Assessment of bone response to systemic therapy in an EORTC trial: preliminary experience with the use of collagen cross-link excretion. European Organization for Research and Treatment of Cancer.
(25/2466)
This study was designed to evaluate new bone resorption and tumour markers as possible alternatives to serial plain radiographs for the assessment of response to treatment. Thirty-seven patients with newly diagnosed bone metastases from breast cancer, randomized to receive oral pamidronate or placebo tablets in addition to anticancer treatment within the context of a multicentre EORTC trial, who were both assessable for radiographic response in bone and had serum and urine samples collected for more than 1 month were studied. The markers of bone metabolism measured included urinary calcium (uCa), hydroxyproline (hyp), the N-telopeptide cross-links of type I collagen (NTx) and total alkaline phosphatase. The tumour markers measured were CA15-3 and cancer-associated serum antigen (CASA). Before treatment, levels of Ntx, uCa and Hyp were elevated in 41%, 24% and 28% respectively, and CA15-3 and CASA increased in 69% and 50%. For assessment of response and identification of progression, Ntx was the most useful bone marker. All markers behaved similarly in no change (NC) and partial response (PR) patients. There was a significant difference (P < or = 0.05) in Ntx levels (compared to baseline) at 1 and 4 months and in CA15-3/CASA at 4 months between patients with PR or NC and those with progressive disease (PD), and at 4 months between those with time to progression (TP) > 7 and those with TP < or = 7 months. The diagnostic efficiency (DE) for prediction of PD following a > 50% increase in Ntx or CA15-3 was 78% and 62% respectively. An algorithm to predict response to therapy has been developed for future prospective evaluation. (+info)
Osteopontin-deficient mice are resistant to ovariectomy-induced bone resorption.
(26/2466)
Osteopontin is one of the major noncollagenous bone matrix proteins produced by osteoblasts and osteoclasts, bone cells that are uniquely responsible for the remodeling of mineralized tissues. Osteoclasts express the alphavbeta3 integrin, which is one of the receptors for osteopontin. Recent knockout studies revealed that noncollagenous bone matrix proteins are functionally important in regulation of bone metabolism. However, the significance of the presence of osteopontin in in vivo has not been known. We report here that osteopontin knockout mice are resistant to ovariectomy-induced bone resorption compared with wild-type mice. Microcomputed tomography analysis indicated about 60% reduction in bone volume by ovariectomy in wild-type mice, whereas the osteopontin-deficient mice exhibited only about 10% reduction in trabecular bone volume after ovariectomy. Reduction in uterine weight was observed similarly in both wild-type and osteopontin-deficient mice, indicating the specificity of the effect of osteopontin deficiency on bone metabolism. We propose that osteopontin is essential for postmenopausal osteoporosis in women. Strategies to counteract osteopontin's action may prove effective in suppressing osteoporosis. (+info)
Bone response to orthodontic loading of endosseous implants in the rabbit calvaria: early continuous distalizing forces.
(27/2466)
The purpose of this experimental study was to evaluate the effect of early orthodontic loading on the stability and bone-implant interface of titanium implants in a rabbit model. Twenty-four short threaded titanium fixtures were inserted in the calvarial mid-sagittal suture of 10 rabbits. Two weeks following insertion, 20 implants (test group) were subjected to continuous distalization forces of 150 g for a period of 8 weeks. The remaining four implants (control group) were left unloaded for the same follow-up interval. Clinically, all implants except for one test fixture were stable, and exhibited no mobility or displacement throughout the experimental loading period. Histologically, all stable implants were well-integrated into bone. No differences could be found between the pressure and tension surfaces of the test implants relative to bone quality and density within a range of 1000 microns from the fixture surface. Similarly, qualitative differences were not observed between the apical and coronal portions of test fixtures. Morphometrically, a mean percentage bone-to-implant contact of 76.00 +/- 18.73 per cent was found at the test pressure sides, 75.00 +/- 11.54 per cent at the test tension sides, and 68.00 +/- 15.55 per cent at the control unloaded surfaces. No statistically significant differences in the percentage of bone-to-metal contact length fraction were found between test pressure surfaces, test tension surfaces, and unloaded control surfaces. Marginal bone resorption around the implant collar or immediately beneath it was found in roughly the same percentage of analysed sites in the test and control fixtures. In contrast, slight bone apposition was demonstrated at the implant collar of the test pressure surfaces, while no apposition or resorption were observed in the test tension zones. This study suggests that short endosseous implants can be used as anchoring units for orthodontic tooth movement early in the post-insertion healing period. (+info)
Changes in calcium homoeostasis in patients undergoing liver transplantation: effects of a single infusion of pamidronate administered pre-operatively.
(28/2466)
Bone turnover, bone loss and fracture risk increase after liver transplantation. It has been postulated that peri-operative administration of a bisphosphonate might prevent bone loss and reduce fracture rate. We studied the effects of a single pre-operative dose of pamidronate on biochemical parameters of skeletal metabolism in the first month after liver transplantation. In a randomized, single-blind study, six of 12 patients with chronic liver disease received 60 mg of pamidronate intravenously on a single occasion 1-30 days before transplantation. Six other patients undergoing transplantation received no pamidronate. We measured serum calcium, phosphate, albumin, bone-specific alkaline phosphatase, plasma parathyroid hormone and tartrate-resistant acid phosphatase before pamidronate infusion and at frequent intervals during the first 30 post-operative days. In treated patients, plasma parathyroid hormone increased 12-fold over baseline values and remained elevated in comparison with baseline at days 26-30; serum calcium and phosphate fell significantly, returning to normal at around day 14 post-operatively. There were no significant changes in any parameter in the untreated group. No changes in bone formation or resorption markers were observed in either group. The large increase in plasma parathyroid hormone concentrations in the treated group is probably secondary to the fall in serum calcium. The magnitude of the increase is much greater than that seen after pamidronate infusion in other patient groups. The lack of change in, or correlation of, serum calcium and plasma parathyroid hormone in the untreated group suggests that additional factors release calcium from bone after liver transplantation, presumably by increasing bone resorption. (+info)
Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts.
(29/2466)
Rheumatoid arthritis (RA) is characterized by a chronic inflammation of the synovial joints resulting from hyperplasia of synovial fibroblasts and infiltration of lymphocytes, macrophages, and plasma cells, all of which manifest signs of activation. Recent studies have revealed the essential role of osteoclasts in joint destruction in RA. Src family tyrosine kinases are implicated in various intracellular signaling pathways, including mitogenic response to growth factors in fibroblasts, activation of lymphocytes, and osteoclastic bone resorption. Therefore, inhibiting Src activity can be a good therapeutic strategy to prevent joint inflammation and destruction in RA. We constructed an adenovirus vector carrying the csk gene, which negatively regulates Src family tyrosine kinases. Csk overexpression in cultured rheumatoid synoviocytes remarkably suppressed Src kinase activity and reduced their proliferation rate and IL-6 production. Bone-resorbing activity of osteoclasts was strongly inhibited by Csk overexpression. Furthermore, local injection of the virus into rat ankle joints with adjuvant arthritis not only ameliorated inflammation but suppressed bone destruction. In conclusion, adenovirus-mediated direct transfer of the csk gene is useful in repressing bone destruction and inflammatory reactions, suggesting the involvement of Src family tyrosine kinases in arthritic joint breakdown and demonstrating the feasibility of intervention in the kinases for gene therapy in RA. off (+info)
C-telopeptide pyridinoline cross-links. Sensitive indicators of periodontal tissue destruction.
(30/2466)
C-telopeptides and related pyridinoline cross-links of bone Type I collagen are sensitive markers of bone resorption in osteolytic diseases such as osteoporosis and osteoarthritis. We have studied the release of C-telopeptide pyridinoline crosslinks of Type I collagen as measures of bone destruction in periodontal disease. Studies in preclinical animal models and humans have demonstrated the relationship between radiographic bone loss and crevicular fluid C-telopeptide levels. We have recently found that C-telopeptide levels correlate strongly with microbial pathogens associated with periodontitis and around endosseous dental implants. Host-modulation of bone-related collagen breakdown has been shown by studies in humans demonstrating that MMP inhibition blocks tissue destruction and release of C-telopeptides in patients with active periodontal disease. (+info)
Interleukin-1 and tumor necrosis factor activities partially account for calvarial bone resorption induced by local injection of lipopolysaccharide.
(31/2466)
The present study was undertaken to test the hypothesis that tumor necrosis factor (TNF) and/or interleukin-1 (IL-1) activity mediates lipopolysaccharide (LPS)-induced bone resorption in vivo. To test this hypothesis, Escherichia coli LPS or Porphyromonas gingivalis LPS was injected into the subcutaneous tissues overlying mouse calvariae. Histological sections, prepared from the center of the lesion, were stained for tartrate-resistant acid phosphatase, and histomorphometric analysis was performed to quantify the osteoclast number and the area of bone resorption. In time course experiments using normal mice, a peak of bone resorption occurred 5 days after endotoxin stimulation. In dose-response experiments, IL-1 receptor type 1 deletion (IL-1R(-/-)), TNF double-receptor p55/p75 deletion (TNF p55(-/-)/p75(-/-)), combined TNF p55 and IL-1 receptor type 1 deletion (TNF p55(-/-)/IL-1R(-/-)), and IL-1beta-converting enzyme-deficient (ICE(-/-)) mice and the respective wild-type mice were injected with 500, 100, or 20 micrograms of P. gingivalis LPS and sacrificed 5 days after LPS injection. At the highest dose (500 micrograms), significant decreases in osteoclast number occurred in mutant mice compared to wild-type mice: (i) a 64% reduction for the TNF p55(-/-)/IL-1R(-/-) mice, (ii) a 57% reduction for the IL-1R(-/-) mice, (iii) a 41% reduction for the TNF p55(-/-)/p75(-/-) mice, and (iv) a 38% reduction for the ICE(-/-) mice. At the two lower doses, bone resorption was apparent but no significant differences between mutant and wild-type animals were observed. The present data indicate that at higher doses, LPS-induced bone resorption is substantially mediated by IL-1 and TNF receptor signaling. Furthermore, IL-1 receptor signaling appears to be slightly more important than TNF receptor signaling. At lower LPS doses, other pathways leading to osteoclast activity that are independent of TNF and IL-1 are involved. (+info)
Prostaglandins and bone: physiology and pathophysiology.
(32/2466)
Prostaglandins (PGs) are potent stimulators of bone formation and resorption and are produced by bone cells. PGs also have inhibitory effects on fully differentiated osteoblasts and osteoclasts. This complex, multifunctional regulation is probably mediated by different PG receptors. Endogenous PGs in bone are produced largely by induction of COX-2, which is highly regulated by hormones and local factors. The development of specific agonists and antagonists for PG receptors and for COX-2 should allow us to define the physiologic and pathophysiologic roles of PGs more precisely and develop new therapeutic approaches to metabolic and inflammatory disorders of the skeleton. (+info)