alendronate, Fosamax
The aminobisphosphonate alendronate inhibits bone loss induced by thyroid hormone in the rat. Comparison between effects on tibiae and vertebrae.

Balena R, Markatos A, Gentile M, Masarachia P, Seedor JG, Rodan GA, Yamamoto M.

Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486.

The aims of this study were to develop a rat model of hyperthyroidism and to determine the efficacy of alendronate in the prevention of thyroid hormone-induced bone loss. Ten week-old Sprague-Dawley rats injected with thyroxine 250 micrograms/kg/day (+T4) or vehicle (-T4) were treated with alendronate (+ALN) or vehicle (-ALN) orally 0.5 mg/kg/day. After 3 weeks of treatment histomorphometric parameters of cancellous bone remodeling were assessed in the proximal tibia and in the first lumbar vertebra. In the secondary spongiosa of the tibia T4 treatment caused significant bone loss, associated with increased bone turnover; trabecular bone volume, trabecular thickness and trabecular number were significantly decreased. Osteoid and osteoclast surfaces increased in +T4/-ALN as compared to control. Alendronate prevented the increase in bone turnover and increased bone volume above control values without interfering with the recruitment of osteoclasts. These changes were not apparent in the vertebra. It is concluded that excess thyroid hormone in the rat induces high turnover bone loss in the tibia which can be prevented by alendronate through an inhibition of osteoclastic activity. The lack of effects of thyroid hormone on the vertebra may be ascribed to a lower rate of basal bone turnover at that site.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8363899&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Inhibition of antigen-presenting cell function by alendronate in vitro.

Sansoni P, Passeri G, Fagnoni F, Mohagheghpour N, Snelli G, Brianti V, Engleman EG.

Clinica Medica Generale, University of Parma, Italy.

Bisphosphonates are potent inhibitors of bone resorption in vivo and are emerging as important and widely used drugs for the treatment of a variety of abnormal bone resorptive processes. In the current study we investigated the in vitro effects of 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate), a recently developed, extremely potent bisphosphonate, on the immune functions of human peripheral blood mononuclear cells (PBMCs). PBMC proliferation induced by lectins, alloantigens, and a nominal antigen (tetanus toxoid) was inhibited in a dose-dependent manner by alendronate. Pretreatment of monocytes, but not T cells, with the compound at concentrations ranging from 10(-4) to 10(-8) M was inhibitory, indicating that alendronate acts selectively on antigen-presenting cells (APCs). Alendronate did not affect the viability of monocytes or T cells or the expression of cell surface molecules known to play critical roles in antigen presentation. Alendronate exhibited dose-dependent inhibition of the production of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) by activated monocytes. The inhibitory effect of 10(-6) M alendronate on PBMC proliferation was reversed by 10 U/ml recombinant rIL-1 beta, whereas other cytokines such as IL-6, TNF-alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) had no effect. Thus, alendronate acts on monocytes to inhibit their antigen-presenting/accessory cell functions through a mechanism that can be overcome by exogenous IL-1. The inhibitory effect of this agent on cytokine production may contribute to its inhibitory effect on bone resorption.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8592949&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Effect of alendronate on fracture healing and bone remodeling in dogs.

Peter CP, Cook WO, Nunamaker DM, Provost MT, Seedor JG, Rodan GA.

Merck Research Laboratories, West Point, PA 19486, USA.

To examine the effect of alendronate (4-amino-1-hydroxybutylidene bisphosphonate) on fracture repair, the drug was given to mature beagle dogs orogastrically at 2 mg/kg/day for 9 weeks preceding fracture. 16 weeks after fracture, or both before and after fracture (25 weeks). A transverse mid-diaphyseal fracture of the right radius was surgically induced and was stabilized by external coaptation splinting. Fracture healing and bone remodeling were evaluated by radiography, gross and histological examination, and bone histomorphometry. The mechanical properties of the fracture callus were determined by a four-point bending test. Radiographs and gross and microscopic examination demonstrated normal bone healing at the fracture site in all dogs. In dogs that received alendronate during the fracture healing period, at 16 weeks the calluses were approximately 2-3 times larger than those in dogs that received a placebo during the healing period. This is consistent with slower callus bone remodeling, an expected pharmacological effect of the compound. Bone histomorphometry demonstrated that treatment with alendronate did not inhibit bone formation or mineralization. Mechanical testing showed that the ultimate load at failure and the flexural rigidity of both the fractured and contralateral intact bone were unaffected by treatment with alendronate. Therefore, in this study, treatment with alendronate before or during fracture healing, or both, resulted in no adverse effects on the union, strength, or mineralization of bone in mature beagle dogs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8618170&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Effects of alendronate on plasma calcium levels, urinary calcium excretion, and bone resorption markers in normal rats: comparison with elcatonin, synthetic eel calcitonin.

Azuma Y, Chokki M, Ohta T, Kiyoki M.

Pharmacological Research Department, Teijin Institute for Biomedical Research, Tokyo, Japan.

In normal rats given alendronate (0.01-6.25 mg/kg) or elcatonin (synthetic eel calcitonin; 0.32-8.0 U/kg), changes in urinary calcium (Ca), pyridinoline (Pyr), and deoxypyridinoline (D-Pyr) excretion during the hypocalcemic response were assessed. Although the lower doses (0.01-0.25 mg/kg) of alendronate did not influence plasma Ca, the high doses (1.25-6.25 mg/kg) significantly decreased plasma Ca by the third day after single iv administration. In these groups, urinary Ca excretion did not show any significant change, but urinary Pyr and D-Pyr excretion decreased significantly at high doses. The hypocalcemic effect lasted for only 1 or 2 days (2-3 days after injection) even at high doses of alendronate. In the group receiving elcatonin (8.0 U/kg, twice daily), a significant decrease in plasma Ca was evident as early as 1 day after the start of administration. This was accompanied by a marked increase in urinary Ca excretion in the early stage without a significant decrease in urinary Pyr or D-Pyr excretion, and the suppression of bone resorption was more pronounced in the late phase of treatment with elcatonin. These results suggest that alendronate decreases plasma Ca chiefly by suppressing bone resorption, whereas elcatonin decreases plasma Ca by inhibiting bone resorption and accelerating Ca excretion. The present data show that both alendronate and elcatonin inhibit bone resorption and exert an antihypercalcemic effect, but the mechanism of action is different in the two drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8641213&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Modulation of adhesion-dependent cAMP signaling by echistatin and alendronate.

Fong JH, Ingber DE.

Department of Surgery, Children's Hospital & Harvard Medical School, Boston, Massachusetts 02115, USA.

We measured intracellular cAMP levels in cells during attachment and spreading on different extracellular matrix (ECM) proteins. Increases in cAMP were observed within minutes when cells attached to fibronectin, vitronectin, and a synthetic RGD-containing fibronectin peptide (Petite 2000), but not when they adhered to another integrin alpha nu beta 3 ligand, echistatin. Because echistatin also inhibits bone resorption, we measured the effects of adding another osteoporosis inhibitor, alendronate, in this system. Alendronate inhibited the cAMP increase induced by ligands that primarily utilize integrin alpha nu beta 3 (vitronectin, Peptite 2000), but not by fibronectin which can also use integrin alpha 5 beta 1. These results show that cell adhesion to ECM can increase intracellular cAPM levels and raise the possibility that inhibitors of osteoporosis may act, in part, by preventing activation of this pathway by integrins.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8660334&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
[Reduction of the Nordin index after therapy with oral alendronate in patients with postmenopausal osteoporosis]

[Article in Italian]

Busi S, Catalano A.

Centro per l'Osteoporosi, Azienda U.S.L., Roma.

The authors observe a significant reduction in value of the Nordin's Index (a sensible test for the screening of the "fast-losers" patients) in 10 women with post-menopausal osteoporosis after therapy with alendronate 5 mg daily per os for six months. The authors propound the measurement of the Nordin's Index in order to assess the alendronate's therapy per os in the post-menopausal osteoporosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8681505&dopt=Abstract alendronate Fosamax