Bone Abstracts

Familial expansile osteolysis (FEO) is characterised by focal areas of increased bone turnover driven by bone-resorbing osteoclasts. The syndrome is caused by a heterozygous tandem insertion duplication mutation within the signal peptide region of TNFRSF11a (encoding receptor activator of NFκB; RANK). Our recent research has demonstrated that heterotrimeric receptor formation may hold the key to the disease phenotype. We have shown previously that, whilst homozygous overe...

Early-onset Paget’s disease of bone (ePDB), familial expansile osteolysis (FEO) and expansile skeletal hyperphosphatasia (ESH) are related syndromes caused by heterozygous tandem insertion duplication mutations within the signal peptide region of TNFRSF11a (encoding receptor activator of NFκB; RANK). Given that patients are always heterozygous for these mutations we have generated thirteen cell lines to investigate the molecular consequences of these mutations in...

The interaction of Receptor Activator of NFkB ligand (RANKL) with its cognate receptor RANK is crucial for osteoclast formation. We studied eight point mutations within human RANK associated with rare forms of osteopetrosis to gain mechanistic insights into the regulation of RANK signalling.We investigated the role of the oligomerisation domain within the cytoplasmic region of RANK studying two mutations (W434X and G280X) identified in rare cases of oste...

Osteoclast-poor autosomal recessive osteopetrosis is characterised by susceptibility to fracture despite high bone mineral density as a consequence of an absence of osteoclasts. One of the 12 receptor activator of NF-κB (RANK) mutations associated with this condition is a frameshift mutation encoding a protein that is truncated within the extracellular, N-terminal domain (R110Pfs). We investigated the effect of this mutation on osteoclast formation, receptor localisation ...

Twelve different mutations in TNFRSF11A (encoding the RANK receptor) have been associated with osteoclast-poor autosomal recessive osteopetrosis in patients. Two truncated RANK proteins resulting from substitution mutations (W434X and G280X), identified in two infants, cause loss of the intracellular oligomerisation motif and in the case of the G280X mutation the TRAF6 binding domain. A third mutation was identified in a 10-year-old patient and is a frameshift mutatio...

Objectives: Clinicians practicing in long-term care (LTC) face unique challenges caring for frail elderly individuals including multiple co-morbidities, polypharmacy, and end of life care, and practice guidelines typically do not address this population. Guidance regarding the management of osteoporosis and fracture prevention in LTC, a high-risk population, is needed.Materials and methods: A survey of LTC physicians informed key questions and outcomes, ...

Background: Osteoporosis is a hereditary multifactorial disease characterised by low bone mass leading to an increased susceptibility to fracture. Bone mineral density (BMD) is the most widely used predictor of fracture risk. Gene variants have been found associated with a low BMD and increased fracture risk; nonetheless studies have identified the relationship between susceptibility genes and fractures independent of BMD.Objective: Eight single nucleoti...

Clinical trials suggest that denosumab (DEN) therapy results in greater increases in bone mineral density (BMD) in treatment-naive patients than in patients switched from bisphosphonates.We retrospectively reviewed charts of all patients treated with DEN at an osteoporosis referral centre in Vancouver, Canada including all patients treated with DEN 60 mg SC every 6 months for 1 year or more, and in whom baseline and follow-up BMDs were available. BMD was...

The Rab family GTPases Rab27a and Rab27b play an important role in the trafficking of lysosome-related organelles in specialised cells, such as melanocytes. Since secretory lysosomes, also considered a lysosome-related organelle, are important for osteoclast and osteoblast function, we hypothesised that Rab27 plays a role in bone physiology. In support of this, a recent study demonstrated impaired transport of RANK ligand to the plasma membrane in osteoblasts from mice lacking...

Background: Zoledronic acid (ZA) for the treatment of osteoporosis (OP) is associated with a transient post-infusional acute phase reaction (APR) due to ZA-mediated activation of γ-δ TCR lymphocytes (γ-δTCR) and production of cytokines.Primary objective: To investigate if OP patients developing APR (APR+) after ZA infusion have lower 25-OH vitamin D (25-OHvD) levels and a higher percentage of γ-δTCR compared to patients with...