Bone Abstracts

Multiple myeloma is usually incurable, the bone marrow niche providing a protective microenvironment for quiescent tumour cells. We hypothesised that manipulation of BMP activity, a regulator of cell differentiation in the bone marrow, might affect control of tumour growth by its niche and in addition alter the lytic bone disease of myeloma. Moreover BMP signalling contributes to the hepcidin upregulation and resultant inflammatory anaemia that is characteristic of myeloma. Re...

Cancer-associated muscle weakness is an important paraneoplastic syndrome for which there is currently no treatment. Human breast cancer bone metastases (MDA-MB-231 cells in immune deficient mice) induce extensive bone destruction, leading to the release of TGF-β from the bone matrix. We have previously shown that bone-derived TGF-β is responsible for muscle weakness in this model. Mechanistically, TGF-β signaling increases the expression of NADPH oxidase 4 (Nox...

Up to half of women treated with an aromatase inhibitor (AI) for breast cancer develop muscle weakness, bone loss, and joint pain. Moreover, an elevated state of osteoclastic bone resorption has been shown to prime the bone microenvironment in ways that accelerate metastatic growth. We hypothesized that AI-induced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases. Four-week female athymic nude mice underwe...

Breast cancer is the most frequent malignancy in women and frequently results in osteolytic bone metastases. Amino-bisphosphonates are a standard bone protective therapy and, similarly to statins, inhibit the mevalonate pathway that is crucial for posttranslational protein modifications (farnesylation and geranylation). Direct anti-tumor effects of amino-bisphosphonates and statins have been suggested but high concentrations are necessary to achieve meaningful effects. Our stu...

Effects of whole bone scaling on isolated osteoblast behaviours are unknown. Exhibiting a huge range in size, inbred canines are an ideal species to determine such relationships. We have therefore undertaken initial studies in both male and female red foxes (Vulpes vulpes), the most abundant and accessible wild canid member in the United Kingdom.Femoral heads were removed from five fresh red fox cadavers (see details on table) and bone fragments...

Hip osteoarthritis is a cause of significant morbidity to people and their canine companions. Medical management is frequently insufficient, leading to surgery to relieve pain and regain mobility. Hip replacements are not without potential complications, including loosening and infection. Currently, there is a focus on uncemented implants to decrease these problems, however these rely on the biology of the femur for osseointegration and long-term stability. It has been previou...

Effects of whole bone scaling on isolated osteoblast behaviour are unknown. With two orders of magnitude range in body mass, dog breeds are well-suited to determine such relationships.Femoral heads from three canine hip replacement surgeries were collected. Bone fragments were washed in PBS+AB/AM, trypsin-digested and incubated in 0.2% collagenase. Cells from resultant supernatant were seeded in DMEM+10% FCS+AB/AM at 37 °C, 5% CO2, g...

Objectives: Murine studies have shown that iron deficiency during pregnancy can cause abnormal phosphate and bone metabolism in offspring by elevating concentrations of fibroblast growth factor-23 (FGF23). FGF23 exists in plasma as an intact phosphate- and vitamin D-regulating hormone and its C-terminal fragment, a cleavage product that possibly antagonises the intact hormone. These findings are pertinent to low-income countries, where the prevalence of iron deficiency in preg...

Objective: Children with hypophosphatasia (HPP) treated with asfotase alfa in a Phase 2 study (NCT00952484) and its open-label extension (NCT01203826) experienced significant improvements in skeletal mineralization and physical function that were sustained through 5 years of treatment (1). Herein, we report data from these studies with a maximum of 7 years of treatment.Methods: Children with HPP aged 6–12 years at baseline received asfotase alfa (3 ...

Objective: To evaluate safety and efficacy after 5 years of treatment with asfotase alfa in adolescents and adults with hypophosphatasia (HPP) in a Phase 2, open-label, randomized, dose-ranging study (NCT01163149).Methods: Treatment with subcutaneous asfotase alfa 0.3 or 0.5 mg/kg per d was compared with no treatment (control) for 6 months in patients aged 13–66 years. After 6 months, all patients (treatment and control groups) received active treat...