Diagnosis and treatment of Paget's disease of bone: position paper from the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS)

Abstract

Introduction: Paget's disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget's disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management.

Methods: Through selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice.

Results and conclusion: Description of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.

Keywords: Biochemical diagnosis of Paget’s disease of bone; Bone deformities; Clinical diagnosis of Paget’s disease of bone; Complications of Paget’s disease of bone; Fragility fractures; Genetics of Paget’s disease of bone; Metabolic bone diseases; Paget’s disease of bone; Paget’s guidelines; Radiological diagnosis of Paget’s disease of bone; Therapy of Paget’s disease of bone.

Fig. 1

Diagnostic flowchart of Paget’s disease of bone under different clinical settings. The diagnostic process changes in relation to the presence or absence of signs and/or symptoms of disease. In asymptomatic disease, the clinical hypothesis is dependent on the presence of suggestive radiological features (from X-ray, CT, or MR analyses performed for other purposes) or the incidental finding of increased total alkaline phosphatase (t-ALP) or any other marker of bone turnover. In the setting of inconclusive radiological and biochemical findings, a bone biopsy may be indicated to confirm diagnosis. *T-ALP or, alternatively other markers of bone turnover (e.g., B-ALP and P1NP); # first level biochemical tests (plasma and urinary calcium and phosphate, renal function indices, protein electrophoresis, liver function tests) and, eventually, parathyroid hormone and 25OH vitamin D

Fig. 2

Radiological presentation of Paget’s disease of Bone. A Lytic phase. Upper panel: circumscribed osteolytic skull lesions in the frontal and occipital regions. Lower panels: osteolytic lesions of the distal femur progressing proximally and assuming the shape of a flame or inverted V. B Mixed phase. Upper panel: circumscribed osteolytic skull lesions, associated with marked thickening of the diploic space; lower panel: extensive involvement in the right hemipelvis with areas of cortical (ilio-pectineal and ilio-ischial lines) and trabecular thickening and circumscribed osteolytic lesions. C Blastic, osteosclerotic phase. Upper panel: marked thickening of the cranial table, particularly the inner calvarial table, together with several areas of focal sclerosis (“cotton wool” appearance) [right]; compression fracture (CF) at a sclerotic pagetic vertebra [left]. Lower panels: pagetic tibias in blastic phase, with diffuse cortical thickening, trabecular osteosclerosis (causing a loss of distinction between cortex and medulla), bone enlargement and deformity. In the right panel is shown a transverse fissure fracture (FF)

Fig. 3

Bone scan features of Paget’s disease of bone. A Whole-body bone scan with technetium-99 m labeled methylene diphosphonate (99mTc-MDP) is required to identify areas of increased metabolic activity that are suggestive of pagetic sites. Some pathognomonic features may be the involvement and enlargement of a whole skeletal district (2B and 2C), the marked deformity, more easily detected in long bones (2A), and the so-called “Mickey mouse” shape of a vertebral body (2D)