Drug treatment strategies for paget's disease: relieving pain and preventing progression.

INTRODUCTION: Paget's disease of bone (PDB) is a focal bone disorder caused by a marked dysregulation of osteoblasts and osteoclasts in basic multicellular units, leading to abnormal and disorganized deposition of collagen fibers (the so-called 'woven bone'). Therefore, pagetic bones are increased in size, and at increased risk for bone pain, deformities, fractures, osteoarthritis, and, more rarely, neoplastic degeneration. AREAS COVERED: In this review, we revise the available information concerning the pharmacological treatment of PDB. EXPERT OPINION: PDB progresses slowly within the affected skeletal sites and, if untreated, often leads to bone overgrowth, with bone pain, deformity, and a likely increased risk of complications. Thus, the primary goal of treatment is the restoration of a normal bone turnover, in order to relieve bone pain or other symptoms and possibly prevent the complications. PDB long remained a poorly treatable disorder until the discovery of antiresorptive agents such as calcitonin first and bisphosphonates (BPs) later. With the recent development of potent intravenous BPs like zoledronate, allowing a better control of disease activity over the long term with a single infusion, has contributed to a marked improvement of the clinical management of this invalidating disorder.

Bisphosphonate-induced osteonecrosis of the jaw: a review of 2,400 patient cases.

PURPOSE: Bisphosphonates (BPs) are bone-remodeling inhibitors that are used to manage bone metastases and osteoporosis. Osteonecrosis of the jaw, however, can occur during treatment. This complication is poorly understood and is called "bisphosphonate-induced osteonecrosis of the jaw" (BIOJ). METHODS: We performed a PubMed-based review of all of the described cases of BIOJ from January 2003 (the year of the first description) to September 2009. Issues of clinical relevance, such as the primary diagnosis and type of treatment, were evaluated for each patient case. RESULTS: We retrieved 2,408 cases, 88% of which were associated with intravenous therapy, primarily with zoledronate. Of the total number of cases, 89% were associated with the treatment of a malignant condition, particularly multiple myeloma (43% of the cases). Of all the BIOJ cases, 67% were preceded by tooth extraction and only 35% of patients were cured. CONCLUSION: Prevention is better than treatment, and the establishment of meticulous oral hygiene and surgical procedures prior to commencing BP treatment is important for preventing BIOJ. Our review summarizes the current knowledge about this severe complication. Future studies, especially basic research studies, are needed to better understand this devastating disease.

Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease.

Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM), Paget's disease of the bone, and frontotemporal dementia (IBMPFD). Patient muscle has degenerating fibers, rimmed vacuoles (RVs), and sarcoplasmic inclusions containing ubiquitin and TDP-43 (TARDNA-binding protein 43). In this study, we find that IBMPFD muscle also accumulates autophagosome-associated proteins, Map1-LC3 (LC3), and p62/sequestosome, which localize to RVs. To test whether VCP participates in autophagy, we silenced VCP or expressed adenosine triphosphatase-inactive VCP. Under basal conditions, loss of VCP activity results in autophagosome accumulation. After autophagic induction, these autophagosomes fail to mature into autolysosomes and degrade LC3. Similarly, IBMPFD mutant VCP expression in cells and animals leads to the accumulation of nondegradative autophagosomes that coalesce at RVs and fail to degrade aggregated proteins. Interestingly, TDP-43 accumulates in the cytosol upon autophagic inhibition, similar to that seen after IBMPFD mutant expression. These data implicate VCP in autophagy and suggest that impaired autophagy explains the pathology seen in IBMPFD muscle, including TDP-43 accumulation.