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Women with skeletal metastases from breast cancer were treated by pamidronate 60 mg i.v. q 4 w or saline at the same interval in a double-blind placebo-controlled randomized study.Patients were recruited at 27 institutions in Sweden and Norway from November 1990 to September 1993. Specific antitumour treatment, endocrine and/or cytotoxic, was individually chosen at the discretion of the physician...
Proteoglycan [PG] synthesis in articular cartilage is critically dependent o mechanical loading. Previous studies have demonstrated stimulation of PG synthesis following cyclical pressurisation of cultured chondrocytes and we have shown consistent membrane hyperpolarisation, activation of small conductance Ca 2+ activated K + ion channels and stimulation of gadolinium [Gd ...
Present knowledge indicates that osteoblasts (Ob) play a central role in osteoclastic bone resorption through an osteoclast-stimulating activity (OSA) which is produced in response to bone resorption promoting hormones or osteotropic factors. Previously, we have shown that the inhibiting action of bisphosphonates (BP) on bone resorption in part is mediated by Ob. A 5 min treatment of Ob with BP,...
Many laboratories have established cell culture systems allowing to investigate the formation of osteoclasts (oc's). The cultures are composed of stromal cells which are grown together with hemopoietic precursors. Using this type of culture system, it was possible to demonstrate the role of cytokines and hormones in oc development. It could, however, not be distinguished, whether the osteoblastic...
Intermittent administration of PTH improves bone formation and mineralization of healthy and osteopenic rats. Concerning mineralization, the interest of researchers has been primarily focused on the calcium content of bone, although magnesium depletion is often associated with osteopenia or osteoporosis. The role of magnesium in bone physiology and pathology is poorly understood.Twenty-two healthy...
Background: Bisphosphonates are potent inhibitors of bone resorption that bind avidly to bone mineral. The exact mechanism of their action remains to be clarified. Their beneficial effects in adult conditions where bone resorption is increased are well documented. No similar data have so far been reported in the pediatric population. Polyostotic fibrous dysplasia (FD) and certain forms of osteogenesis...
We have previously reported the partial characterization of a novel cytosolic antigen associated with osteoclasts. In addition we demonstrated that the antibody can be used to identify osteoclasts in sections of normal and pathological bone. In this study we show that the antigen can be isolated from osteoclastoma and detected in dot blots. The antigen is SDS-labile and cannot be Western blotted...
The most common cause of failure of total hip and other arthroplasties is aseptic loosening of the prosthesis. Growing evidence indicates that the adverse tissue response to prosthesis wear particles is an important contributor to bone loss around the implants. We have investigated the possibility that inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins are expressed in...
Bisphosphonates are drugs which inhibit bone resorption and are being used as thrapies for osteoporosis. The molecular mechanisms by which bisphosphonates exert their biological effects are still unclear. It is generally assumed that uptake of these highly polar molecules by cells is limited. To determine whether bisphosphonates are internalzed and therefore may act intracellularly, we have examined...
Increased osteoclast activity has been associated with lytic bone metastases. The collagen crosslinks pyridinoline (PYD), deoxypyridinoline (DPD), and more recently the crosslink N-telopeptide (NTX) are markers of bone resorption and are elevated in many patients with lytic bone metastases. Bisphosphonates are inhibitors of osteoclast activity and should result in decreased crosslink values. We...
The arrangement of osteoblasts on parietal bone surface was reported to be related to the orientation of collagen fibres in the osteoid surface immediately underneath the cells (Jones et al. 1975). More recently, it was reported that the amount and distribution of bone, formed in vitro on polystyrene dishes, was influenced by the roughness of the underlying substratum (Gomi et al., 1993). However,...
There is increasing evidence that bisphosphonates have an intracellular mechanism of action, since cells that are highly phagocytic or endocytic, such as osteoclasts and macrophages, appear to be most susceptible to the toxic or anti-proliferative effects of these compounds. Liposomal encapsulation of bisphosphonates also enhances the potency of the drugs towards phagocytic cells, since a high intracellular...
In adult bone osteoblasts are derived from primitive, multipotential cells associated with the bone surface and soft fibrous tissue of the marrow stroma. The identification of factors that regulate proliferation and osteogenic commitment of marrow stromal precursors is essential for the treatment of osteoporosis. The platelet-derived growth factor (PDGF) family consists of closely related dimers...
Measurement of the urinary excretion of degradation products of the C-telopeptides of type I collagen in the CrossLaps TM ELISA has been shown to be a sensitive and specific index of bone resorption (Garnero et al. J Clin Endocrin Met, 1994, 79, 780-85; Bonde et al. Clin Chem, 1994, 40, 2022-25). The CrossLaps TM ELISA is based on a polyclonal antibody to an 8 amino acid...
Prostaglandin G/H synthase-2 (PGHS-2), the major enzyme in the conversion of arachidonic acid to prostaglandins (PG), is an early response gene which mediates the acute regulation of PGs by cytokines, growth factors and hormones. To examine the effects of differentiation on PGHS-2 expression, we used MC3T3-E1 cells stably transfected with -371/+70 bp of the PGHS-2 promoter fused to a luciferase reporter...
Objective: Human osteocalcin (hOC) is a 49 aa peptide with three carboxylated glu-residues (gla). The release of hOC to the circulation is usually perceived as a marker of bone formation but some forms of circulating hOC have been suggested to reflect the bone resorption process. Immunoassays for hOC frequently show poor agreement with each other presumably because of differences in assay design,...
Assessment of all economic consequences today is an integral part of any socioeconomic evaluation of a drug. A first step involves analyses of resource use alongside clinical trials. Controlled clinical trials are accepted as the best source of data on effectiveness of a medical procedure and should also include economic endpoints.We report on cost evaluation in a prospective, randomized double-blind...
Transversal pQCT scans of femur midshaft and distal metaphysis and histomorphometrical sections of proximal tibial metaphysis from immobilized (IM) or overloaded (OL) legs of rats otherwise untreated, or receiving sc doses of 200 ug/kg/d hPTH(1-38) 75 d (PT), then withdrawn for 60 d (Pw) or sequenced by a 60-d sc treatment with 5 ug/kg 2/wk risedronate (PR), or given only the bisphosphonate (R),...
Neovascularization of cartilage is a step of endochondral ossification but its mechanism and control are still obscure. Capillary invasion is initiated and sustained by terminal capillary cells by secretion of proteases and collagenase. These activated cells produce also oxygen-derived free radicals (ODFR) able to degrade cartilage macromolecules. Supposing that these active species partecipate...
A small study of the effects of injectable salmon calcitonin (Civitelli et al., 1988 JCI) suggested that bone turnover rates, as assessed by biochemical markers, might predict response to antiresorptive therapy. It is also believed that untreated postmenopausal women with higher rates of bone turnover are likely to experience more rapid loss than those with lower turnover. To explore these potential...
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