Background: Osteoporosis is a silent skeletal disease characterized by low bone mass and
destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an
imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation.
Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory
pathway for bone remodelling.
Objective: This review aimed to provide an overview of the relationship between mevalonate pathway
and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic
Discussion: Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate
essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone
formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which
produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a
well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A
(HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to
increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E
commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase.
Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has
not been tested in humans.
Conclusion: Mevalonate pathway can be exploited to develop effective antiosteoporosis agents.