This issue of eMedRef provides information to clinicians on the pathophysiology, diagnosis, and therapeutics of Paget's disease

Bryce, Brandon

University of Missouri: MOspace

Paget’s Disease Page 1 of 4    7.1.09 Paget's Disease (Osteitis Deformans) Background 1. Definition  o Metabolic bone disease characterized by accelerated bone resorption and formation, resulting in bone that is less organized and more susceptible to deformity and fracture 2. General info  o Unknown etiology o Viral and genetic factors have been implied  Pathophysiology  1. Pathology of disease  o Affected osteoclasts increase in both size and number causing increased rate of bone resorption o In response, osteoblasts form bone in a more rapid and less organized manner, resulting in a mosaic pattern 2. Incidence/prevalence  o 1-3% of adults >40 yo o Incidence increases with age 3. Risk factors  o Higher prevalence in western Europe (UK, Germany and France) and populations that have immigrated to Australia, North and South America, New Zealand, and South Africa 4. Morbidity/mortality  o 70% asymptomatic (most cases discovered incidentally) o Fractures are most common o Deafness o Tumors o Bone deformities  Diagnostics 1. History  o Symptomatic patients will often present with deep, aching bone pain, even at rest o Paget's in the skull can cause narrowing of foramina, resulting in hearing loss, cranial nerve palsies, and risk of brainstem compression 2. Physical examination  o Skeletal deformities   Bowing of lower extremities  Frontal bossing o Increased warmth over affected area 3. Diagnostic testing  o Labs   Elevated total serum alkaline phosphatase  Vitamin D levels to rule out deficiency    Paget’s Disease Page 2 of 4    7.1.09  Serum calcium to rule out hyperparathyroidism   Normal in Paget's  Urinary deoxypyridinoline and N-telopeptide of type I collagen are less reliable and more expensive o Imaging   Radiographs   Active sites often have an osteolytic front (classically 'blade of grass' lesion)  Long bones will show cortical thickening and sclerotic changes  Bone Scans   Most sensitive in detecting sites of active lesions, but are less specific  CT and MRI can help differentiate between malignant and Paget's bone  Biopsy is definitive  Differential Diagnosis 1. Osteosarcoma  o Tendency to be located in metaphysis of long bones o Imaging   X-ray: sunburst sign (spiculated periosteal reaction)  X-ray: periosteal formation at edge of soft tissue o Core needle Bx for definitive Dx 2. Hyperparathyroidism (Osteitis fibrosa cystica)  o PE   Proximal muscle weakness  Bone pain  Brisk stretch reflexes of muscles o Labs   Elevated serum Ca/ alkaline phosphatase  Elevated PTH (severe) o Imaging   "Salt-and-pepper" appearance of calvarium  Brown's "tumors" (collections of osteoclasts, causing lytic lesions in long bones and pelvis)  Resorption of terminal phalanges, distal clavicles 3. Osteomalacia (Vitamin D deficiency)  o Low serum 25(OH)2D or low 1,25(OH)2D levels o Hypophosphatemia o Increase in alkaline phosphatase o Pathologic fracture   Fracture associated with abnormalities as stated herein 4. Traumatic fracture  o History of trauma o Absence of serum markers o Absence of characteristics on X-ray for classic Paget's or cancer      Paget’s Disease Page 3 of 4    7.1.09 5. Osteoporosis  o Testing to r/o secondary osteoporosis   PTHrP (parathyroid hormone related protein) – associated with humoral malignancy  Elevated PTH (parathyroid hormone) – hyperparathyroid, associated with hypercalcemia  Malignancy (bone mets) – depressed PTH o Bone density scanning for classifying severity of disease  Therapeutics 1. Initiation of treatment  o Literature suggests treating the following patients (SOR:B)   Symptomatic  Asymptomatic with biochemical markers suggestive of bone remodeling (Serum Alkaline Phosphatase or SALP 125-150% above normal) o Patients with active lesions in weight bearing limbs or near major joints 2. Bisphosphonates  o Mainstay of treatment of Paget's is to normalize SALP (serum alkaline phosphatase) (SOR:A)  o Oral   Alendronate 40 mg/d for 6 months   Normalization of SALP in 63% of patients in US trial  Retreatment when normal or nadir levels rise >25%  Risedronate 30 mg/d for 2 months   Normalization of SALP in 73% in US trial  Retreatment indications same as for Alendronate  Etidronate 400 mg/d for 6 months, with at least 6 month interval before retreatment   Normalization of SALP in 15%  Tiludronate 400 mg/d for 3 months   Normalization of SALP in 35% of patients o IV   Pamidronate 30-90 mg given over 2-3 hour infusion   For mild disease, single 60-90 mg dose is commonly used  For more advanced disease, 1-2 infusions per week on nonconsecutive days of 90 mg can be given up to 180-360 mg  o Normal SALP in approximately 50% of patients o Fever, flu-like symptoms are most common adverse affects, seen after the first dose  Zoledronic acid   Currently in consideration for FDA approval  5 mg, 15 minute infusion  Normal SALP in up to 89% 6 months after treatment  Adverse effects similar to pamidronate 3. Calcitonin  o Salmon calcitonin given 100 U daily for several months   Normalization of SALP in approximately 50% of patients  Use of calcitonin has decreased due to efficacy of bisphosphonates Paget’s Disease Page 4 of 4    7.1.09 Follow up 1. Office  o Every 6-12 months in asymptomatic patients, or in treated stable patients to follow serum alkaline phosphate levels o Lifetime follow up (rare chance of osteosarcoma) o Earlier follow up with recurrence of symptoms 2. Specialist referral  o Complex or non-union fractures should be referred to orthopedics  Prognosis (SOR:B)  1. Paget's disease is a relatively benign condition with the majority of patients asymptomatic  o Exceptions are bone pain, deformity, and possible fracture in weight bearing bones 2. The majority of patients treated for elevated SALP achieve a normal level, but this has not been shown to change prognosis 3. Left untreated, osteolytic changes can extend and bone deformities are more likely  References 1. Roodman, DG and Windle, JJ. 2005. Paget disease of bone.The Journal of Clinical Investigation. 115:2. 2. Siris, ES et al. 2006. Medical Management of Paget's Disease of Bone: Indications for Treatment and Review of Current Therapies. Journal of Bone and Mineral Research. 21:2 (supplement). 3. Schneider D, Hofmann MT, Peterson JA. 2002. Diagnosis and Treatment of Paget's Disease of Bone. American Family Physician. 65:10.  4. Whyte MP. 2006. Paget's Disease of Bone. The New England Journal of Medicine. 355:6. 5. Dennis L. Kasper DL, Eugene Braunwald E, et al. Harrison's online (Harrison's Principles of Internal Medicine). 16th Edition. Ch. 334. © 2005. Accessed Dec. 1 2007. 6. DynaMed Editorial Team. Paget's Disease. Last updated Sept 25, 2007. Available from DynaMed: http://medjournal.hmc.psu.edu.3371/dynamed. Accessed Dec. 1 2007.    Author:  Brandon Bryce, MD, Penn State Hershey Medical Center, PA  Editor:  Melissa Stiles, MD, Fox Valley FMR, University of WI   

Paget's disease (osteitis deformans)

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