Bone material properties in actively bone-forming trabeculae in postmenopausal women with osteoporosis after three years of treatment with once-yearly Zoledronic acid.

Zoledronic acid (ZOL), a third-generation aminobisphosphonate, showed pronounced antifracture efficacy in a phase III clinical trial [Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT)] when administered yearly (5-mg infusions of ZOL), producing significant reductions in morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively, over a 3-year period. The purpose of this study was to analyze the biopsies obtained during the HORIZON clinical trial (152 patients, 82 ZOL and 70 placebo) by means of Raman microspectroscopy (a vibrational spectroscopic technique capable of analyzing undecalcified bone tissue with a spatial resolution of approximately 0.6 µm) to determine the effect of ZOL therapy on bone material properties (in particular mineral/matrix ratio, lamellar organization, carbonate and proteoglycan (based on spectral identification of glycosaminoglycan) content, and mineral maturity/crystallinity) at similar tissue age (based on the presence of tetracycline double labels).

Circulating fibronectin affects bone matrix, whereas osteoblast fibronectin modulates osteoblast function.

The bone matrix is composed mostly of collagen, but the initial and continuous presence of fibronectin was found to be crucial for collagen matrix integrity in vitro. It has been assumed that osteoblasts produce the fibronectin required for bone matrix formation. Using transgenic mice, we conditionally deleted fibronectin in the osteoblasts and in the liver using the cre-loxP system.

Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure.

Unlabelled: In a substudy of the HORIZON pivotal fracture trial, in which yearly intravenous zoledronic acid 5 mg was found to significantly reduce risk of various fracture types in patients with postmenopausal osteoporosis, 152 patients underwent bone biopsy. Zoledronic acid reduced bone turnover by 63% and preserved bone structure and volume, with evidence of ongoing bone remodeling in 99% of biopsies obtained.

Introduction: In the HORIZON pivotal fracture trial (PFT), enrolling 7,736 women with postmenopausal osteoporosis, three annual intravenous infusions of the bisphosphonate zoledronic acid (5 mg) significantly reduced morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively.

TNF-induced structural joint damage is mediated by IL-1.

Blocking TNF effectively inhibits inflammation and structural damage in human rheumatoid arthritis (RA). However, so far it is unclear whether the effect of TNF is a direct one or indirect on up-regulation of other mediators. IL-1 may be one of these candidates because it has a central role in animal models of arthritis, and inhibition of IL-1 is used as a therapy of human RA.

Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis.

Background: Bisphosphonates exhibit direct antitumor activity in animal models, but only at high doses that are incompatible with the clinical dosing regimens approved for the treatment of cancer patients with skeletal metastases. We compared the antitumor effects of clinical dosing regimens of the bisphosphonates zoledronic acid and clodronate in a mouse model of bone metastasis.

Methods: Mice (n = 6-10 per group) were treated with zoledronic acid, clodronate, or vehicle starting before (preventive protocols) or after (treatment protocols) intravenous injection with human B02/GFP.

The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis.

Morphogenesis and remodeling of bone involve synthesis of bone matrix by osteoblasts and coordinate resorption of bone by osteoclasts. Defective bone remodeling caused by altered osteoclast activity underlies a multitude of osteopenic disorders. Receptor activator of NF-kappaB (RANK) and its ligand RANKL have been identified as essential factors involved in osteoclast development and bone remodeling, but their mechanism and interacting factors have not been fully characterized.