alendronate, Fosamax
Effects of alendronate on bone loss in pre- and postmenopausal hyperthyroid women treated with methimazole.

Lupoli G, Nuzzo V, Di Carlo C, Affinito P, Vollery M, Vitale G, Cascone E, Arlotta F, Nappi C.

Department of Molecular and Clinical Endocrinology and Oncology, School of Medicine, University Federico II, Naples, Italy.

High levels of thyroid hormones accelerate bone turnover. The aim of the present study was to evaluate the effects of treatment with alendronate in patients affected by hyperthyroidism and osteoporosis. We studied 40 hyperthyroid patients with bone loss, divided into two groups according to menopausal state. Before treatment and after 6 and 12 months, serum thyroid hormones levels, serum osteocalcin level and bone mineral density were evaluated. In all patients we observed an increase in bone mineral density after treatment with alendronate, and a corresponding decrease in serum osteocalcin level.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8915664&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Technetium-99m-alendronate: a new radiopharmaceutical for bone scanning.

Arteaga de Murphy C, Melendez-Alafort L, Montoya-Molina C, Sepulveda-Mendez J.

Departamento de Medicina Nuclear y Clinica de Tiroides, Instituto Nacional de la Nutricion Salvador Zubiran, Mexico, D.F.

The purpose of this paper is to report the preparation of a new technetium-99m-radiopharmaceutical for bone scanning. The chelating agent for 99mTc is a new bisphosphonate, alendronate, 4-amino-1-hydroxy-butylidene-1, 1-bisphosphonate (ABP) used as a treatment for osteoporosis. ABP, because of its amino group, seems to be better suited to form a strong and stable complex with technetium-99m and therefore might be better than 99mTc-etidronate (HEDP) or 99mTc-medronate (MDP) for bone scanning. A sterile dry kit containing APB, a reducing agent and a stabilizer was prepared. The parameters studied were molar concentrations, pH, shelf life, labeling efficiency and radiochemical purity. The oven dried sterile kit was formulated with 5 mg ABP, 0.25 mg stannous fluoride and 0.025 mg gentisic acid at pH 2.5-3.5. The labeling efficiency with 20-1500 MBq of pertechnetate (99mTcO4-) was over 95% at room temperature and was stable for 5 h. Technetium-99m-alendronate was tested in two rabbits and it proved to be a promising new radiopharmaceutical for bone scanning. Work is underway to study 99mTc-ABP biodistribution in a statistically significant number of laboratory animals and, later on, to determine radiopharmacokinetic parameters in normal volunteers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8987181&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Nonclinical model for assessing gastric effects of bisphosphonates.

Blank MA, Ems BL, Gibson GW, Myers WR, Berman SK, Phipps RJ, Smith PN.

Procter & Gamble Pharmaceuticals, Miami Valley Laboratories, Cincinnati, Ohio 45253, USA.

Gastrointestinal intolerance has been associated with amino bisphosphonate therapy in the clinic. The objective of this study was to develop a model for assessing bisphosphonate-induced gastric damage that may aid in the development of future bisphosphonate therapies. Rats were dosed concomitantly with indomethacin (40 mg/kg, subcutaneously) and an amino or pyridinyl bisphosphonate (orally at. 150, 225 or 300 mg/kg). The bisphosphonates studied were pamidronate and alendronate (primary amino bisphosphonates) and risedronate and NE-97221 (pyridinyl bisphosphonates). Macroscopically, alendronate induced significantly (P < 0.05) more antral damage (both lesion length and number) than pamidronate and risedronate at 225 and 300 mg/kg, and more than NE-97221 at 300 mg/kg. NE-97221 induced significantly more antral damage (lesion length) than risedronate at 225 mg/kg and a greater number of lesions compared to pamidronate and risedronate at 225 and 300 mg/kg. The model was validated histologically, and macroscopic findings correlated with histologic evidence of antral mucosal necrosis and inflammatory infiltration of the lamina propria. The calcium chelators EGTA and EDTA did not induce gastric damage in this model when dosed according to the same protocol as the nitrogen-containing bisphosphonates. This suggests that calcium chelation does not account for the gastric effects in this model. The fasted, indomethacin-treated rat provides a novel nonclinical model to assess gastric effects of bisphosphonates, which may aid in the development of future bisphosphonate therapies. These data suggest that when expressed on an actual or anticipated clinical dose basis for osteoporosis (pamidronate, 150 mg; alendronate, 5-10 mg; risedronate and NE-97221, 5 mg), primary amino bisphosphonates may have a greater potential for inducing gastric damage than do pyridinyl bisphosphonates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9052507&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Effect of alendronate treatment on the osteoclastogenic potential of bone marrow cells in mice.

van Beek ER, Lowik CW, Papapoulos SE.

Department of Endocrinology and Metabolic Diseases, University Hospital, Leiden, the Netherlands.

Bisphosphonates suppress bone resorption by inhibiting the activity of mature osteoclasts as well as the formation of osteoclasts from bone marrow-derived precursor cells. It is not yet known at which level of osteoclast development this latter action is exerted and whether this is due to a systemic effect of circulating bisphosphonate or to an action at the bone surface, given the property of these compounds to concentrate specifically at active bone sites. We addressed these questions in an ex vivo study in mice. The animals were treated with the bisphosphonate alendronate for various periods, and the central compartment of the bone marrow was isolated and cultured together with osteoclast-free fetal mouse bone explants. In this way the capacity of bone marrow cells, exposed previously to alendronate in vivo, to generate osteoclasts and induce resorption in vitro was examined. Alendronate (0.25 mg/kg, subcutaneously) given to mice for periods up to 4 weeks suppressed bone resorption, as expected, but did not affect the capacity of bone marrow cells to develop into mature osteoclasts and resorb the calcified matrix of bone explants. In addition, using monoclonal antibodies specific for different macrophage-granulocyte precursor subsets, we found that alendronate treatment did not affect the pattern of antigen expression of bone marrow cells, which is in line with the lack of an effect of the bisphosphonate on the ability of bone marrow cells to induce resorption in vitro. In contrast, in control experiments, lipopolysaccharide (0.1 mg) treatment induced marked changes in the pattern of antigen expression of bone marrow cells. In conclusion, our studies demonstrate that the inhibition of bone resorption by alendronate does not involve alteration of the osteoclastogenic potential of osteoclast progenitors (precursors) from the central bone marrow compartment. Moreover, this treatment did not alter the expression of markers specific for monocyte-macrophage precursors as well as mature macrophages. These results suggest that the effects of alendronate are exerted at the bone surface at late osteoclast precursors (and mature osteoclasts).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9108353&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Effects of alendronate and taxol on PC-3 ML cell bone metastases in SCID mice.

Stearns ME, Wang M.

Department of Pathology, Medical Colleges of Pennsylvania, Allegheny University of Health Sciences, Philadelphia 19102, USA.

The combined influence of alendronate, a bisphosphonate compound, and taxol on the establishment and growth of human PC-3 ML subclones injected intravenously via the tail vein in SCID mice was investigated. The pretreatment of SCID mice with alendronate (0.04-0.1 mg/kg twice weekly or 0.1 mg/kg weekly) partially blocked the establishment of bone metastases by human PC-3 ML cells and resulted in tumor formation in the peritoneum and other soft tissues. However, alendronate pretreatment of mice (0.1 mg/kg twice weekly or weekly) and dosing along with taxol (10-50 mg/kg/day, twice weekly, or weekly) blocked the growth of PC-3 ML tumors in the bone marrow and soft tissues in a statistically significant manner and improved survival rates significantly (p < 0.001) by 4-5 weeks. ELISAs and zymography of matrix metalloproteinase production in vitro and in vivo showed that alendronate and taxol alone partially inhibited metalloproteinase production, but that taxol in combination with alendronate totally blocked protease production and release. The combined activities of alendronate and taxol appeared to inhibit the establishment and growth of tumors in SCID mice, perhaps, in part, as a result of inhibition of protease production and release.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9186547&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Osteoclast activation: potent inhibition by the bisphosphonate alendronate through a nonresorptive mechanism.

Owens JM, Fuller K, Chambers TJ.

Department of Histopathology, St. George's Hospital Medical School, London, United Kingdom.

Alendronate, an aminobisphosphonate used in the treatment of osteoporosis, is a potent inhibitor of bone resorption. Its mechanism of action is unknown. Because it localizes to bone surfaces, we compared the sensitivity of components of the resorptive process to incubation on alendronate-coated bone surfaces. We found that bone resorption by osteoclasts isolated from neonatal rat bone was unaffected by alendronate (10(-4) M). Osteoclast production in bone marrow cultures, as assessed by the production of calcitonin-receptor positive cells, was observed even at 10(-4) M, but bone resorption in these cultures was almost completely abolished by 10(-5) M alendronate. The greater sensitivity of osteoclast activation to inhibition by alendronate that these results suggest was supported by similar inhibition of osteoblast-mediated activation of osteoclasts from neonatal rat bone. Thus, activation of osteoclasts by osteoblastic/stromal cells is apparently the most sensitive component of the pathway whereby bone resorption is affected. Moreover, the ability of alendronate to suppress osteoclastic activation does not depend on resorption-mediated release of alendronate from bone surfaces. This ability extends the range of cell types and processes that might be affected by alendronate, beyond those in the immediate vicinity of resorbing cells, to include any cell that comes into contact with alendronate-coated bone surfaces.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9207928&dopt=Abstract alendronate Fosamax