Definition

A disorder of bone architecture resulting from a disturbance in the rate of bone turnover, characterized by an osteolytic then an osteoblastic or sclerotic phase.

History (Posen 1992)

There is a possibility that the agents responsible for Paget’s disease didn’t become widely distributed until the industrial revolution.

Sir James Paget published his paper on “osteitis deformans” in 1877.

Epidemiology (Posen 1992)

Overall rate is 3-4% of middle-aged patients and 10-15% of elderly patients in Northern Europe.

1. Geographic variations
   -There is a wide geographic variation between countries and even cities, e.g. foci of Paget’s in Lancashire and in Malta
   -It is virtually non-existent in Japan
2. Sex distribution
   -More common in men than in women in younger people
3. Temporal clusters
4. Familial clustering – may be autosomal dominant inheritance.  The relative risk in 1^st degree relatives is 1 in 7.

Aetiology

Paget thought the condition was inflammatory

Now thought to be caused by a slow virus
-Virus like particles are found in osteoclasts
-May be of measles (paramyxovirus) or adenovirus-type
-Has never been grown

Increased levels of IL-6 are found in Paget focuses

A candidate gene on chromosome 18q has been isolated.

There is an association between Paget’s disease and primary hyperparathyroidism.

Histology

Cortex    -thickened. 

Corticomedullary demarcation lost

Trabeculae:  both thick and thin.  Mosaic pattern.

Osteoclasts:  increased in number and size.  Nuclei are numerous and remarkably large

Osteoblasts:  also increased in activity

Hypervascular

Significant peritrabecular fibrosis (also seen in other hypermetabolic conditions such as hyperparathyroidism)

Clinical manifestations

Usually asymmetrical.  Most commonly involves the spine, femur, skull, pelvis and sternum.

10-20% at least are asymptomatic, and are diagnosed from XR taken post trauma.

Can also be diagnosed from a battery of blood tests showing an elevated alkaline phosphatase.

In symptomatic Paget’s disease, the most common presentations are:

1. Bone pain – due to periosteal stretching
2. Skeletal deformity
3. Changes in skin temperature
4. Pathologic fracture – approx 10%
5. Symptoms related to nerve compression

Other presentations include

1. High output congestive cardiac failure
2. Osteosarcoma

Patients with Pagets have an increased incidence of DISH (diffuse idiopathic skeletal hyperostosis) (14-30%), gout and pseudogout.

Back pain

Usually patients are quite young (35-40)

Significant back pain

Increased alkaline  phosphatase

Hot on bone scan

XR show increased density but may not show expansion

WHENEVER PATIENTS HAVE INCREASED DENSITY IN A VERTEBRAL BODY THE DIFFERENTIAL DIAGNOSIS SHOULD INCLUDE PAGET’S DISEASE

Other differential diagnoses to consider include:

1. Prostate cancer 
2. Breast cancer
3. Hodgkin’s disease
4. Haemangioma (on X-ray findings)

Thickening of the vertebral body and neural arch can lead to spinal stenosis.

Bone pain

Typically in the femur, tibia, pelvis or lower spine.  Occurs in active disease, due to periosteal stretching.

Can be due to exacerbation of osteoarthritis.

Often due to impending fracture.

This fracture usually begins as a transverse line on the convexity or tension side of the bone and progresses across the cement lines.  The transverse radiolucent line is described as a pseudofracture.

Patients with pseudofracture are usually managed with protected weight bearing and immobilization in a cast until there is relief of pain.  Prophylactic nailing is made problematic by the associated deformity.

“Fracture healing can be impaired, resulting in delayed union and nonunion” (Dee 1997).

Bone tumour Associations

Giant cell tumors are most common benign tumors.  They respond very well to corticosteroids.

Osteosarcomas are most common malignant tumor: they occur perhaps in .1% of total patient group and are rapidly progressive and incurable.  The teleangiectatic variety is common.

Radiology

1. Overall bone size is enlarged.
2. Cortex is thickened.
3. Trabecular pattern is coarsened and irregular.
4. Mixed lytic and blastic pattern
5. Early in the course of the disease a flame shaped osteolytic wedge may be seen advancing along the bone (this usually progresses at around 1cm/year in untreated patients); in the skull there can be a striking radiolucency resulting in a large circular lytic defect called osteoporosis circumscripta.
6. In the vertebral bodies there can be a generalized increase in density but more commonly there is a “picture frame” appearance.  Paget’s involvement leads to an increase in the size of the vertebra, which helps to distinguish from tumour.
7. In long bones the disease usually starts at one end of the bone and advances towards the other.  That is, it starts in an epiphysis and progresses towards the diaphysis
8. Bowing deformity.
9. Fracture and pseudofracture.  One buzz word for the fractures in Paget’s is “chalk stick”.
10. Secondary arthritic changes may occur.
11. Pelvic XR: thickening of the iliopectineal line (brim sign); SIJ (sacroiliac joint) often fused (DDx is seronegative arthropathy).
12. Protrusio

Nuclear medicine

Should be done at time of diagnosis to define involved bones.

Can be used to distinguish between areas of tumor and Paget’s.

Gallium scans are hot with tumors but not with Paget’s.

Doesn’t pick up burned out sclerotic lesions.

Lab studies

Alkaline phosphatase is elevated – up to 20-30 times normal.

1. Located in the plasma membrane of osteoblasts.
2. Reflects the number and functional state of osteoblasts; that is the level of bone formation.
3. Correlates roughly with the extent of skeletal involvement.
4. Serial determinations provide biochemical index of disease activity.  The serum alkaline phosphatase should be measured annually.

Acid phosphatase is at upper level of normal or mildly elevated

Serum calcium and phosphate are normal

LFTs should be done concurrently; if they are elevated then the bony isoenzyme can be isolated

Urinary hydroxyproline (which is a reflection of osteoclastic bone and collagen resorption) is not done routinely; it requires a meat-free diet and a 24-hour urine collection. Pyridinoline cross links can also be measured in the urine. N-telopeptides are another urinary measure of bone resorption.  Crosslaps can be measured in the serum and provide a measure of bone resorption.

Treatment

Asymptomatic patients with near normal body chemistry whose weight bearing bones are not involved don’t need treatment.

Should stage the disease with a full body bone scan and XR of affected regions.

Medical treatment

Indications for treatment

1. Pain or other symptoms
2. Asymptomatic patients with lesions which may go on to cause symptoms e.g. arthritis
3. Note that immobilization of Paget’s patients may lead to hypercalcaemia and hypercalciuria with kidney stones.

Calcitonin

1. With the availability of bisphosphonates calcitonin is becoming obsolete.
2. Binds to adenylate cyclase and turns off osteoclasts
3. Dosage: 50-100U intranasally daily then three times weekly
4. Causes fall in serum calcium and decreased resorption of bone
5. Urinary hydroxyproline decreases in a matter of days
6. Long term benefits
   -Relief of bone pain – occurs in a couple of weeks
   -Reduction in cardiac output
   -May reverse neurological deficits
   -Healing of osteolytic lesions
   -Reduction of bleeding associated with surgery
7. Side effects
   -Nausea and flushing (up to 30%)
   -Diarrhoea
   -Pain at injection site
   -Resistance can develop (up to 20% in patients treated with salmon calcitonin)
8. Treatment needs to be continued long term

Bisphosphonates

1. Potent inhibitors of bone resorption
2. Bind to hydroxyapatite crystals – poisons osteoclasts; induces apoptosis and decreases their recruitment
3. New bone formed during treatment is lamellar
4. Agent of choice is alendronate (Fosamax) which can be given orally, doesn’t cause osteomalacia and is more effective than etidronate or calcitonin

The dose is 40mg daily for six months.  Compare with dose for osteoporosis (10mg/day).  The main side effect of Fosamax is oesophagitis, and the patient should remain upright for 30mins after taking the tablet.

Pamidronate (Aredia) is given intravenously as oral dosage causes severe oesophagitis.  IV pamidronate may cause iridocyclitis or a flu like illness.  Most patients receive 60mg over four hours every 8-12 months.

The goal of treatment is to achieve a mid-range normal level of SAP.  Treatment is restarted when the SAP climbs to 25% higher than this.

Orthopaedic surgical procedures

Fractures

1. High complication rate 
2. Delayed union or non-union is seen more frequently in the sclerotic phase of the disease.   The nonunion rate after fractures ranges from 15-40% (OCNA Merkow 1990).  Chapman’s says that there are high rates of nonunion in neck of femur fractures, but with these exceptions  fractures heal in Paget’s with abundant callus.
3. Stress or pseudofractures occur most commonly in the tibia or femur and should be treated by protected weight bearing.  If pain persists for more than 3-6 months prophylactic surgical treatment is warranted.
4. Completed fractures are usually transverse or short oblique – chalk stick
5. Femoral neck fractures are a problem and frequently don’t heal, with a nonunion rate of 75-90%.
6. Intertrochanteric fractures will usually unite.
7. Corrective osteotomies are frequently required.

Elective orthopaedics

Hip replacement

1. 25% rate of protrusio 
2. Femoral neck is frequently in varus
3. Anterolateral bowing of the femur (usually not a major problem because the femoral canal is widened).
4. Cement should be used (unless needing corrective osteotomies)
5. Rate of loosening is increased (10-15% at 10 years)
6. Increased blood loss – should pre treat with bisphosphonates
7. Difficulty in reaming sclerotic bone
8. Heterotopic ossification – up to 50%. – may need prophylaxis.