alendronate, Fosamax
A controlled study of the effects of alendronate in a growing mouse model of osteogenesis imperfecta.

Camacho NP, Raggio CL, Doty SB, Root L, Zraick V, Ilg WA, Toledano TR, Boskey AL.

Research Division, The Hospital for Special Surgery, New York, NY 10021, USA.

Recent studies have reported that bisphosphonates reduce fracture incidence and improve bone density in children with osteogenesis imperfecta (OI). However, questions still persist concerning the effect of these drugs on bone properties such as ultrastructure and quality, particularly in the growing patient. To address these issues, the third-generation bisphosphonate alendronate was evaluated in the growing oim/oim mouse, an animal model of moderate-to-severe OI. Alendronate was administered to 6-week-old mice during a period of active growth at a dosage of 73 microg alendronate/kg/day for the first 4 weeks and 26 microg alendronate/kg/day for the next 4 weeks. Positive treatment effects included a reduction in the number of fractures sustained by the alendronate-treated oim/oim mice compared with untreated oim/oim mice (2.1+/-2.0 vs 3.2+/-1.6 fractures per mouse), increased femoral metaphyseal density (0.111+/-0.02 vs 0.034+/-0.04 g/cm2), a tendency towards reduced tibial bowing (4.0+/-3.7 vs 6.1+/-5.8 degrees), and towards increased femoral diameter (1.22+/-0.12 vs 1.15+/-0.11 mm). Potential negative effects included a persistence of calcified cartilage in the treated oim/oim metaphyses compared with treated wildtype (+/+) (33.8+/-11.1 vs 22.1+/-10.2%), and significantly shorter femora compared with nontreated oim/oim mice (14.8+/-0.67 vs 15.3+/-0.37 mm). This preclinical study demonstrates that alendronate is effective in reducing fractures in a growing mouse model of OI, and is also an important indicator of potential positive and negative outcomes of third-generation bisphosphonate therapy in children with OI.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11683430&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
A theoretical analysis of the contributions of remodeling space, mineralization, and bone balance to changes in bone mineral density during alendronate treatment.

Hernandez CJ, Beaupre GS, Marcus R, Carter DR.

Rehabilitation Research and Development Center, VA Palo Alto Health Care System, CA, Palo Alto, USA. hernandez96 post.harvard.edu

In patients with osteoporosis, alendronate treatment causes an increase in bone mineral density (BMD) and a decrease in fracture incidence. Alendronate acts by changing the bone remodeling process. Changes in bone remodeling resulting in decreased remodeling space, increased bone balance per remodeling cycle, and increased mineralization (ash mass/bone mass) have all been associated with alendronate treatment. Understanding the relative contributions of these parameters to BMD increases could help predict the utility of long-term (>10 years) or intermittent treatment strategies, as well as treatment strategies in which another pharmaceutical is administered concurrently. We have developed a computer simulation of bone remodeling to compare the contributions of focal bone balance and mineralization on BMD by simulating alendronate treatment using a bone balance method (decreased remodeling space, increased focal bone balance, uniform bone mineralization) and a mineralization method (decreased remodeling space, neutral focal bone balance, varying bone mineralization). Although both methods are able to predict BMD increases caused by alendronate over short periods, our findings suggest that the mineralization method may be more descriptive of long-term alendronate treatment. This implies that mineralization may be a larger contributor to BMD changes caused by alendronate than the focal bone balance. Based on this finding we offer a hypothesis to describe how remodeling space, focal bone balance, and mineralization each contribute to alendronate-induced BMD changes. Future analyses with this method could be used to identify improved dosing regimens and to predict which osteoporosis treatments would best complement each other.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11728920&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Inhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis.

Halasy-Nagy JM, Rodan GA, Reszka AA.

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

Bisphosphonate inhibition of bone resorption was proposed to be due to osteoclast apoptosis. We tested this hypothesis for both the N-containing bisphosphonates alendronate and risedronate, which inhibit farnesyldiphosphate synthase and thus protein isoprenylation, and for clodronate and etidronate, which are metabolized to adenosine triphosphate (ATP) analogs. We found, in dose-response studies, that alendronate and risedronate inhibit bone resorption (in pit assays) at doses tenfold lower than those reducing osteoclast number. At an N-bisphosphonate dose that inhibited resorption and induced apoptosis, the antiapoptotic caspase inhibitor, Z-VAD-FMK, maintained osteoclast (Oc) number but did not prevent inhibition of resorption. Furthermore, when cells were treated with either alendronate alone or in combination with Z-VAD-FMK for 24 or 48 h, subsequent addition of geranylgeraniol, which restores geranylgeranylation, returned bone resorption to control levels. On the other hand, Z-VAD-FMK did block etidronate and clodronate inhibition of resorption. Moreover, in cells treated with etidronate, but not alendronate or risedronate, Z-VAD-FMK also prevented actin disruption, an early sign of osteoclast inhibition by bisphosphonates. These observations indicate that, whereas induction of apoptosis plays a major role in etidronate and clodronate inhibition of resorption, alendronate and risedronate suppression of bone resorption is independent of their effects on apoptosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11728926&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate for the treatment of osteoporosis in men.

Adami S, Prizzi R, Colapietro F.

Riabilitazione Reumatologica, Universita di Verona, Ospedale di Valeggio, Italy.

The incidence of osteoporotic fracture in males is approximately one-third of that observed in women, but information on specific therapies is almost exclusively limited to bisphosphonate alendronate. The most important study with this compound included 241 men, randomized to receive either alendronate 10 mg/day or placebo. In another study 134 men were given either 10 mg alendronate or alfacalcidiol 1 microg/day. After 24 months, the treatment with alendronate bone mineral density (BMD) significantly increased in both studies by 7-10% at the lumbar spine and by 2.5-5.2% at the femoral neck. These changes were associated with decreases in vertebral fracture rate and in stature loss, both statistically significant when the data of the two trials were meta-analysed. The BMD changes after alendronate therapy were comparable to those observed in postmenopausal osteoporosis. This was confirmed in a trial specifically designed to compare alendronate efficacy in men and postmenopausal women with either primary or secondary osteoporosis. Gender-comparative efficacy data can also be inferred from clinical trials in glucocorticoid-induced osteoporosis of alendronate, risedronate, and etidronate, carried out in both women and men. By combining the results of all these trials, bisphosphonate efficacy in terms of both BMD changes and fracture incidence appears to be moderate in premenopausal women but quite obvious and comparable in males and postmenopausal women.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11730259&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
The effect of alendronate (Fosamax) and implant surface on bone integration and remodeling in a canine model.

Frenkel SR, Jaffe WL, Valle CD, Jazrawi L, Maurer S, Baitner A, Wright K, Sala D, Hawkins M, Di Cesare PE.

Musculoskeletal Research Center and Department of Orthopaedic Surgery, New York University Hospital for Joint Diseases, New York, New York 10003, USA. sally.frenkel excite.com

Patients at high risk for osteoporosis and its associated morbidity, including postmenopausal women, are being pharmacologically managed to stabilize and improve bone mass. Alendronate sodium (Fosamax) is a commonly used antiresorptive agent effective in osteopenic women for reducing bone resorption, increasing bone density, and decreasing fracture incidence. With the increased incidence of alendronate-treated women who are undergoing hip replacement or fracture repair by prosthesis placement, data are needed to predict how alendronate affects host bone integration with uncemented surfaces. The aim of this study was to determine the effect of alendronate on new bone formation and attachment to implant surfaces in a normal and simulated estrogen-deficient, calcium-deficient canine model, using an implantable bone growth chamber. Alendronate did not affect host bone integration to surfaces commonly used in uncemented total joint arthroplasty, but there were significant differences dependent solely on the type of surface. Copyright 2001 John Wiley & Sons, Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11745516&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Sintered dicalcium pyrophosphate increases bone mass in ovariectomized rats.

Sun JS, Huang YC, Tsuang YH, Chen LT, Lin FH.

Department of Orthopedic Surgery, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan, Republic of China.

Bisphosphonates are synthetic pyrophosphate analogs that can be used for the treatment of osteoporosis. Sintered dicalcium pyrophosphate, as a pyrophosphate analog, may be useful in the clinical setting for osteoporosis. In this study, an ovariectomized rat model is used to evaluate the effects of orally administered sintered dicalcium pyrophosphate on bone mass. Thirty-six female rats were used in this study. They randomly were divided into six groups: a negative normal control group, a positive osteoporosis control group, and ovariectomized groups treated either with alendronate sodium (one group) or sintered dicalcium pyrophosphate (three groups, each at a different level). The animals were sacrificed at 4 weeks after treatment. For all the rats, whole blood samples were obtained for the biochemical study. Bone ashes of long bones were measured and studied and histologic studies of cancellous bone were carried out. The ingestion of either alendronate or sintered dicalcium pyrophosphate did not have any deleterious effect on the major visceral organs. Ingestion of alendronate or sintered pyrophosphate decreased the bony porosity and increased bone mineral contents in the long bones of ovariectomized rats. Thus sintered dicalcium pyrophosphate can increase bone mass in the ovariectomized rat. Copyright 2001 John Wiley & Sons, Inc. J Biomed Mater Res 59: 246-253, 2002

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11745559&dopt=Abstract alendronate Fosamax