alendronate, Fosamax
How myeloma cells escape bisphosphonate-mediated killing: development of specific resistance with preserved sensitivity to conventional chemotherapeutics.

Salomo M, Jurlander J, Nielsen LB, Gimsing P.

Department of Haematology, University of Copenhagen, Denmark. salomo rh.dk

Although amino-bisphosphonates (N-BPs) induce apoptosis of myeloma cells in vitro, most in-vivo studies fail to demonstrate a corresponding antitumour effect. This discrepancy might reflect the development of resistance to the antitumour effects of N-BP in myeloma cells when they are exposed to N-BP for a prolonged time. To test this hypothesis, two N-BP-sensitive human myeloma cell lines were continuously exposed to increasing concentrations of the N-BP alendronate for 6 weeks. During this treatment period, 10 out of 10 sublines developed reduced apoptotic and antiproliferative responses to alendronate treatment. This de novo alendronate resistance was accompanied by resistance to another N-BP (zoledronate) but not to an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase or Fas ligand. Importantly, N-BP-resistant myeloma cells also remained sensitive to conventional myeloma chemotherapeutics (melphalan, doxorubicin and vincristine). Further analysis of the N-BP-resistant cells revealed an increased activity of the N-BP-specific target enzyme farnesyl pyrophosphate synthase, without upregulation of its gene transcription. Our results suggest that continuous exposure of myeloma cells to alendronate leads to the development of N-BP resistance. This is associated with an increased activity of farnesyl pyrophosphate synthase and does not evolve from defective apoptotic pathways. Importantly, the antitumour effects of conventional myeloma chemotherapeutics are preserved in the N-BP-resistant myeloma cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12846887&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Inhibition of mevalonate pathway is involved in alendronate-induced cell growth inhibition, but not in cytokine secretion from macrophages in vitro.

Toyras A, Ollikainen J, Taskinen M, Monkkonen J.

Department of Pharmaceutics, University of Kuopio, PO Box 1627, FIN-70211, Kuopio, Finland. anu.toyras uku.fi

Bisphosphonates are antiresorptive drugs used for the treatment of metabolic bone diseases. They can be divided into two different pharmacological classes: nitrogen-containing and non-nitrogen-containing bisphosphonates. Non-nitrogen-containing bisphosphonates, like clodronate, are metabolised to a toxic ATP-analogue preventing osteoclast mediated bone resorption. Nitrogen-containing bisphosphonates, including alendronate, prevent osteoclast function by inhibiting the mevalonate pathway. Clodronate is known to have anti-inflammatory properties while alendronate induces cytokine secretion from lipopolysaccharide- (LPS) induced macrophages. This study investigates whether the cytotoxicity and cytokine production induced by alendronate and LPS could be counteracted by clodronate or products of mevalonate pathway: oxidized low density lipoprotein (ox-LDL), farnesol and geranylgeraniol. Treatment with alendronate increased LPS-induced secretion of IL-1beta, IL-6 and TNF-alpha from RAW 264 macrophages 2.4-, 1.4- and 1.8-fold, respectively. This treatment was cytotoxic for macrophages as indicated by lowered cell viability. Clodronate and ox-LDL both counteracted the cytokine secretion and cytotoxicity of alendronate. Farnesol and geranylgeraniol did neither reverse the cytokine secretion nor reduce the cytotoxicity of alendronate. Clodronate and ox-LDL were able to counteract the effects of alendronate on macrophages in vitro, probably by their known ability to inhibit DNA binding activity of transcription factors, nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1). These findings suggest that inhibition of mevalonate pathway is not the mechanism responsible for the proinflammatory response caused by alendronate, as it is in alendronate-induced apoptosis and prevention of osteoclast function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12885386&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Effects of alendronate on structural properties of trabecular bone in dogs.

Jianhua H, Liang Z, Lilian Z, Gongyi H.

Department of Orthopaedics, Beijing Hospital, Beijing 100730.

OBJECTIVE: To evaluate the effects of alendronate on the structural properties of trabecular bone. METHODS: Alendronate was administered at a daily p.o. dose of 0.5 mg/kg over a 12-week period in hound dogs (n = 8 for both the control and treated group), and the structural indices of the lumbar vertebral (L1 and L2) trabecular bone were assessed directly from 3-D images. RESULTS: Treatment with alendronate increased bone volume fraction by 9.5% and 7.7% in L1 and L2 respectively. Trabecular thickness significantly increased after alendronate treatment, whereas trabecular separation remained constant. The degree of anisotropy for the alendronate-treated group was decreased compared with that of the control group. Bone surface to volume ratio declined significantly in the alendronate-treated group, whereas alendronate induced a higher bone surface density. CONCLUSION: Alendronate increased the structural properties of canine trabecular bone after short-term treatment at a dose of 0.5 mg x k(-1) x day(-1).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12901507&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Preventive effects of sequential treatment with alendronate and 1 alpha-hydroxyvitamin D3 on bone mass and strength in ovariectomized rats.

Ito M, Azuma Y, Takagi H, Kamimura T, Komoriya K, Ohta T, Kawaguchi H.

Pharmacological Research Department, Teijin Institute for Bio-medical Research, Teijin Ltd., 4-3-2 Asahigaoka, Hino, 191-8512 Tokyo, Japan.

Because accumulating evidence has shown that bisphosphonates are unable to maintain their bone-sparing effects after the withdrawal of the drug, a replacement treatment is needed when bisphosphonate treatment cannot be continued for some reason. The present study investigated the preventive effects of alendronate followed by 1alpha(OH)D3 on the mass and mechanical strength of trabecular and cortical bones in ovariectomized rats. Sprague-Dawley rats were ovariectomized or sham-operated at 48 weeks of age. Ovariectomized rats treated with vehicle alone (OVX group) showed significant decreases in bone mineral density (BMD) and mechanical strength of the lumbar vertebra and the midfemur during a 20-week period after the operation as compared with sham-operated rats. These decreases were prevented by continuous treatment with alendronate (0.5 mg/kg/day, po) for 20 weeks (ALN-C group), whereas the values reverted to those of the OVX group when alendronate was withdrawn at 10 weeks (ALN-W group). The sequential treatment with alendronate and 1alpha(OH)D3 (0.05 microg/kg/day, po) for 10 weeks each (ALN --> 1alpha group) resulted in higher BMD and mechanical strength of the lumbar vertebra and the midfemur in this group than in the OVX and ALN-W groups. The increase in mechanical strength was proportional to that in BMD at both sites, suggesting that the stimulatory effects of these treatments on bone strength were due to those on bone mass. Analyses of histology, computed tomography, and biochemical markers confirmed the preventive effects of the sequential treatment. Therefore, we propose that 1alpha(OH)D3 may be a good choice to replace alendronate when alendronate treatment cannot be continued for some reason.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12919703&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Combined local application of tetracycline and bisphosphonate reduces alveolar bone resorption in rats.

Yaffe A, Herman A, Bahar H, Binderman I.

Department of Prosthodontics, Hebrew University Hadassah School of Dental Medicine, Jerusalem, Israel. yaffeavi netvision.net.il

BACKGROUND: Recent animal studies have shown that a combination of chemically-modified tetracyclines together with bisphosphonates, when delivered systemically, are synergistically effective in suppressing periodontal bone loss. In the present study, we explored the combined efficacy of local delivery of alendronate and tetracyclines in reducing alveolar bone loss. METHODS: Eighty-six (86) male Wistar rats were used in these experiments. The flap was elevated using a special periosteal elevator, on both sides of the mandible, as described previously. A gelfoam pellet containing the drugs was applied between the alveolar bone and the mucoperiosteal flap, according to the experimental protocol. The rats were divided into 5 treatment groups: 1) alendronate; 2) doxycycline hyclate 10% (DOXY); 3) tetracycline hydrochloride 1% (TET); 4) alendronate + DOXY; and 5) alendronate + TET. In the operated control sites (C), saline was applied. The rats were sacrificed 21 days following the flap procedure. Sections of the mandibles (1.5 mm), in a buccal-lingual direction, underwent microradiography and were analyzed for bone loss. RESULTS: DOXY alone was most effective in reducing bone loss. Alendronate was also effective in reducing bone loss as shown in previous reports. TET did not reduce bone loss significantly when used alone. In combination with alendronate TET was synergistically effective. The combined local treatment of alendronate + DOXY showed no additive effect. CONCLUSIONS: In the present study, we found that tetracyclines can be most effective in reducing alveolar bone loss when applied locally. The combined local treatment of alendronate and tetracycline may have a synergistic effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12931767&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Long-term predictions of the therapeutic equivalence of daily and less than daily alendronate dosing.

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

Department of Orthopedics, The Mount Sinai School of Medicine, New York, New York 10029, USA.

Less than daily alendronate dosing has been identified as an attractive alternative to daily dosing for patients and physicians. A recent 2-year study found bone mineral density (BMD) changes caused by weekly alendronate dosing therapeutically equivalent to that caused by daily dosing. There are no methods that can be used to predict how long therapeutic equivalence will be maintained after the first 2 years of treatment. In addition, it is unclear if dosing less frequently than weekly also might be therapeutically equivalent to daily dosing. In this study we use a computer simulation to develop predictions of the therapeutic equivalence of daily and less than daily dosing over time periods as long as a decade. The computer simulation uses a cell-based computer model of bone remodeling and a quantitative description of alendronate pharmacokinetics/pharmacodynamics (PK/PD). The analyses suggest that less than daily dosing regimens do not increase BMD as much as daily dosing. However, model predictions suggest that dosing as frequent as weekly still may be therapeutically equivalent to daily dosing over periods as long as 10 years. In addition, the simulations predict dosing less frequently than weekly may be therapeutically equivalent to daily dosing within the first year of treatment but may not be therapeutically equivalent after 10 years. Hypotheses based on these simulations may be useful for determining which dosing regimen may be most attractive for clinical trials.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12211437&dopt=Abstract alendronate Fosamax