Synergistic action of statins and nitrogen-containing bisphosphonates in the development of rhabdomyolysis in L6 rat skeletal myoblasts.
OBJECTIVE
Nitrogen-containing bisphosphonates, which are widely used to treat osteoporosis, act as inhibitors of farnesyl pyrophosphate synthase, one of the key enzymes of the mevalonate pathway, and thus may have the potential to enhance the effect of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase). In this study, we evaluated the synergistic effect of two nitrogen-containing bisphosphonates, alendronate and risedronate, in statin-induced apoptosis in rat skeletal L6 myoblasts.


METHODS
L6 rat myoblasts were differentiated with drugs. DNA fragmentation was measured and small GTPase was detected by immunoblotting.


RESULTS
Alendronate and risedronate caused dose-dependent apoptosis of L6 myoblasts. Risedronate induced detachment of rho GTPase from the cell membrane, followed by activation of the caspase-8-related cascade. Risedronate-induced apoptosis was synergistically enhanced with atorvastatin and significantly reduced by addition of geranylgeraniol. By contrast, alendronate did not reduce membrane GTPases and the apoptosis was caspase independent.


CONCLUSIONS
These results suggest that risedronate-induced apoptosis is related to geranylgeranyl pyrophosphate depletion followed by rho detachment, whereas alendronate affects are independent of rho. Our results suggest a risk of synergistic action between nitrogen-containing bisphosphonates and statins in the development of rhabdomyolysis when treating osteoporosis in women with hyperlipidaemia.
Nishiguchi
Tomoko
T
School of Pharmaceutical Sciences and Institute for Biosciences, Mukogawa Women's University, Hyogo, Japan.
Akiyoshi
Takeshi
T
Anami
Setsuko
S
Nakabayashi
Toshikatsu
T
Matsuyama
Kenji
K
Matzno
Sumio
S
D019386:Alendronate / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D050071:Bone Density Conservation Agents / Q000009:adverse effects* / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D053938:DNA Fragmentation; D004164:Diphosphonates / Q000009:adverse effects* / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation; D012968:Etidronic Acid / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D006538:Heptanoic Acids / Q000009:adverse effects* / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011758:Pyrroles / Q000009:adverse effects* / Q000494:pharmacology; D051381:Rats; D012206:Rhabdomyolysis / Q000139:chemically induced; D000068296:Risedronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D020169:Caspases; D000068296:Risedronic Acid; D012968:Etidronic Acid; D019386:Alendronate