PAGET'S DISEASE AND SPINE

*the second most common metabolic bone disturbance in the United States, after osteoporosis

*prevalence of approximately 1 in 1,000 persons

*the vertebrae, pelvic bones, and femora are the most common

*pathologic lesion is characterized by an excess of hyperactive osteoclasts and osteoblasts, with an intense increase in bone resorption, marrow replacement by hypervascular fibrous tissue, and a haphazard attempt by the body to regenerate bone .

*new bone synthesized to replace the bone that has been lost appears as a disorganized, woven bone tissue and is of poor quality .

*increased cellular activity and turnover of bone matrix in Paget's disease is evidenced by increased urinary output of collagen breakdown by-products

*Presentations:
1.subclinical case is discovered when a patient has a radiograph taken or a serum alkaline phosphatase level measured for an unrelated reason
2.an obvious bony deformity, pain, and extraskeletal involvement
3.high--output heart failure may result from an arteriovenous fistula that develops in the hypervascular pagetic bone
4.Back pain has been reported to occur in 11 to 43% of patients who have Paget's disease involving the spine .central or lateral stenosis, nonspecific syndrome of stiffness, ache and fatigue due to arthritic changes in the facet joints, Pathologic fractures , the most common sites are the fourth and fifth lumbar vertebrae . When these vertebrae are severely affected, spinal stenosis is a common finding.

*arterial steal phenomenon, whereby hypervascular pagetic bone “steals” blood from the neural tissue, is also a possible etiology for the observed symptoms

*direct compression of the vascular supply of the neural tissue

*Malignant degeneration occurs in 1 to 10% of patients with Paget's disease and is the most serious complication of this disorder.The most frequently occurring malignant tumors in pagetic bone are osteogenic sarcoma, followed by fibrosarcoma. Other less common tumors include chondrosarcoma, malignant fibrous histiocytoma, and reticulum-cell sarcoma. The most common site for pagetic tumor involvement is the femur, followed by the humerus, pelvis, and tibia.

*The DIAGNOSIS of Paget's disease is based on history, physical examination, radiographic evaluation, and measurement of biochemical markers.

*Because urinary measurement of hydroxy-proline or hydroxylysine is expensive and cumbersome, however, the measurement of alkaline phosphatase has become the preferred laboratory test.

*There is an elevated urinary excretion of hydroxyproline and hydroxylysine; both are degradation products of bone's organic matrix. Patients with Paget's disease can excrete up to 20 times more hydroxyproline than normal persons .

*A urinary assay has been developed that measures the pyridinium derivatives hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), which are intermolecular cross-links of collagen collectively known as pyridinoline cross-links .

*Using a specific HP and LP assay, Uebelhart et al. showed that the urine of patients with active Paget's disease had a 12-fold increase in pyridinolines .

*HP and LP decrease significantly after treatment with aminopropylidene bisphosphonate, a potent inhibitor of bone resorption, which indicates that urinary excretion of HP and LP reflects only collagen degradation occurring during osteoclastic resorption and not the degradation of newly synthesized collagen.

*Bone biopsy is rarely needed for diagnosis , opnly when malignant degeneration is suspected.

Treatment:-

basis: suppression of osteoclastic activity.

approved agents: salmon and human calcitonin and several bisphosphonates. Plicamycin (previously mithramycin), although not approved by the FDA for the treatment of Paget's disease, is available by prescription.

indication for treatment and the choice of therapeutic agent continue to be debated. Currently, the most widely followed indication for initiation of treatment is a serum alkaline phosphate level that is at least three times normal.

Treatment is intended to alleviate patients' symptoms by suppressing osteoclastic activity. A decline in alkaline phosphatase or pyridinium cross-link levels of 50% or more can ameliorate symptoms in up to two-thirdsof patients. Bone pain, headache, and low back pain are most likely to be relieved. Conversely, pain due to arthritic changes and bony deformity does not improve with medical treatment.

Human and salmon calcitonins are available as subcutaneous or intramuscular injection (salmon calcitonin is also available as a nasal spray). Doses generally range from 50 U three times per week to 100 to 200 U per day in severe cases. Symptoms may begin to improve over several weeks, and biochemical markers begin to decline after 3 to 8 months. Decreasing effectiveness over time has been observed. Side effects are few and minimal, as noted previously.

Plicamycin is a potent and toxic therapeutic modality that is indicated only for severe refractory cases, such as those involving spinal cord compression. It is administered intravenously and is infused every second to third day for five to ten infusions per cycle. Its action is to inhibit osteoclastic activity, as well as reduce the hypervascularity associated with Paget's disease.

Alendronate and risedronate can be used at doses higher than those used for osteoporosis. For example, whereas a daily dose of alendronate for osteoporosis is 10 mg, for Paget's disease, a 40-mg dose is recommended. Pamidronate (Aredia) has recently been approved for the treatment of hypercalcemia of malignancy and has been used to treat refractory Paget's disease. It is administered as an intravenous infusion, and its use requires careful medical monitoring.
Other therapies, such as gallium nitrate, also have been used in experimental settings.