alendronate, Fosamax
Qualitative analysis of peripheral peri-implant bone and influence of alendronate sodium on early bone regeneration.

Meraw SJ, Reeve CM.

The Mayo Clinic Section of Periodontics, Department of Dental Specialties, Mayo Clinic and Mayo Foundation, Rochester, MN, USA.

BACKGROUND: Alendronate sodium increases alveolar bone density with systemic use. It inhibits osteoclast activity and is thought to result in a net increase in osteoblastic activity. However, little is known about local in vivo use. The purpose of this study was to evaluate the effect of local delivery of alendronate on bone regeneration within peri-implant defects. Peri-implant bone was examined histomorphometrically to evaluate the amount of supporting bone peripheral to the bone-implant interface. METHODS: Six adult hound dogs were evenly divided into 2 groups, with one group receiving alendronate-coated dental implants and the other group serving as controls. Dental implants were placed immediately after extraction of right and left second, third, and fourth mandibular premolars. Forty-eight dental implants were placed (2 types in each dog: 24 hydroxyapatite [HA]-coated and 24 titanium machine-polished [TMP]), for a total of 4 variables. A bioabsorbable collagen membrane was secured over the implants and defects, and the flaps closed primarily. The dogs were sacrificed on day 28. Specimens were sectioned, mounted, and stained with Stevenel's blue and van Gieson's picric fuchsin. The amount of bone adjacent and 1 mm peripheral to the implant surface was recorded with a computerized microscopic digitizer. RESULTS: Locally applied alendronate resulted in significantly increased amounts of bone (P<0.0002, ANOVA) in the peripheral area with both HA and TMP implants. However, the most influential factor in the amount of peripheral bone was the type of implant surface (P<0.0001). CONCLUSIONS: Local application of alendronate is useful in increasing the amount of peripheral peri-implant bone. Also, the amount of supporting bone was not related to the bone-to-implant contact but to the surface characteristics of the implant. The findings of the present study indicate that the evaluation of dental implant-supporting bone should include peripheral bone as well as bone-to-implant interface.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10534078&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate interacts with the inhibitory effect of 1,25(OH)2D3 on parathyroid hormone-related protein expression in human osteoblastic cells.

Gomez-Garcia L, Esbrit P, Carreno L, Sabando P, Garcia-Flores M, Martinez ME.

Research Division, Hospital La Paz, Madrid, Spain.

The bisphosphonate alendronate is a potent inhibitor of bone resorption by its direct action on osteoclasts. In addition, there is some data suggesting that alendronate could also inhibit bone resorption indirectly by interacting with osteoblasts. Parathyroid hormone-related protein (PTHrP) produced by osteoblasts and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are regulators of bone remodeling, which have interrelated actions in these cells. In this study, we assessed whether alendronate can affect PTHrP expression in the presence or absence of 1,25(OH)2D3 in human primary osteoblastic (hOB) cells from trabecular bone. Cell total RNA was isolated, and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was carried out using human PTHrP-specific primers. PTHrP in the hOB cell-conditioned medium was analyzed by a specific immunoradiometric assay. We found that PTHrP mRNA and secreted PTHrP were maximally inhibited by 10(-8) - 10(-6) M of 1,25(OH)2D3 treatment within 8-72 h in hOB cells. Alendronate (10(-14) - 10(-8) M) modified neither PTHrP mRNA nor PTHrP secretion, although it consistently abrogated the decrease in PTHrP production induced by 1,25(OH)2D3 in these cells. On the other hand, alendronate within the same dose range did not affect either the vitamin D receptor (VDR) mRNA or osteocalcin secretion, with or without 1,25(OH)2D3, in hOB cells. The inhibitory effect of alendronate on the 1,25(OH)2D3-induced decrease in PTHrP in these cells was mimicked by the calcium ionophore A23187 (5 x 10-6 M), while it was eliminated by 5 x 10(-5) M of nifedipine. Furthermore, although alendronate alone failed to affect [Ca2+]i in these cells, it stimulated [Ca2+]i after pretreatment of hOB cells with 10(-8) M of 1,25(OH)2D3, an effect that was abolished by 5 x 10(-5) M of nifedipine. These results show that alendronate disrupts the modulatory effect of 1,25(OH)2D3 on PTHrP production in hOB cells. Our findings indicate that an increase in calcium influx appears to be involved in the mechanism mediating this effect of alendronate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12510808&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Long-term therapy of ovariectomy-induced osteopenia with parathyroid hormone analog SDZ PTS 893 and bone maintenance in retired breeder rats.

Thomsen JS, Mosekilde LI, Gasser JA.

Department of Cell Biology, Institute of Anatomy, University of Aarhus, Denmark.

The aim of the study was to assess the long-term anabolic effect of the parathyroid hormone (PTH) analog SDZ PTS 893 in a dose-response manner, and to determine the ability of the antiresorptive agents estradiol and alendronate to maintain bone mass after withdrawal of SDZ PTS 893. One hundred thirty retired breeder Wistar rats were distributed into 13 groups with 10 rats in each group: 1 baseline group, 2 sham groups, and 10 ovariectomized groups. Treatment was initiated 12 weeks after ovariectomy. SDZ PTS 893 treatment was administered daily subcutaneously (Monday to Friday) for 36 weeks. Treatment regimens were as follows: (1) baseline (-12 weeks); (2) ovariectomy (ovx) (0 weeks); (3) sham (36 weeks); (4) ovx (36 weeks); (5) SDZ PTS 893 12.5 microg/kg/day (36 weeks); (6) SDZ PTS 893 25 microg/kg/day (36 weeks); (7) SDZ PTS 893 50 microg/kg/day (36 weeks); (8) SDZ PTS 893 100 microg/kg/day (36 weeks); for the maintenance part of the study: (9) sham (48 weeks); ovx animals treated with SDZ PTS 893, 50 microg/kg/day for 36 weeks followed by 12 weeks of treatment regimens: (10) placebo; (11) SDZ PTS 893 50 microg/kg/day; (12) estradiol 10 microg/kg/day; or (13) alendronate 28 microg/kg (2 injections/week). The effects of ovx, SDZ PTS 893 treatment, and maintenance regimens were measured at four skeletal sites: lumbar vertebra; femoral diaphysis; distal femoral metaphysis; and proximal femoral metaphysis (femoral neck). At these sites, bone density and bone strength were measured as treatment endpoints. Furthermore, bone dimensions were measured at the midpoint of the femur. The results showed that SDZ PTS 893 increased bone strength in a dose-dependent manner at all skeletal sites tested. At the vertebral body and distal femoral metaphysis, apparent ash density increased in a similar way. There was a slight decrease in cortical density at the mid-diaphyseal site. Static histomorphometry showed increased bone area due to a decreased marrow area (endosteal net bone gain) but also due to increased tissue area (periosteal net bone gain). For maintenance, continuous SDZ PTS 893 therapy was most efficient, followed by alendronate and estradiol treatment with regard to preservation of bone mass and strength. It is concluded that the new PTH analog SDZ PTS 893 has a highly anabolic, dose- and time-dependent effect on all skeletal sites tested. Bone formation is induced at both endosteal and periosteal surfaces.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10574576&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1 kinase during apoptosis. A link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase.

Reszka AA, Halasy-Nagy JM, Masarachia PJ, Rodan GA.

Department of Bone Biology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. Alfred_Reszka merck.com

Bisphosphonates (BPs) include potent inhibitors of bone resorption used to treat osteoporosis and other bone diseases. BPs directly or indirectly induce apoptosis in osteoclasts, the bone resorbing cells, and this may play a role in inhibition of bone resorption. Little is known about downstream mediators of apoptosis in osteoclasts, which are difficult to culture. Using purified osteoclasts, we examined the effects of alendronate, risedronate, pamidronate, etidronate, and clodronate on apoptosis and signaling kinases. All BPs induce caspase-dependent formation of pyknotic nuclei and cleavage of Mammalian Sterile 20-like (Mst) kinase 1 to form the active 34-kDa species associated with apoptosis. Withdrawal of serum and of macrophage colony stimulating factor, necessary for survival of purified osteoclasts, or treatment with staurosporine also induce apoptosis and caspase cleavage of Mst1. Consistent with their inhibition of the mevalonate pathway, apoptosis and cleavage of Mst1 kinase induced by alendronate, risedronate, and lovastatin, but not clodronate, are blocked by geranylgeraniol, a precursor of geranylgeranyl diphosphate. Together these findings suggest that BPs act directly on the osteoclast to induce apoptosis and that caspase cleavage of Mst1 kinase is part of the apoptotic pathway. For alendronate and risedronate, these events seem to be downstream of inhibition of geranylgeranylation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10574973&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
[A cost-effectiveness analysis of alendronate compared to placebo in the prevention of hip fracture]

[Article in Spanish]

Rodriguez Escolar C, Fidalgo Garcia ML, Rubio Cebrian S.

Servicio de Farmacia, Atencion Primaria de las Areas 3 y 8 del INSALUD, Madrid. farmacia ui-area3.rediris.es

OBJECTIVE: To examine if the treatment with alendronate to prevent hip fracture (HF) in female with established osteoporosis is more cost-effectiveness than placebo, and if changes in efficacy, cost and incidence of adverse reactions of the treatment can affect the ratio, and the direction of decision. DESIGN: The study is based on a decision tree model to examine the cost-effectiveness ratio (CE) of alendronate (10 mg/d alendronate, 500 mg/d calcium and 250 IU vitamin D3) versus placebo (500 mg/d calcium and 250 IU vitamin D3). The treatment of 1000 patients with established osteoporosis and its course of events and probabilities during three years of treatment is simulated. RESULTS: The efficacy of each alternative is obtained by controlled clinical trials. The considered costs, from the first perspective of the services provider, and expressed in pesetas per year in 1998, are direct health tangibles: pharmacological treatment, HF surgery and treatment of serious adverse reactions (SAR). An analysis of simple univariate sensibility and one of incremental is applied on the efficacy, cost and incidence of adverse reactions to alendronate. The ratio CE of alendronate is 297.879 pesetas/success (patient without fracture and without SAR) and 23.301 pesetas/success for placebo. For the hypothesis of a 100% alendronate efficacy, the ratio CE is 287.217 pesetas/success and without SAR is 297.830 pesetas/success. A cost of 210 pesetas/alendronate box will determine that this alternative is as cost-effective as placebo. CONCLUSIONS: The administration of alendronate to prevent HF on postmenopausal female with established osteoporosis is not the option to take into account. Just a decrease of the cost of alendronate below its crossing value will turn it into a cost-effective alternative.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10592546&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
N-bisphosphonates cause gastric epithelial injury independent of effects on the microcirculation.

Wallace JL, Dicay M, McKnight W, Bastaki S, Blank MA.

Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. wallacej ucalgary.ca

BACKGROUND: Nitrogen-containing bisphosphonates have been shown to be effective for the treatment of osteoporosis and Paget's disease of bone. Unfortunately, these drugs also have the capacity to irritate the upper gastrointestinal mucosa. In this study we investigated the ability of alendronate and pamidronate to directly damage the gastric epithelium and attempted to determine whether these drugs caused injury through gastric microcirculatory alterations. METHODS: An ex vivo gastric chamber model was used. Effects of topically applied alendronate and pamidronate on transmucosal potential difference and epithelial integrity (histology) were determined. Also, the effects of agents capable of preventing microvascular injury in the stomach (PGE2 and two nitric oxide donors) were examined for their ability to prevent gastric injury induced by the two N-bisphosphonates. RESULTS: Alendronate and pamidronate caused a concentration-dependent decrease in transmucosal potential difference, widespread epithelial injury and infiltration of neutrophils into the mucosa. PGE2 and the two nitric oxide donors did not prevent the changes in potential difference or the epithelial injury, but did reduce neutrophil infiltration. Significant release of PGE2 into the lumen was observed following application of the two bisphosphonates, but neither drug altered mucosal blood flow. CONCLUSIONS: These results suggest that these N-bis- phosphonates directly damage the gastric epithelium independent of actions on the microvasculature.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10594404&dopt=Abstract alendronate Fosamax