Statins and Osteoporosis: Can These Lipid-Lowering Drugs also Bolster Bones?

We review the basic and clinical data about the effects of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors or statins on bone; however, definitive studies are needed before statins can be considered indicated for preventing or treating osteoporosis.

Osteoporosis: Scope of the Problem

Osteoporosis, the most common disease of bone, affects about 30 million people in the United States(2) and as many as 100 million people worldwide. As the elderly population grows, the prevalence is expected to increase.

Osteoporosis is characterized by reduced bone mass, microarchitectural deterioration, and increased skeletal fragility. Fractures do not usually occur until bone mass falls to 30% to 50% below normal.

Although the precise cause of osteoporosis is unknown, an imbalance between bone formation and resorption presumably causes bone mass to decline in adulthood, and osteoporosis occurs when the amount of bone removed from the skeleton by bone-resorbing osteoclasts exceeds the amount formed by osteoblasts during the coupled process of remodeling. Treatment of osteoporosis is aimed toward restoring this balance.

Drugs such as bisphosphonates, estrogen, and selective estrogen receptor modulators are widely used to slow bone loss. Although these agents reduce the incidence of fractures, they do not significantly increase bone formation. In theory, a drug that stimulates bone formation and helps restore bone strength would constitute a major breakthrough in osteoporosis treatment.(3) Remarkably, statin drugs may do this.

If Statins Build Bone, How Do they Do It?

If statins prove to build bone, two recently elucidated pathways may explain the effect.

Inhibition of mevalonate production The first discovery came from investigators at several laboratories who were working independently to determine how bisphosphonates inhibit osteoclasts. These workers noted that cholesterol synthesis and osteoclast activation both involve the same biochemical cascade (Figure 1).(4-7)

Figure 1. Cholesterol synthesis and osteoclast activation use the same pathway.

Cholesterol synthesis has several steps. First, HMG-CoA is converted into mevalonate by the enzyme HMG-CoA reductase (which the statin drugs inhibit). Next, mevalonate is converted to geranyl pyrophosphate, which in turn is converted to farnesyl pyrophosphate by the enzyme farnesyl pyrophosphate synthase (which the bisphosphonate drugs inhibit). Next comes squalene and finally cholesterol.

Osteoclasts use the intermediate molecules farnesyl pyrophosphate and geranylgeranyl pyrophosphate (made from farnesyl pyrophosphate) to modify and activate the key intracellular proteins-glutamyl transpeptidases and GTPases-in a process called prenylation.(8) Bisphosphonates, such as alendronate and risedronate, prevent the formation of these lipid products(5) by inhibiting farnesyl synthase(9); statins (as classic inhibitors of HMG-CoA) are equally effective at preventing osteoclast activation in vitro by preventing mevalonate production.

When exposed to statins or bisphosphonates, osteoclasts die by apoptosis. In turn, bone remodeling is reduced, bone resorption decreases, and the balance of bone resorption and formation is restored. More important, as demonstrated in clinical trials with bisphosphonates, this process reduces the incidence of fragility-related fractures.(10-12)

The structure of bisphosphonates, however, differs significantly from that of statins. Bisphosphonates contain a domain that mimics pyrophosphate and binds tightly to exposed mineralized surfaces under the osteoclast's ruffled border; statins lack this structure. This important difference makes it difficult to predict with confidence whether statins will retain biologic activity against osteoclasts in vivo.

Activation of the bone morphogenetic protein-2 promoter

The second mechanism by which statins may affect the skeleton was uncovered by Mundy et al,(13) who screened a library of more than 30,000 natural compounds for osteoinductive substances that activate the promoter for bone morphogenetic protein-2. This protein is a growth factor that causes osteoblasts to proliferate, mature, and create new bone. Only lovastatin, derived from the fungus Aspergillus terreus,(14) was found to have this effect.

When lovastatin was injected into organ cultures of calvarial bones from neonate mice three times a day for 5 days, bone volume increased nearly 50% compared with placebo.(13) Histologic examination revealed enhanced bone-forming surfaces and osteoid accumulation.

Similar effects were found with fluvastatin, simvastatin, and mevastatin, which specifically increased expression of bone morphogenetic protein-2 mRNA and more than doubled production of bone morphogenetic protein-2 by osteoblast-like cell lines in vitro.(13)

Further studies demonstrated that ovariectomized female rats (a model of postmenopausal osteoporosis) that were given simvastatin by mouth had an increase in trabecular bone volume of 39% to 94%.(13)

Cruz AC, Gruber BL. Statins and Osteoporosis: Can these Lipid-Lowering Drugs also Bolster Bones? Cleve Clin J Med 2002;69:277-278.