alendronate, Fosamax
Disintegration/dissolution profiles of copies of Fosamax (alendronate).

Epstein S, Cryer B, Ragi S, Zanchetta JR, Walliser J, Chow J, Johnson MA, Leyes AE.

Mount Sinai School of Medicine, New York, NY, USA. bonedocsol aol.com

OBJECTIVE: Poor quality has been reported for some generics and other copies of original products. We performed a pilot study to compare the disintegration/dissolution profiles of FOSAMAX (alendronate) 70 mg tablets with those of copies of FOSAMAX that were manufactured outside the United States. RESEARCH DESIGN AND METHODS: We used the standard United States Pharmacopeia (USP) disintegration method to evaluate FOSAMAX 70 mg tablets and 13 copies. At least 12 (n = 12) dosage units were tested for each product (except Fosmin, n = 10). The dissolution profiles of FOSAMAX and one representative copy were also compared. RESULTS: Nine copies (Osteomax, Defixal, Fosmin, Endronax, Osteomix, Genalmen, Fixopan, Osteoplus, and Fosval) disintegrated two- to ten-fold faster than FOSAMAX. Three other copies (Neobon, Regenesis, and Ostenan) disintegrated at least five-fold slower than FOSAMAX. Neobon is a softgel capsule, so special consideration was given to this different dosage form. One copy (Arendal) did not fall into either category but exhibited potentially large inter- and intra-lot variability. Dissolution of alendronate from Regenesis lagged behind that from FOSAMAX. CONCLUSION: Slower disintegration may reduce efficacy because bisphosphonates must be taken in the fasting state and contact with food or even certain beverages severely reduces bioavailability. Faster disintegration (or the use of gel-caps or other alterations to the drug formulation) could increase the risk of esophagitis, an adverse event associated with prolonged contact of the esophagus with bisphosphonates. These disintegration and dissolution results suggest that important differences may exist between FOSAMAX and its copies with regard to bioavailability, pharmacokinetics, and clinical efficacy and safety profiles. Additional testing is warranted to evaluate the pharmacokinetics and clinical safety of these copies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14687450&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate inhibits lysophosphatidic acid-induced migration of human ovarian cancer cells by attenuating the activation of rho.

Sawada K, Morishige K, Tahara M, Kawagishi R, Ikebuchi Y, Tasaka K, Murata Y.

Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Japan.

Alendronate, a nitrogen-containing bisphosphonate, is a potent inhibitor of bone resorption used for the treatment and prevention of osteoporosis. Recent findings suggest that alendronate and other nitrogen-containing bisphosphonates inhibit the mevalonate pathway and thereby inhibit the synthesis of products derived from this metabolite. This, in turn, prevents the prenylation of a number of small GTPases, which regulate cell growth, motility, and invasion. We studied the effect of alendronate on in vitro migration of human ovarian cancer cells. Lysophosphatidic acid (LPA) induced a dose-dependent increase of migration of cancer cells by promoting Rho/Rho-associated kinase signaling. The induction of cancer cell migration by LPA was inhibited by the addition of alendronate in a dose-dependent manner. Treatment of ovarian cancer cells with alendronate resulted in inactivation of Rho, changes of cell morphology, loss of stress fiber formation, and focal adhesion assembly, and the suppression of phosphorylation of myosin light chain and tyrosine phosphorylation of focal adhesion proteins, which are essential processes for cell migration. The effects of alendronate on cancer cells were prevented by the addition of geranylgeranyol, which is the metabolic intermediate of the mevalonate pathway. These results suggest that alendronate inhibits Rho activation by preventing geranylgeranylation, which results in inhibition of LPA-induced migration of human ovarian cancer cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12414621&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
The effect of alendronate sodium on spinal fusion: a rabbit model.

Lehman RA Jr, Kuklo TR, Freedman BA, Cowart JR, Mense MG, Riew KD.

Department of Orthopaedic Surgery and Rehabilitation, Walter Reed Army Medical Center, Washington, DC 20307, USA. Ronald.Lehman NA.AMEDD.ARMY.MIL

BACKGROUND CONTEXT: Bisphosphonates affect bone remodeling and increase bone mass through the inhibition of osteoclasts. Their effect on osteoblasts, and the balance between osteoblastic and osteoclastic activity on bone turnover and healing, is not completely understood. Specifically, the effect of bisphosphonates on spinal fusion has yet to be determined. With the increasing use of bisphosphonates in the elderly population, this effect needs to be delineated. PURPOSE: To evaluate the effect of alendronate sodium after an intertransverse process spinal fusion in a rabbit model. STUDY DESIGN/SETTING: Randomized double-blinded in vivo study of the effect of alendronate sodium in a spinal fusion model. METHODS: Fifty New Zealand white rabbits underwent a posterolateral L5-L6 intertransverse process arthrodesis with autogenous iliac crest bone graft. The rabbits were then randomly divided into two groups. Group I received 3 cc of saline placebo per oral gavage, and Group II received 200 micrograms (approximately 0.05 mg/kg/day) of alendronate sodium dissolved in 3 cc of saline per day for 8 weeks. Upon completion, the rabbits were sacrificed and the lumbar spines harvested, radiographed and graded for motion across the fusion site with manual palpation. Two independent pathologists then prepared and sectioned each left and right fusion mass. Three random x10 fields were examined and graded for both the cephalad and caudad ends of each section (516 fields). Fusion quality was graded using an established histological scoring scale (score 0 to 7 based on fibrous and bone content of the fusion mass). RESULTS: Two rabbits died on the day of operation, and 48 rabbits survived the operation. Five additional rabbits died within the first 2 postoperative weeks. Thus, 43 rabbits (21 in Group I, 22 in Group II) completed the 8-week course of treatment. Grading each side separately, 26 of 42 fusion masses (62%) in Group I and 24 of 44 fusion masses (55%) in Group II had radiographic evidence of fusion (p=.76). With gross palpation, 11 of 21 motion segments (52%) in Group I versus 13 of 22 motion segments (59%) in Group II were determined to have a solid fusion (p=.76). Histologically, Group I had a higher median score (6.0; range, 0 to 7 vs. 1.0; range, 0 to 7; p<.0001) and a higher fusion rate (76% vs. 45%; p=.004) than Group II. CONCLUSIONS: Alendronate sodium appears to inhibit or delay bone fusion in a rabbit model. Presumably, this occurs as a result of uncoupling the balanced osteoclastic and osteoblastic activity inherent to bone healing. These findings suggest that a discontinuance of alendronate sodium postoperatively during the acute fusion period may be warranted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14749192&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate reduces the daily consumption of insulin (DCI) in patients with senile type I diabetes and osteoporosis.

Maugeri D, Panebianco P, Rosso D, Calanna A, Speciale S, Santangelo A, Rizza I, Motta M, Lentini A, Malaguarnera M.

Department of Senescent, Urological and Neurological Sciences, University of Catania, Via Messina 829, 95126 Catania, Italy. dmaugeri tin.it

The use of Alendronate for the treatment of senile diabetes with osteopenia or osteoporosis is a common practice today, although the reasons for the success of this treatment are not completely understood. We investigated 40 elderly female patients, over 70 years of age, divided in two Groups (A and B) 20 cases of each, with insulin-dependent senile diabetes and fair metabolic balance, with an average disease duration of 30 +/- 4 years. They all had osteoporosis shown by the mean T-score of bone mineral densitometry. The Groups were treated as follows, Group A with 10 mg/day of Alendronate per os, with morning fasting plus a supplementation of calcium and vitamin D3, while the Group B received only calcium and vitamin D3 per os. Bone mineral density (BMD) expressed in mg/cm2, and in terms of T-score and Z-score at the spine (L1-L4) was monitored over time after 12 and 24 months, using dexa technique with a Lunar DPX densitometer. Moreover, the variation of daily consumption of insulin (DCI) of all the study population was calculated 12 and 24 months after the start of treatments. The data of Group A showed an improvement of osteoporosis, as evidenced by the increase of BMD at both times of measurement, accompanied by a significant reduction in the DCI (-21.6% by the 12th month, and -36.2% by the end of the observation period). In the Group B only small, statistically insignificant changes were observed in both the BMD and DCI. The most plausible explanation of reduction of DCI in Group A seems to be that Alendronate has improved the clinical symptoms of osteoporosis (pain, rigidity, and reduction of movements) through its action on the bone mass recovery and slowing down the bone turnover and under these conditions the diabetic patients improved their own physical performance. The better and more extensive movements certainly produced a reduction in the DCI, since a correct and adequate physical activity does contribute to an improved glucose metabolism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14764315&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Can the increase of bone mineral density following bisphosphonates treatments be explained by biomechanical considerations?

Pioletti DP, Rakotomanana LR.

Bone Bioengineering Group, STI/BIO-E/CRO, Center for Orthopedic Research, Bat. AAB, EPFL, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland. dominique.pioletti epfl.ch

OBJECTIVE: We hypothesized that bone mineral density increase following bisphosphonates treatments may be explained by the influence of the drug on the mechanical bone remodeling parameters. BACKGROUND: Patients treated with bisphosphonates continuously increase their bone mineral density. This increase is explained in the first 12-18 months following the treatment by the filling of the transient remodeling deficit. Recently, results of a clinical study of alendronate treatment over 7 years still show a continuous increase of bone mineral density. These results raised several questions regarding our understanding of bisphosphonates mode of action. METHODS: Bone remodeling is influenced by different factors including mechanical forces. In the present study, we propose then to consider the effect of bisphosphonates also under biomechanical considerations. RESULTS: Identification of the model with the clinical data showed that daily treatment of 10 and 20 mg alendronate decreased the bone turnover rate by 2% and 11%, respectively, in comparison with the 5 mg alendronate treatment. Moreover, the alendronate treatments decreases the resorption threshold stimulus by 19% (25%, 28%) for the 5 mg (10 and 20 mg, respectively) compared to placebo. CONCLUSIONS: The increase of bone mineral density following bisphosphonates treatment may then be explained by biomechanical considerations. Based on this description, bisphosphonates treatment may indeed change the susceptibility of bone to its biomechanical environment decreasing the mechanical threshold where bone should undergo resorption.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14967580&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Effect of alendronate on osteoclast differentiation and bone volume in transplanted bone.

Kawata T, Tenjou K, Tokimasa C, Fujita T, Kaku M, Matsuki A, Kohno S, Tsutsui K, Ohtani J, Motokawa M, Shigekawa M, Tohma Y, Tanne K.

Department of Orthodontics and Craniofacial Developmental Biology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.

Alendronate, one of the bisphosphonates, is known to have an inhibitory effect on bone resorption. The purpose of this study was to investigate the effects of alendronate on ectopic bone graft resorption and to determine the optimal dose in the mouse. The grafted bone in the control group disappeared due to resorption by osteoclasts within 5 weeks. In the experimental groups, the area of bone tissue decreased by only 20-40% at 5 weeks post-operatively. At 8 and 9 weeks after surgery, the decreased area of bone structure was significantly less in all the 10(-4) M injected alendronate-immersed groups than in the 10(-4) M non-injected alendronate-immersed. At 9 weeks after surgery, the number of osteoclasts were significantly less in the 10(-4) M injected alendronate-treated groups than in the 10(-4) M non-injected alendronate-treated groups. These results suggest that alendronate inhibits resorption of ectopic bone graft at concentrations of 10(-4) and 10(-6) M.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14993741&dopt=Abstract alendronate Fosamax