Over 15 years ago, it was shown that certain BP derivatives (isoprenoid (phosphinylmethyl) phosphonates) weakly inhibit the cholesterol biosynthetic enzyme squalene synthase.51 The search for more potent inhibitors that might block cholesterol production revealed that the N-BPs incadronate (YM175) and ibandronate potently inhibit squalene synthase.52 Subsequent studies examined the structure-activity relationship (SAR) for inhibition of squalene synthase.53-55 In vivo testing showed that certain compounds suppressed serum cholesterol in rodents.53 Other cholesterol-lowering bisphosphonates were shown to trigger degradation of hydroxymethylglutaryl coenzyme A (HMG-CoA).56-58 In the same context, utility of squalene synthase inhibition by bisphosphonate was also used for the development of an assay to measure zoledronate levels in animals and clinical serum samples.59 Although cholesterol itself is important for osteoclast signaling and survival, the osteoclast relies on low-density lipoprotein (LDL) as an external source rather than synthesis through internal pathways.60'61 Therefore, although ALN, like another N-BP, pamidronate, has been shown to inhibit cholesterol synthesis, this is through inhibition of an enzyme other than squalene synthase. Restoration of cholesterol in the ALN-treated osteoclast does nothing to interfere with its inhibitory action on bone resorption.62 This then lead to a search for other possible enzymes that could account for its antiresorptive effects.
Was this article helpful?
Discover secrets, myths, truths, lies and strategies for dealing effectively with cholesterol, now and forever! Uncover techniques, remedies and alternative for lowering your cholesterol quickly and significantly in just ONE MONTH! Find insights into the screenings, meanings and numbers involved in lowering cholesterol and the implications, consideration it has for your lifestyle and future!