Zoledronate.

Zoledronate is the most potent and most long-acting bisphosphonate in clinical use, and is administered as an intravenous infusion. Its major uses are in osteoporosis, Paget's disease, and in myeloma and cancers to reduce adverse skeletal related events (SREs). In benign disease, it is a first- or second-line treatment for osteoporosis, achieving anti-fracture efficacy comparable to that of the RANKL blocker, denosumab, over 3 years, and it reduces fracture risk in osteopenic older women.

Zoledronic acid efficacy and safety over five years in postmenopausal osteoporosis.

Unlabelled: In a 5-year study involving 119 postmenopausal women, zoledronic acid 4 mg given once-yearly for 2, 3 or 5 years was well tolerated with no evidence of excessive bone turnover reduction or any safety signals. BMD increased significantly. Bone turnover markers decreased from baseline and were maintained within premenopausal reference ranges.

First-dose analgesic effect of the cyclo-oxygenase-2 selective inhibitor lumiracoxib in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled comparison with celecoxib [NCT00267215].

Cyclo-oxygenase-2 selective inhibitors are frequently used to manage osteoarthritis. We compared the analgesic efficacy of the novel cyclo-oxygenase-2 selective inhibitor lumiracoxib (Prexige) versus placebo and celecoxib in patients with knee osteoarthritis. This seven day, double-blind, placebo and active comparator controlled, parallel group study included 364 patients aged > or = 50 years with moderate-to-severe symptomatic knee osteoarthritis.

Intravenous zoledronic acid in postmenopausal women with low bone mineral density.

Background: Bisphosphonates are effective agents for the management of osteoporosis. Their low bioavailability and low potency necessitate frequent administration on an empty stomach, which may reduce compliance. Gastrointestinal intolerance limits maximal dosing.

The effect of intranasal salmon calcitonin on postmenopausal bone turnover as assessed by biochemical markers: evidence of maximal effect after 8 weeks of continuous treatment.

Although treatment with intranasal salmon calcitonin (sCT) has been shown to effectively inhibit postmenopausal bone loss, there is still controversy over both timing and the duration of its application. In an open prospective study, we therefore assessed the effect of shortterm intranasal sCT on postmenopausal bone turnover, employing biochemical markers of bone metabolism. Ten early postmenopausal, previously untreated women (1-5 years after menopause) with biochemical evidence of increased bone resorption and a low bone mineral density at baseline were treated with intranasal sCT (100 IU B.

The effect of rat parathyroid hormone (1-34) infusion on urinary 3-hydroxypyridinium cross-link excretion in the rat.

The utility of measurement of the urinary excretion of the 3-hydroxypyridinium cross-links, pyridinoline (Pyr) and deoxypyridinoline (Dpyr) as indices of bone resorption in rats was investigated. Total Pyr and Dpyr excretion were measured in young rats treated by s.c.

N-terminal truncation of salmon calcitonin leads to calcitonin antagonists. Structure activity relationship of N-terminally truncated salmon calcitonin fragments in vitro and in vivo.

Structural requirements for binding to the bone calcitonin (CT) receptor and for CT bioactivity both in vitro and in vivo were assessed for a series of N-terminally truncated, N alpha-acetylated, fragments of salmon calcitonin (sCT). Sequential deletion of amino acid residues from the amino-terminus of [Ala7]sCT-(2-32) peptide amide first led to partial agonists and, upon deletion of residues 1 to 7, to a high affinity antagonist, N alpha-acetyl-sCT-(8-32)-NH2. The presence of two separate domains within the sCT sequence is proposed: (I) a binding domain comprising residues 9-32 and (II) an activation domain requiring residues 3 to 6.

Somatostatin receptors are restricted to a subpopulation of osteoblast-like cells during endochondral bone formation.

Specific binding sites for the peptide hormone somatostatin have previously been demonstrated in long bones from neonatal rats. In the present study, the distribution of somatostatin receptors during embryonic bone formation has been investigated using the stable radioiodinated somatostatin analogue, SDZ 204-090. Somatostatin receptors in rat long bones were first detectable at the time of invasion of the cartilage model by osteogenic cells.

Phosphate transport adaptation in rat jejunum and plasma level of 1,25-dihydroxyvitamin D3.

Intestinal absorption of inorganic phosphate (Pi) increases in response to a reduction in the dietary supply of Pi. In this work this adaptive response has been characterized in jejunal brush border membrane vesicles and studied in temporal relationship with the change in the plasma level of 1,25(OH)2D3. The results indicate that in rat jejunal brush border membrane vesicles the activity of the sodium-dependent Pi transport system is stimulated by a low Pi diet.

Stimulation of bone formation in vivo by transforming growth factor-beta: remodeling of woven bone and lack of inhibition by indomethacin.

Local effects of transforming growth factor-beta (TGF beta) on bone have been investigated in growing mice. The influence of indomethacin on TGF beta effects was also examined. Five daily injections of TGF beta-1 or -2 were administered subcutaneously over the frontal and parietal bones of seven-week-old mice.

Interleukin-6 is produced by bone and modulated by parathyroid hormone.

Interleukin-6 (IL-6) is a cellular regulatory molecule, the diverse functions of which relate to cells both within and outside the immune system. In this report we demonstrated that bone tissue, specifically osteoblasts, produce interleukin-6 and that this function can be modulated by the osteotrophic hormone parathyroid hormone (PTH). Given that the complex process of bone remodeling is now thought to be regulated not only by systemic hormones but also by locally produced factors, the existence of a parathyroid hormone-stimulated production of interleukin-6 by osteoblasts may have important physiological significance.

Short- and long-term effects of a single dose of bisphosphonates on retinoid-induced bone resorption in thyroparathyroidectomized rats.

The inhibitory effect of a single subcutaneous (s.c.) dose of three different bisphosphonates (Bps)--4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP), 2-(2-pyridinyl)-ethylidene-1,1-bisphosphonate (2-PEBP), and dichloromethylene-bisphosphonate (Cl2MBP)--was studied in a model of retinoid-induced bone resorption, which consists of assessing the hypercalcemic effect of the arotinoid Ro 13-6298 given s.

Bisphosphonates inhibit 1,25-dihydroxyvitamin D3-induced increase of osteocalcin in plasma of rats in vivo and in culture medium of rat calvaria in vitro.

In order to test whether bisphosphonates, which are potent inhibitors of osteoclastic bone resorption, may also act upon osteoblasts, we studied the effect of dichloromethylenebisphosphonate (Cl2MBP) and 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP) on in vivo levels and in vitro release of osteocalcin, a bone-specific protein produced by osteoblasts. In rats, 161 mumol/kg of Cl2MBP or 1.61 mumol/kg AHBuBP strongly inhibited the increase of plasma osteocalcin induced by 1,25(OH)2D3.

Parathyroid hormone-independent regulation of 1,25(OH)2D in response to inhibition of bone resorption.

Both plasma level of 1,25-dihydroxyvitamin D [1,25(OH)2D] and intestinal Ca absorption increase after biphosphonate-induced inhibition of bone resorption. Parathyroid hormone (PTH) has been considered a key mediating element of this homeostatic response. In the present work, the role of PTH was assessed by studying the influence of 1-hydroxypentane-1,1-bisphosphonate (HPeBP) on vitamin D and Ca metabolism in both intact and thyroparathyroidectomized (TPTX) rats.

Production of hemopoietic growth factors by bone tissue and bone cells in culture.

This study was carried out to determine whether bone might be a source of hemopoietic growth factors. Both neonatal murine calvaria and primary cultures of cells isolated from calvaria released, upon stimulation with lipopolysaccharide, an activity that stimulated the growth of the interleukin (IL) 3-dependent cell lines, 32D cl, 123, and NSF 60. Upon gel filtration, this activity eluted with a molecular weight of 30,000 kDa.

Hypercalcemia induced with an arotinoid in thyroparathyroidectomized rats. New model to study bone resorption in vivo.

A model of stimulated bone resorption was developed using a synthetic retinoid in thyroparathyroidectomized rats. The retinoid induced an increase in bone resorption and in the number of vertebral subperiosteal osteoclasts. The resulting increase in plasma Ca could be used as an easily measured index of bone resorption.

Effect of a single injection of two new bisphosphonates on the hypercalcemia and hypercalciuria induced by Walker carcinosarcoma 256/B in thyroparathyroidectomized rats.

The effect of one single injection of two new bisphosphonates, 4-amino-1-hydroxybutylidene-1,1-bisphosphonate and 2-(2-pyridyl)ethylidene-1,1-bisphosphonate, and of dichloromethylenebisphosphonate on the hypercalcemia and hypercalciuria induced by the Walker carcinosarcoma 256/B in the thyroparathyroidectomized rat was evaluated. When given either before or after the development of hypercalcemia and hypercalciuria, 16.1 mumol/kg 4-amino-1-hydroxybutylidene-1,1-bisphosphonate or 2-(2-pyridyl)ethylidene-1,1-bisphosphonate totally inhibited hypercalciuria, whereas hypercalcemia was only partially reduced over the 14 days of the experiment.

Effect of synthetic calcium pyrophosphate and hydroxyapatite crystals on the interaction of human blood mononuclear cells with chondrocytes, synovial cells, and fibroblasts.

Synthetic calcium pyrophosphate dihydrate crystals and, to a lesser extent, synthetic hydroxyapatite crystals increased the amount of interleukin-1/mononuclear cell factor released by human blood monocytes, as measured by collagenase and prostaglandin E2 production by rabbit chondrocytes, human dermal fibroblasts, and adherent rheumatoid synovial cells. The same crystals also directly induced collagenase and prostaglandin E2 secretion by rabbit chondrocytes, and potentiated the action of interleukin-1/mononuclear cell factor on chondrocytes. These mechanisms may be important in the pathogenesis of the destructive arthropathies associated with these crystals.

Murine osteoblastlike cells and the osteogenic cell MC3T3-E1 release a macrophage colony-stimulating activity in culture.

The osteoclast may be of hematopoietic lineage and as such its development could be regulated by colony-stimulating factors. Since there is much interest as to whether osteoblasts influence bone resorption, we examined whether bone cells produce colony-stimulating activity. Both cells isolated from neonatal calvaria and the osteogenic cell MC3T3-E1 were found to constitutively release a colony-stimulating activity possessing characteristics of a macrophage colony-stimulating factor, as determined by basic biochemical purification and by identity of colonies induced in cultures of bone marrow cells.

The increase in skin 7-dehydrocholesterol induced by an hypocholesterolemic agent is associated with elevated 25-hydroxyvitamin D3 plasma level.

Vitamin D3 is generated in skin by UV irradiation of 7-dehydrocholesterol (7-DEHC). Whether the 7-DEHC amount in skin affects vitamin D3 formation, and thereby the plasma level of 25-hydroxyvitamin D3 (25[OH]D3) is not known. In the present work we report on the influence on vitamin D and Ca metabolism of a new hypocholesterolemic agent, HCG-917 (0-2-[hydroxy-3-]N'-(2-chlorophenyl)-N-piperazinyl-1- [propyl]-4-chloro-benz-aldoxim-hydrochloride) which inhibits 7-DEHC reductase and thereby increases skin 7-DEHC.

[The regulation of bone remodeling].

The adult skeleton is subject to a remodeling process which must be tightly regulated to keep bone mass constant. Bone resorption and bone formation are coupled. After a brief review of the cellular mechanisms of bone remodeling, its regulation is discussed.

Reduced parathyroid hormone response to peroral phosphate in osteoporotic patients.

To determine whether PTH secretion can be stimulated in osteoporosis by peroral phosphate (1.5 g phosphorus), we have compared serum PTH and urinary cyclic AMP responses in 8 osteoporotic patients with vertebral compression fractures to those of 7 age-matched control subjects. While there was no statistically significant difference in the rise of serum phosphate and urinary phosphate excretion and in the fall of serumionized calcium concentrations, serum PTH and urinary cyclic AMP were increased in control subjects, but not in osteoporotic patients (osteoporotics vs.

Influence of vitamin D3 metabolites on the production of interleukins 1,2 and 3.

We investigated the effect of vitamin D3 metabolites on the release of the three interleukins (IL) IL 1, IL 2 and IL 3 by mononuclear cells. Models for the production of these mediators were the release of IL 1 by the murine macrophage cell line P388D1, of IL2 by rat spleen cells, and of IL 3 by the murine WEHI-3 cell line. IL 1 production was significantly increased with 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) at 10(-10)M and above.