken for other reasons (1, 5).

When symptoms do occur, they depend on the location and extent of bone involvement and may include (1, 3):

• Bone Pain: The most common symptom, often described as a deep, aching pain in the affected bone(s), which may worsen at night. Pain can also result from secondary arthritis or microfractures.
• Bone Deformities: Enlargement or bowing of bones, particularly noticeable in the skull (increased head size), clavicle, or long bones of the limbs (e.g., bowed legs).
• Fractures: Pathological fractures can occur in weakened pagetic bone, even with minor trauma. Transverse fractures, especially in the femur, are characteristic.
• Joint Pain and Arthritis: Abnormal bone structure near joints can lead to secondary osteoarthritis, causing joint pain, stiffness, and reduced mobility.
• Neurological Complications: Enlargement of skull or spinal bones can compress nerves, leading to:
  • Headaches
  • Hearing loss (due to involvement of temporal bone/ossicles or nerve compression)
  • Dizziness (vertigo)
  • Symptoms of spinal stenosis (back pain, leg pain/numbness/weakness) or radiculopathy (nerve root pain)
• Increased Warmth: The skin over affected bones may feel warm due to increased blood flow in the highly vascular pagetic bone.
• High-Output Heart Failure: In rare cases with extensive skeletal involvement (affecting >15-30% of the skeleton), the greatly increased blood flow through the bones can strain the heart.

Commonly Affected Bones

Paget's disease can affect any bone but is most commonly found in the (1, 3):

• Pelvis
• Femur (thigh bone)
• Spine (vertebrae)
• Skull
• Tibia (shin bone)
• Clavicle (collarbone)
• Humerus (upper arm bone)

It can be monostotic (affecting a single bone) or polyostotic (affecting multiple bones).

Diagnosis

Diagnosis is typically based on a combination of clinical findings, laboratory tests, and imaging studies (1, 2).

• Laboratory Tests:
  • Serum Alkaline Phosphatase (ALP): Usually significantly elevated, reflecting increased osteoblastic activity. Levels correlate with disease activity and extent. Bone-specific ALP may also be measured (1, 3).
  • Serum calcium and phosphate levels are typically normal.
  • Markers of bone resorption (e.g., urine N-telopeptide (NTX) or serum C-telopeptide (CTX)) may also be elevated.
• Imaging Studies:
  • X-rays: Often diagnostic, revealing characteristic features depending on the phase (1, 3):
    • Lytic lesions (e.g., osteoporosis circumscripta in the skull, V-shaped "blade of grass" lesion in long bones)
    • Cortical thickening
    • Bone expansion and deformity (e.g., bowing)
    • Coarsened trabecular pattern
    • Mixed lytic and sclerotic areas
    • Sclerotic changes (e.g., "cotton wool" appearance in the skull, "picture frame" vertebra)
  • Radionuclide Bone Scan (Scintigraphy): Highly sensitive for detecting active Paget's lesions, showing areas of increased tracer uptake. Useful for determining the extent of skeletal involvement (identifying all affected bones) (1, 2).
  
  Lateral skull X-ray showing characteristic features of Paget's disease: diploic thickening (widening of the space between skull tables) and patchy sclerotic areas resembling "cotton wool," particularly visible in the frontal bone.

• Bone Biopsy: Rarely needed for diagnosis, but may be performed if there is suspicion of malignant transformation (Paget's sarcoma) or to differentiate from other conditions like metastatic cancer (1).

Complications

Potential complications of Paget's disease include (1, 3):

• Pathological fractures
• Secondary osteoarthritis in joints adjacent to affected bone
• Bone deformities (e.g., bowed legs, enlarged skull)
• Nerve compression syndromes (e.g., hearing loss, spinal stenosis, radiculopathy)
• Chronic pain
• Increased risk of kidney stones (due to increased bone turnover, though serum calcium is usually normal)
• High-output heart failure (rare, with extensive disease)
• Paget's Sarcoma: A rare but serious complication where the pagetic bone undergoes malignant transformation into osteosarcoma or another sarcoma type (occurs in <1% of patients). Suspect if there is a sudden increase in pain, swelling, or a new soft tissue mass over an affected bone (1).

Treatment

Treatment is not always necessary, especially in asymptomatic patients with limited involvement and normal ALP levels. The main goals of treatment are to relieve pain, reduce bone turnover (normalize ALP if possible), prevent complications like fractures and deformities, and manage existing complications (1, 2, 5).

Indications for treatment typically include (1, 2, 5):

• Symptomatic disease (bone pain, neurological complications, arthritis related to Paget's)
• High levels of bone turnover markers (e.g., markedly elevated ALP)
• Involvement of bones at high risk for complications (e.g., weight-bearing bones like femur/tibia, vertebrae, skull base)
• Planned orthopedic surgery on a pagetic bone (to reduce bleeding and improve healing)
• Hypercalcemia due to immobilization

Treatment options include:

• Bisphosphonates: The mainstay of treatment. These drugs inhibit osteoclast activity, reducing bone resorption and subsequently bone formation, leading to lower ALP levels and pain relief (1, 2).
  • Zoledronic acid (intravenous): Often considered first-line due to high efficacy and long duration of action (a single infusion can induce remission for years) (1, 4).
  • Oral bisphosphonates (e.g., Alendronate, Risedronate, Tiludronate): Also effective but require specific dosing instructions (e.g., taking on an empty stomach) (1, 2).
• Calcitonin: Less effective than bisphosphonates and requires subcutaneous injections. Mainly used if bisphosphonates are contraindicated or not tolerated. Can provide some pain relief (1, 5).
• Supportive Care:
  • Pain management: Analgesics (e.g., NSAIDs, acetaminophen).
  • Physical therapy: To maintain mobility, strengthen muscles, and improve balance.
  • Assistive devices: Canes or walkers if needed.
  • Adequate calcium and vitamin D intake should be ensured, especially when using bisphosphonates (1, 2).
• Surgery: May be required for (1):
  • Treating fractures
  • Correcting severe deformities
  • Replacing joints severely affected by secondary arthritis (e.g., hip or knee replacement)
  • Decompressing nerves
  • Treating Paget's sarcoma (requires specialized oncologic management)

Monitoring involves tracking symptoms and serum ALP levels (1, 2).

Differential Diagnosis

It is important to differentiate Paget's disease from other conditions that can cause bone pain, elevated ALP, or similar imaging findings (1, 3):

Condition	Key Differentiating Features
Osteoarthritis	Joint pain related to cartilage wear, characteristic X-ray findings (joint space narrowing, osteophytes). ALP typically normal unless there's a coexisting condition. Bone scan uptake localized to joints.
Metastatic Bone Disease	History of primary cancer often present. Lesions are typically lytic or blastic but usually lack the cortical thickening and bone expansion seen in Paget's. Bone biopsy may be needed. Serum calcium may be elevated.
Primary Hyperparathyroidism	Elevated serum calcium and PTH levels. Bone changes ("brown tumors", subperiosteal resorption) differ from Paget's. ALP may be elevated but calcium/PTH abnormalities are key.
Osteomyelitis	Bone infection. Presents with fever, localized pain, redness, swelling. Imaging shows bone destruction, periosteal reaction, possibly sequestrum. Inflammatory markers (ESR, CRP) elevated.
Fibrous Dysplasia	Developmental anomaly where normal bone is replaced by fibrous tissue. Often presents in younger individuals. X-rays show "ground glass" appearance, thinning of cortex, possible deformity. ALP may be mildly elevated.
Osteomalacia	Defective mineralization. Often due to severe Vitamin D deficiency. Low/normal calcium, low phosphate, elevated ALP, very low Vitamin D. X-rays show Looser zones (pseudofractures). Diffuse bone pain and muscle weakness common.

References

1. Ralston SH, Corral-Gudino L, Cooper C, et al. Diagnosis and Management of Paget's Disease of Bone in Adults: A Clinical Guideline. J Bone Miner Res. 2019;34(4):579-604. doi:10.1002/jbmr.3657
2. Singer FR, Bone HG 3rd, Hosking DJ, et al. Paget's disease of bone: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(12):4408-4422. doi:10.1210/jc.2014-2910
3. Shaker JL. Paget Disease of Bone. [Updated 2023 Jun 20]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279063/
4. Reid IR, Lyles K, Su G, et al. A single infusion of zoledronic acid produces sustained remissions in Paget disease: data to 6.5 years. J Bone Miner Res. 2011;26(9):2261-2270. doi:10.1002/jbmr.438
5. Siris ES, Lyles KW, Singer FR, Meunier PJ. Medical management of Paget's disease of bone: indications for treatment and review of current therapies. J Bone Miner Res. 2006;21 Suppl 2:P91-P98. doi:10.1359/jbmr.06s216
6. The Paget's Association (UK Charity). Information Resources. Available at: https://www.paget.org.uk/