1. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Paget’s sjúkdómur í beini

2. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Portrait of Sir James Paget Osteitis deformans was first described in 1876 at the Medical Chirurgical Society meeting in England by Sir James Paget, a well-known English surgeon. Now known as Paget's disease, the term osteitis deformans had arisen from the concept that the disease was an inflammation of bone resulting in deformities. Paget's disease of bone should not be confused with Paget's disease of the breast or vulva, which are types of malignant disease that also bear the discoverer's name. The focus of this slide collection is Paget's disease of bone.

3. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Paget's First Patient This drawing of Paget's first patient, published in his original paper, demonstrates the characteristic appearance that may occur with severe disease. In his original description, Paget wrote "The disease begins in middle age or later (and) affects most frequently the long bones of the lower extremities and the skull...The bones enlarge and soften, and those bearing weight yield and become unnaturally curved and misshapen." At the bottom of the slide, a marked increase in hat size is apparent. The patient also appears to be in pain.

4. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Epidemiology The prevalence of Paget's disease is substantial in certain areas of the world, while it is rare in others. The diagnosis is usually made after the age of 50. The numbers of male and female patients are nearly equal, and family history may be positive for Paget's disease in up to 40% of patients. In some families Paget's disease is linked to a locus on chromosome 18.

5. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Bone Showing Active Lesion of Paget's Disease The histologic aspects of Paget's disease are characterized by an alteration in osteoclastic activity, which results in an accelerated rate of bone resorption, and increased osteoblastic activity. In this slide, a hematoxylin and eosin-decalcified stained section shows an active lesion of Paget's disease with large, multinucleated osteoblasts. One osteoclast has at least 50 nuclei. Multinucleation is striking and typical of Paget's disease. Also, numerous osteoblasts are repairing bone previously resorbed by the osteoclasts. The marrow is grossly abnormal with an intensely fibrovascular appearance that is typical of active disease.

6. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Composite Sections of Normal and Pagetic Bone These polarized views show normal compact bone (left) and pagetic bone (right). The normal bone has a highly organized lamellar structure. Paget's disease demonstrates a chaotic picture of lamellar and woven bone with disorganized structure, the so-called "mosaic" pattern.

7. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Section of Osteoclast Nucleus Containing Measleslike Nucleocapsid Paget's disease progresses slowly; considerable evidence indicates that a slow viral infection of bone may be involved. This electron micrograph shows the nucleus of an osteoclast. The central structure resembles an array of nucleocapsids of measles virus or other paramyxoviruses. This is a characteristic lesion often found in the nuclei and sometimes in the cytoplasm of patients with Paget's disease. Immunostaining has demonstrated the nucleocapsid antigens of measles virus and respiratory syncytial virus in most patients with Paget's disease. Measles virus and canine distemper virus mRNA have been found in some but not all studies.

8. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Radiograph of a Skull Demonstrates Osteoporosis Circumscripta This lateral x-ray film of the skull shows a large circumscribed area of bone loss which has been termed osteoporosis circumscripta, a common manifestation of Paget's disease. This film demonstrates an early lesion of Paget's disease.

9. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Radiograph of a Femur A localized wedge-shaped osteolytic lesion is often the initial radiographic feature of Paget's disease. More commonly, osteolytic foci and sclerotic foci are observed in the same bone. The appearance of an osteolytic wedge advancing up or down the bone is typical of the osteolytic phase of Paget's disease in a long bone. In this x-ray film, a distal osteolytic lesion has progressed proximally from the region of the knee. The contrast between the resorbed bone (lower portion) and the radiodense, healthy bone (upper portion) is notable.

10. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Radiograph of a Tibia Demonstrate Severe Osteolytic Activity An area of severe osteolytic activity, which is associated with a small degree of bony expansion, is visible in the distal region of the tibia.

11. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Radiograph of a Skull Shows Late-Stage Disease The intermediate phase of Paget's disease is characterized by an alteration in osteoclastic activity, that results in an accelerated rate of bone resorption followed by greatly increased osteoblastic activity. As the disease advances, the cortices become coarsely trabeculated and thickened, and the bone broadens and bows. In the late, "sclerotic" phase of Paget's disease, seen here in the skull, bone resorption continues, but overgrowth of bone predominates. The late stage is characterized by a tremendous thickening of the cranial vault with chaotic bone structure. Areas of lytic activity can be noted toward the posterior aspect of the skull. In weight-bearing long bones, this process usually results in structurally weakened bone that has an increased tendency to deform or fracture.

12. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com A Bone Scan Showing Widespread Disease Any bone can be affected in Paget's disease; however, most frequently the spine, skull, pelvis, and weight-bearing bones of the lower extremities are involved. Some patients have only one affected bone, and others may have two, three, or more affected bones. This bone scan of a patient with extensive Paget's disease demonstrates increased activity in the skull, right humerus, pelvis, right and left femurs, right and left tibiae, and thoracic and lumbar spine.

13. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Biochemical Findings in Paget's Disease The biochemical findings in Paget's disease reflect the increased rates of bone resorption and bone formation. Urinary hydroxyproline, and, more recently, urinary collagen cross- link excretion correlate with the extent of skeletal involvement and disease activity. Fasting urinary calcium/creatinine may be increased when bone resorption significantly exceeds bone formation. Either total or bone-specific alkaline phosphatase reflects the overall rate of bone formation. Serum osteocalcin is a less sensitive index of disease activity.

14. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Metabolic Complicatons of Paget's Disease Bone biopsies and biochemical measurements indicate increased cellular and metabolic activity in active Paget's disease. When bone resorption exceeds bone formation, hypercalciuria and/or hypercalcemia may develop. The latter is rare and when it occurs, it is usually in an immobilized patient. In some but not all studies an increased incidence of primary hyperparathyroidism has been reported. Some studies have associated the gouty diathesis, which can include hyperuricosuria, uric acid stones, and even full-blown gout with Paget's disease. This could be related to increased purine metabolism in bone cells.

15. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Musculoskeletal Complications of Paget's Disease The most common complications of the structural weakness of pagetic bone are pain, deformity, and pathologic fractures. Degenerative arthritis of the hip, knee, ankle, and other joints is also common in Paget's disease and may be confused with direct skeletal pain.

16. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Musculoskeletal Complications: Pelvic Involvement and Degenerative Arthritis This radiograph of the pelvis demonstrates protrusio acetabali of the left hip with severe loss of joint space. Paget's disease is seen only in the left hemipelvis.

17. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Musculoskeletal Complications: Lower Extremities The lower extremities of this patient with Paget's disease demonstrate the frequent asymmetry of the disease. Severe bowing of the right tibia in this patient resulted in knee pain and ankle pain. The left tibia also appears to be somewhat bowed, but x- ray films did not reveal Paget's disease.

18. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Musculoskeletal Complications: Fissure Fracture Fissure fractures are linear opacities found in the cortex of lower-extremity bones and may evolve into complete fractures. Also called stress or insufficiency fractures, they occur more frequently than complete transverse fractures. They usually occur on the tension, or convex, side of a bowed, weight-bearing long bone, as seen in this radiograph of this patient with Paget's disease. Fissure fractures can be single or multiple.

19. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Neurologic Complications of Paget's Disease When pagetic bone is adjacent to neural structures, expanded bone size may produce neurologic sequelae. It is possible that dysfunction may also occur from a vascular steal syndrome. The pathogenesis of angioid streaks is unresolved.

20. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Neoplastic Complications of Paget's Disease Related Osteogenic Sarcoma High-risk sites for malignant transformation include the extremities and pelvis. This radiograph demonstrates lesions of osteogenic sarcoma that are scattered throughout the pelvis. Sarcomatous transformation should be suspected when there is a sudden onset of pain, rapid worsening of previous pain, increased deformity, or a rapid increase in the serum alkaline phosphatase level.

21. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Indications for Treatment of Paget's Disease The primary objectives of treatment for Paget's disease should be to relieve current symptoms, prevent progression of the disease and thereby help avoid complications.

22. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Approved Therapies for Paget's Disease of Bone in U.S. Six prescription drugs are currently approved and available for treating Paget's disease in the U.S. There is one brand of parenteral salmon calcitonin. A nasal spray form of salmon calcitonin is approved for osteoporosis but not Paget's disease. Human calcitonin is no longer available. Five bisphosphonates are now approved. Four are oral (etidronate, alendronate, tiludronate, and risedronate) and one is intravenous (pamidronate). Because the frequency of associated secondary osteoarthritis, nonsteroidal anti-inflammatory agents are often added to the specific therapies to help control pain.

23. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Pamidronate Disodium (Aredia®) Though the approved regimen is 30 mg intravenous infusion over 4 hours on 3 consecutive days, a more commonly used regimen is 60 mg or 90 mg intravenous infusions over 2-4 hours. A single infusion is effective in mild disease, 2-3 or more infusions may be required in more severe disease. A course of pamidronate may be readministered at intervals as needed.

24. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Alendronate Sodium (Fosamax®) Alendronate must be taken with 6-8 oz of tap water at least 30 minutes before breakfast daily for 6 months. Alendronate treatment has been shown to produce biochemical remission in approximately 2/3 of treated patients. Care must be taken to avoid esophageal irritation by drinking a large glass of water with the tablet and by remaining upright for at least 30 minutes after taking the medication.

25. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Risedronate Sodium (Actonel™) Risedronate must be taken with 6-8 oz of tap water at least 30 minutes before breakfast daily for 2 months. Patients should remain upright for at least 30 minutes. Risedronate has been shown to be effective in producing biochemical remission in approximately 75% of patients.

26. Prófessor Gunnar Sigurðsson September 2003 www.efnaskipti.com Patient Follow-Up Follow-up for patients with Paget's disease should include monitoring serum alkaline phosphatase (SAP) annually in untreated patients with mild cases. In treated patients, SAP is usually monitored every 3-4 months. Alternatively, urinary collagen cross-link measurements can be used. Annual x-ray studies should be done when osteolytic disease is present, to determine if treatment has caused healing of the pagetic lesions, or if there is significant progression of the lesions.