Welcome to the Paget's disease section of the Endocrine Society's fellow training series. There is speculation that Beethoven had Paget's disease of the bone. The objectives will be for you to assess who is at higher risk for Paget's disease, diagnose, and manage it. The prevalence of Paget's disease is about 3% in Western Europe, Greece, North America, and Australia. Disease onset is typically after age 55, with a slight predominance in men. Bone turnover and remodeling accelerates in Paget's, resulting in disorganized deposition of lamellar bone interspersed with woven bone. This increases bone volume and impairs integrity. Highly vascular stromal tissue replaces the marrow. This can increase bleeding during orthopedic surgery. It can also contribute to high output heart failure and hydrocephalus. People with Paget's disease often have it in their families as well. The inheritance pattern appears to be autosomal dominant with variable penetrance, like this example pedigree. These pictures show a man with Paget's. His hat is in the center picture and demonstrates an increase in skull size over time. Patients with Paget's may be asymptomatic or have symptoms from bone overgrowth and deformities. The pain of Paget's lesions is persistently achy and may get worse at night or with weight bearing. Common sites are the skull, spine, pelvis, femur, and tibia. Paget's of the temporal bone may cause hearing loss. Paget's can also arise from osteoarthritis, nerve impingement, and fractures. Paget's pseudofractures are fissures on convex surfaces of bowing bones. This contrasts with osteomalacia where fissures occur on concave surfaces. Fractures are typically transverse. You can see a pseudofracture in the picture on the left and a transverse fracture in the picture on the right. Osteosarcoma is a rare but usually fatal complication occurring in fortunately less than 1% of people with Paget's. It presents with increasing bone pain, local swelling, and fracture. Giant cell tumors may also arise in Pagetic bone and are usually benign. They respond to radiation and surgery. You can see an osteosarcoma in the picture on the right and a giant cell tumor in the picture on the left. Imaging shows osteolytic lesions early in disease. They show osteoblastic lesions and bone thickening later in disease. Radiographic workup for Paget starts with a bone scan and then plain films of affected areas, such as this picture of a man with Paget's disease of the right tibia and L1. Plain films can identify impending fractures, tumors, and osteoarthritis. If pain is refractory to medical treatment, consider CT or MRI for further evaluation. Serum alkaline phosphatase is usually elevated. Its level corresponds with disease extent and activity. GGT, bone-specific alkaline phosphatase, procollagen type 1N terminal propeptide, and C-telepeptide can help distinguish bone from liver etiologies. Other bone turnover markers that can be elevated include urinary N-telepeptide and urinary hydroxyproline. Calcium is typically normal unless there is significant immobility or primary hyperparathyroidism. Who should get pharmacotherapy for Paget's disease? Is it A, a symptomatic patient with a low alkaline phosphatase level, B, a symptomatic patient with imaging without focal lesions, C, an asymptomatic patient with Paget's lesions in the skull, or D, an asymptomatic patient with alkaline phosphatase levels just above the upper limit of normal? The best answer is C, because asymptomatic patients with lesions of the skull, spine, weight-bearing bones, or abutting joints would benefit from pharmacotherapy to promote mobility. A could be correct if it were a symptomatic patient with elevated alkaline phosphatase levels, B could be correct if it were a symptomatic patient and imaging consistent with active Paget's disease, D could be correct if it were an asymptomatic patient with alkaline phosphatase levels two times the upper limit of normal. Bisphosphonates can ease pain and slow bone turnover. They cause apoptosis of osteoclasts and promote deposition of normal lamellar bone. This can normalize alkaline phosphatase, heolytic lesions, and decrease uptake on bone scans. This chart shows dosing for different bisphosphonates for someone with Paget's. Notice that it is slightly different than what you give to someone with osteoporosis. There was a randomized, double-blinded, controlled trial comparing zilindronate 5 mg IV for a one-time dose to racindronate 30 mg daily for a two-month course. The trial duration was six months. Alkaline phosphatase normalized in 89% of patients with zilindronate, but only in 58% with racindronate. This was statistically significant. 86% of patients had a therapeutic response with zilindronate compared to 74% with racindronate. This was also statistically significant. Additionally, zilindronate showed a more rapid onset of action and superior effect on quality of life, including pain relief. Individuals with a therapeutic response in the previous READ study entered a follow-up study. The remission rate at two years was 98% with zilindronate and 57% with racindronate. The remission rate at five years was 87% with racindronate, but only 38% with racindronate, as you can see in the graph on the left. The graph on the right shows the short-form health survey, which is a measure of quality of life. Patients who received zilindronate consistently scored better on this survey than those who received racindronate. Another treatment option is calcitonin. It is available to patients with marginal renal function. Dosing in pagets is 50 to 100 units every one to three days indefinitely. It decreases bone turnover markers 50% initially, however, it may become less effective over time. Its main benefits are reducing pain, stabilizing hearing, and decreasing bone vascularity. Side effects include flushing and nausea. Pharmacotherapy can prevent or slow hearing loss and osteoarthritis. It can even reverse paralysis by correcting ischemia. It reduces bleeding during orthopedic procedures, especially if you start IV bisphosphonates one to two months prior to surgery, or start weaker bisphosphonates three to four months prior to surgery. They can decrease the chance of prosthetics from becoming loose. However, pharmacotherapy cannot reverse bone deformity or fully remove radiographic evidence of pagets lesions. Secondary consequences of pagets may benefit from hearing aids, analgesics, physical therapy, and walkers. If you do not give patients pharmacotherapy, please check them annually for signs of disease progression. If you do give pharmacotherapy, please check serum alkaline phosphatase three to six months after that. Once bone turnover markers plateau, check them every one to two years for zilindronate, or every six to 12 months for less effective drugs. For patients who have osteolytic lesions, repeat x-rays at one year to assess for improvement with therapy or worsening without it. You typically do not need to repeat bone scans unless they are the only way to assess change in patients whose bone turnover markers were normal at baseline. Consider surgery with joint arthroplasty for significant arthritis, fixation for fractures, osteotomy for deformity, spinal decompression, and resections for bone tumors. In summary, diagnose pagets disease of the bone with elevated alkaline phosphatase levels and bone scans, followed by x-rays of concerning lesions. Offer bisphosphonate therapy for bone pain, deformities, neurologic involvement, pagets lesions of weight-bearing bones, spine, skull, or near joints. A one-time dose of zilindronate is often all that many patients will need. Thank you for your attention.

Paget's disease

diagnosis

management

complications

bisphosphonates