Alendronate, a double-edged sword acting in the mevalonate pathway (original) (raw)
Related papers
Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent …
Journal of Bone …, 1998
Background: Bisphosphonates are an important class of antiresorptive drugs used in the treatment of metabolic bone diseases. Recent studies have shown that nitrogen-containing bisphosphonates induced apoptosis in rabbit osteoclasts and prevented prenylated small GTPase. However, whether bisphosphonates inhibit osteoclast formation has not been determined. In the present study, we investigated the inhibitory effect of minodronate and alendronate on the osteoclast formation and clarified the mechanism involved in a mouse macrophage-like cell lines C7 and RAW264.7. Results: It was found that minodronate and alendronate inhibited the osteoclast formation of C7 cells induced by receptor activator of NF-κB ligand and macrophage colony stimulating factor, which are inhibited by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. It was also found that minodronate and alendronate inhibited the osteoclast formation of RAW264.7 cells induced by receptor activator of NF-κB ligand. Furthermore, minodronate and alendornate decreased phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt; similarly, U0126, a mitogen protein kinase kinase 1/2 (MEK1/2) inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, inhibited osteoclast formation. Conclusions: This indicates that minodronate and alendronate inhibit GGPP biosynthesis in the mevalonate pathway and then signal transduction in the MEK/ERK and PI3K/Akt pathways, thereby inhibiting osteoclast formation. These results suggest a novel effect of bisphosphonates that could be effective in the treatment of bone metabolic diseases, such as osteoporosis.
A Novel H2S-releasing Amino-Bisphosphonate which combines bone anti-catabolic and anabolic functions
Scientific Reports
Bisphosphonates (BPs) are the first-line treatment of bone loss resulting from various pathological conditions. Due to their high affinity to bone they have been used to develop conjugates with proanabolic or anti-catabolic drugs. We recently demontrated that hydrogen sulfide (H 2 S), promotes osteogenesis and inhibits osteoclast differentiation. Here we developed an innovative molecule, named DM-22, obtained from the combination of alendronate (AL) and the H 2 S-releasing moiety arylisothiocyanate. DM-22 and AL were assayed in vitro in the concentration range 1-33 μM for effects on viability and function of human osteoclasts (h-OCs) and mesenchymal stromal cells (h-MSCs) undergoing osteogenic differentiation. Amperometric measures revealed that DM-22 releases H 2 S at a slow rate with a thiol-dependent mechanism. DM-22 significantly inhibited h-OCs differentiation and function, maintaining a residual h-OCs viability even at the high dose of 33 μM. Contrary to AL, in h-MSCs DM-22 did not induce cytotoxicity as revealed by LDH assay, significantly stimulated mineralization as measured by Alizarin Red staining and increased mRNA expression of Collagen I as compared to control cultures. In conclusion, DM-22 is a new BP which inhibits h-OCs function and stimulate osteogenic differentiation of h-MSCs, without cytotoxicity. DM-22 is an ideal candidate for a novel family of osteoanabolic drugs. A progressive decline in bone strength is a common consequence of aging and several bone-wasting diseases in humans. Osteoporosis, the most prevalent cause of bone fragility, affects 1 in 2 women and 1 in 5 men age 50 and above and causes up to 9 million fractures per year worldwide 1,2. Among pharmacological therapies, bisphosphonates (BPs) are the first-line and the most prescribed treatment for a number of diseases leading to abnormal bone turnover, including osteoporosis 1. Key to the mechanism of action of BPs is the high affinity of these molecules for the mineralized bone matrix, which arises from the P-C-P backbone structure 3,4. Once BPs bind hydroxyapatite within the bone matrix, the acidic pH caused by osteoclasts (OCs) resorption induces their dissociation from the mineral surface and the subsequent internalization within the OCs 5. Owing to their strong affinity for the bony mineralized matrix, BPs have been broadly developed both as a powerful drugs for bone metabolism and as a carrier to achieve a targeted delivery of bone active molecules 6,7. Among BPs, amino BPs (N-BPs) were found to be far more potent than simple BPs at inhibiting bone resorption 8. N-BPs inhibit the mevalonate pathway by targeting the farnesyl diphosphate synthase (FPPS) 9 , leading to the accumulation of unprenilated GTPases in the cytoplasm, which results in toxicity and cell death 9,10. Clinical studies have conclusively showed that long-term use (up to 10 years) of BPs is associated to a good safety profile and to a significant reduction in the risk of vertebral, non-vertebral and hip fractures 11,12. However, several studies have associated BPs therapy with a potential risk of osteonecrosis of the jaw 13,14 and atypical subtrochanteric femoral fractures; at the cellular level, prolonged exposure to BPs was shown to eventually cause the suppression of osteoblast function both by direct and OC-mediated mechanisms 15. The inability to restore the lost
ATRAID regulates the action of nitrogen-containing bisphosphonates on bone
2018
Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFFs) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase (FDPS), resulting in defects in protein prenylation. Yet it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired thera...
Background: Various pharmacological agents are known to create an imbalance in the normal physiology of bone remodeling. Cyclosporine-A (Cs-A) is one of the drugs that is widely used in transplantation and has its main side effect as gingival hyperplasia and alveolar bone loss by their action on the inflammatory mediators. Bisphosphonates are a new class of drugs that inhibit bone resorption by decreasing the osteoclast activity and number. The aim of the present study was to evaluate the effect of concomitant administration of alendronate on cyclosporin-A induced alveolar bone loss in a rat model. Methods: A total of forty male Wistar rats weighing 90-150 grams were randomly divided into four groups, consisting of ten rats in each group. The study was conducted for a period of 60 days. Group I was the control group which received normal saline daily. Group II received subcutaneous injection of Cs-A 10mg/kg body weight daily, Group III received subcutaneous injection of alendronate 0.3mg/kg body weight on a weekly basis. Group IV received subcutaneous injection of both Cs-A 10mg/kg body weight and alendronate 0.3mg/kg body weight. At the end of the study (60 days), blood samples were drawn for the biochemical analysis to evaluate the serum calcium, alkaline phosphatase and osteocalcin levels. Simultaneously, the rats were sacrificed and the mandibles were further processed for the morphometric analysis. Results: The morphometric analysis exhibited an increased alveolar bone loss in Cs-A treated rats whereas the combination (Cs-A +ALN) group showed marked inhibition of Cs-A induced alveolar bone loss. Also, there was a distinct pattern of increased level of biochemical markers (serum osteocalcin, alkaline phosphatase & calcium levels) in the combination group, though the level was found to decreased in the Cs-A treated rats. Conclusion: Within the limits of our experimental study, it can be concluded that Cs-A has a distinct resorptive effect on alveolar bone and the adjunctive use of alendronate leads to a reversal of the cyclosporine A-induced bone loss.
Calcified Tissue International, 2003
Bisphosphonates exert a potent inhibitory effect on bone resorption. Several studies have been performed, with contradictory results, to ascertain whether the effect of bisphosphonates on osteoclasts could be produced, at least in part, by modulation of the synthesis of resorption-promoting factors by osteoblasts. The aim of this study was to evaluate the effect of etidronate (10)4-10)9 M) and alendronate (10)7-10)12 M) on the production of IL-6 and IL-11 using human osteoblast cultures. Cytokines were quantified by ELI-SA, and mRNA expression was tested. Treatment with alendronate and etidronate had no effect on the synthesis of IL-6 or IL-11, and IL-6 and IL-11 mRNA levels. These results were obtained both in nonstimulated cultures and in cultures stimulated by means of TNF-a, IL-1b, and TNF-a+IL-1b, with or without FCS. In conclusion, a possible indirect osteoclast-mediated effect of alendronate and etidronate on bone resorption would not be exerted through reduction in osteoblastic synthesis of IL-6 and IL-11.
Aminobisphosphonates Cause Osteoblast Apoptosis and Inhibit Bone Nodule Formation In Vitro
Calcified Tissue International, 2008
Bisphosphonates are widely used for the treatment of bone diseases associated with increased osteoclastic bone resorption. Bisphosphonates are known to inhibit biochemical markers of bone formation in vivo, but it is unclear to what extent this is a consequence of osteoclast inhibition or a direct inhibitory effect on cells of the osteoblast lineage. In order to investigate this issue, we studied the effects of various bisphosphonates on osteoblast growth and differentiation in vitro. The aminobisphosphonates pamidronate and alendronate inhibited osteoblast growth, caused osteoblast apoptosis, and inhibited protein prenylation in osteoblasts in a dose-dependent manner over the concentration range 20−100 μM. Further studies showed that alendronate in a dose of 0.1 mg/kg inhibited protein prenylation in calvarial osteoblasts in vivo, indicating that alendronate can be taken up by osteoblasts in sufficient amounts to inhibit protein prenylation at clinically relevant doses. Pamidronate and alendronate inhibited bone nodule formation at concentrations 10-fold lower than those required to inhibit osteoblast growth. These effects were not observed with non-nitrogen-containing bisphosphonates or with other inhibitors of protein prenylation and were only partially reversed by cotreatment with a fourfold molar excess of ß-glycerol phosphate. We conclude that aminobisphosphonates cause osteoblast apoptosis in vitro at micromolar concentrations and inhibit osteoblast differentiation at nanomolar concentrations by mechanisms that are independent of effects on protein prenylation and may be due in part to inhibition of mineralization. While these results need to be interpreted with caution because of uncertainty about the concentrations of bisphosphonates that osteoblasts are exposed to in vivo, our studies clearly demonstrate that bisphosphonates exert strong inhibitory effects on cells of the osteoblast lineage at similar concentrations to those that cause osteoclast inhibition. This raises the possibility that inhibition of bone formation by bisphosphonates may be due in part to a direct inhibitory effect on cells of the osteoblast lineage.
Experimental osteonecrosis: development of a model in rodents administered alendronate
Brazilian Oral Research, 2016
The main objective of this study was to cause bisphosphonate-related osteonecrosis of the jaws to develop in a rodent model. Adult male Holtzman rats were assigned to one of two experimental groups to receive alendronate (AL; 1 mg/kg/week; n = 6) or saline solution (CTL; n = 6). After 60 days of drug therapy, all animals were subjected to first lower molar extraction, and 28 days later, animals were euthanized. All rats treated with alendronate developed osteonecrosis, presenting as ulcers and necrotic bone, associated with a significant infection process, especially at the inter-alveolar septum area and crestal regions. The degree of vascularization, the levels of C-telopeptide cross-linked collagen type I and bone-specific alkaline phosphatase, as well as the bone volume were significantly reduced in these animals. Furthermore, on radiographic analysis, animals treated with alendronate presented evident sclerosis of the lamina dura of the lower first molar alveolar socket associated with decreased radiographic density in this area. These findings indicate that the protocol developed in the present study opens new perspectives and could be a good starting model for future property design.
Bone, 2011
Although a major effect of bisphosphonates on bone is inhibition of resorption resulting from their ability to interfere with osteoclast function, these agents also prevent osteoblast and osteocyte apoptosis in vitro and in vivo. However, the contribution of the latter property to the overall beneficial effects of the drugs on bone remains unknown. We compared herein the action on glucocorticoid-induced bone disease of the classical bisphosphonate alendronate with that of IG9402, a bisphosphonate analog that preserves osteoblast and osteocyte viability but does not induce osteoclast apoptosis in vitro. The bisphosphonates were injected daily (2.3 μmol/kg) to 5month-old Swiss Webster mice (6-11 per group), starting three days prior to implantation of pellets releasing the glucocorticoid prednisolone (2.1 mg/kg/d). IG9402 did not affect levels of circulating C-telopeptide or osteocalcin, markers of resorption and formation, respectively, nor did it decrease mRNA levels of osteocalcin or collagen1A1 in bone. On the other hand, alendronate decreased all these parameters. Moreover, IG9402 did not reduce cancellous mineralizing surface, mineral apposition rate or bone formation rate, whereas alendronate induced a decrease in each of these bone formation measures. These findings demonstrate that in contrast to alendronate, IG9402 does not inhibit bone turnover. Both alendronate and IG9402, on the other hand, activated survival kinase signaling in vivo, as evidenced by induction of ERK phosphorylation in bone. Furthermore, both bisphosphonates prevented the increase in osteoblast and osteocyte apoptosis as well as the decrease in vertebral bone mass and strength induced by glucocorticoids. We conclude that a bisphosphonate that does not affect osteoclasts prevents osteoblast and osteocyte apoptosis and the loss of bone strength induced by glucocorticoids in mice.