Potential Role for Increasing Bone Mass
and Reducing Fractures in Elderly Disorders
Statins Update: Part II

by Jim English

After a drug has been approved for widespread clinical use to treat one condition, clinicians and patients often report that the drug also has surprising and unanticipated effects on other health conditions. Aspirin is a prime example of just such a drug. Introduced as an analgesic in 1897, over the next century aspirin was found to possess a host of health benefits — reducing inflammation, inhibiting blood clotting and lowering risk of heart attack. A recent finding is that statins, a family of powerful cholesterol-lowering compounds, are turning out to deliver an unexpectedly broad range of health benefits.

Statins
Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG CoA] reductase inhibitors) are potent cholesterol-lowering substances that have proven to be extremely effective at lowering LDL levels and reducing risk of heart attacks and strokes. Synthetic HMG-CoA reductase inhibitor drugs currently prescribed to lower cholesterol levels include fluvastatin (Lescol®), cerivastatin (Baycol®), atorvastatin (Lipitor®), simvastatin (Zocor®), pravastatin (Pravachol®) and lovastatin (Mevacor®). In addition to these expensive synthetic statin drugs, lovastatin also occurs naturally as a food product called red yeast rice extract.

A growing number of studies are now beginning to reveal unanticipated benefits from the statins. In the previous article (“Breaking Research on Health Benefits of Statins") we reported that statins have been shown to lower incidence of Alzheimer's disease by up to 73 percent, as compared to patients using other medications for hypertension or cardiovascular disease.1 Furthermore, recent data from the Heart and Estrogen/Progestin Replacement Study (HERS) reports that women taking statins have a 50% lower risk of venous thrombosis than nonusers.2

Additional research on statins suggest that they can also:

• Modify endothelial function,
• Control inflammatory responses,
• Promote plaque stability,
• Inhibit thrombus formation,
• Reduce platelet aggregation
• Increase collagen and smooth muscle cells
• Mitigate plaque disruption
• Maintain a favorable balance between prothrombotic and fibrinolytic mechanisms.3

In this article we continue our examination of the growing list of health benefits of statins by reviewing research on their potential for reducing the risk of bone fractures in the elderly.

Osteoporosis
Osteoporosis is a major public health threat for more than 28 million Americans, 80 percent of whom are women. In the U.S. today, 10 million individuals already have the disease and 18 million more have low bone mass, placing them at increased risk for osteoporosis.4

Healthy bone mass and density result when the body maintains a delicate balance between the breaking down and absorbing of old bone (resorption) and formation of healthy new bone. Osteoporosis (porous bone) is a metabolic bone disease that upsets this homeostasis, resulting in the structural deterioration of bone tissue and a loss of bone mass. This imbalance contributes to bone fragility and an increased susceptibility to fractures, particularly of the hip, spine and wrist. Fractures of the hip frequently require hospitalization and surgery, and can lead to permanent disability and death. Spinal or vertebral fractures, while not life-threatening, have serious consequences, including loss of height, severe back pain, and deformity.

All currently available, approved therapies for osteoporosis work by inhibiting the normal breakdown and resorption of bone. Such antiresorptive therapies include Calcitonin (a hormone that decreases bone resorption), estrogen replacement therapy (pairing estrogen with progesterone), selective estrogen receptor modulators (Raloxifene), and bisphosphonates (alendronate sodium and risedronate sodium). By inhibiting the resorption phase of the bone remodeling cycle, these therapies, while unable to increase bone mass, have been shown to improve bone mineral density and modestly reduce the risk of new fractures.5

Anabolic Bone Remodeling
While inhibiting bone resorption offers therapeutic treatment for osteoporosis, it cannot repair existing skeletal damage. Anabolic therapy, utilizing agents to directly stimulate new bone growth, may potentially be a more effective approach, especially if used in conjunction with current antiresorptive therapies.

Early efforts to stimulate skeletal anabolic growth have been disappointing. Sodium fluoride was initially shown to increase bone mass, and observational studies suggested some reduction in risk of vertebral fracture.6 When researchers conducted a randomized trial they discovered that, while sodium fluoride did increase spine bone density, it also stimulated the formation of abnormal bone. Not only did sodium fluoride fail to reduce the risk of vertebral fractures, it actually increased the risk of peripheral fractures.7

Research into other therapies to encourage the formation of new bone growth continues. Promising candidates include selective androgen receptor modulators, parathyroid hormone analogs, oxytocin analogs, and statins. Of these, statins have received attention based on their ability to exhibit anabolic effects in the skeleton, and encourage the formation of new bone growth.8

Statins and Increased Bone-Mineral Density
The discovery that statins promote new bone growth was the result of a deliberate search for a chemical called bone morphogenic protein 2, a natural growth factor that causes osteoblasts to proliferate, mature, and form new bone. After screening thousands of candidate chemicals, the researchers found that two statin drugs, lovastatin and simvastatin, formed new cortical bone in mice in following five days of subcutaneous injections. When the researchers fed lovastatin and simvastatin to mice orally, they found that trabecular bone volume increased by 90%.9 Importantly, early observations suggests that the new bone stimulated by statins appears normal.10

Statins and Bone Fractures
Spurred on by the success of animal studies showing that statins increased bone formation, volume, and density, researchers began to look for evidence that these agents could reduce bone fractures in humans. In one case-controlled study, researchers examined ten years worth of patient records, gathered from some 300 general medical practice clinics in England. After analyzing data on 91,611 patients aged 50 years or older, including 28,340 individuals taking lipid-lowering drugs, the researchers reported finding a large and statistically significant reduction in fractures among patients taking statins, with a 45% lower risk of all types of fractures and 88% lower risk of hip fractures.11

These findings were supported when a second team of researchers conducted a case-control study involving 6,110 New Jersey residents, aged 65 years or older. The researchers found that the risk of hip fractures decreased with increasing statin use during the previous three years, resulting in a 43% to 50% lower risk of hip fractures in statin users vs. nonusers of statins. In their report the authors state, “Clear relationships were observed between the degree of reduction in hip fracture risk and the extent of statin use.”12

This was followed by reports of significant increases in bone-mineral density in postmenopausal women taking statins.13 Based on these early observational studies researchers found that women and men taking statins had a substantially lower risk of fractures and higher bone densities than those who were not taking statins.

New Findings
As is often the case with new research, two follow-up studies published in the April 11, 2001 issue of JAMA failed to find evidence to support the use of statins for reducing fractures. In one study designed to assess whether statins have clinically significant effects on bone, researchers in New Zealand randomly assigned pravastatin or placebo to 9,014 patients. After six years of follow up the researchers reported finding no significant effect on fracture risk.14 In a second study researchers in England compared 81,880 patients, aged 50 years or older who had suffered a fracture against 81,880 matched controls. Again, researchers concluded that they found little reduction in fractures when statins were used in dosages prescribed in the study.15

Meta-Analysis Supports Statins Use for Fractures
In the latest study, presented to scientists attending the June 11, 2001 joint meeting of the International Bone and Mineral Society and the European Calcified Tissue Society in Madrid, Spain, researchers report that statins do seem to have a protective effect against hip and non-spine fractures.16

Dr. Douglas C. Bauer of the University of California at San Francisco reported that the findings of the meta-analysis confirm the results of some, but not all, recent observational studies, stating, “The sum total of evidence favors the protective effects of this type of medication.”

Dr. Bauer and colleagues assessed statin use and fracture risk after conducting a meta-analysis of eight observational studies. The studies analyzed risks of hip fracture in a total of 151,500 individuals, and risks of non-spine fracture in a total of 57,621 individuals.

The researchers found “a 57% reduction in hip fractures and a 34% reduction in non-spine fractures among statin users,” according to Dr. Bauer.

Dr. Bauer added that six of the eight studies included the use of non-statin lipid-lowering medications, which showed no protective effect against fractures. When the researchers analyzed the findings with and without data from the Women's Health Initiative they found “very similar results in the protective effect of statins.”

Conclusion
A rapidly growing body of research is revealing a wide range of unanticipated benefits from cholesterol-lowering statins, including lowering incidence of Alzheimer's disease by up to 73%, and lowering risk of venous thrombosis by up 50%. New research now supports earlier findings that statin users benefit from reduction in hip fractures non-spine fractures.

As previously reported, red yeast rice extract, a natural source of lova-statin, has been proven effective in a number of clinical trials for promoting healthy cholesterol levels. Lovastatin, the main active ingredient in red yeast rice, has been extensively researched and found to be extremely effective at lowering LDL levels and reducing risk of heart attack and strokes. These results lend credible support for the efficacy of red yeast rice in maintaining a healthy cardiovascular system.

Red yeast has been proven as effective as pharmaceutical statin drugs, such as Mevacor, but at about one-fifth the cost, and is available without a prescription. The additional findings of a benefit in the reduction of fracture incidence and increased bone density further support the role of red yeast rice extract in a nutritional regimen.

Since red yeast rice extract may reduce tissue CoQ10 levels, it is recommended to take additional CoQ10 when red yeast rice extract or statin drugs are taken.

Abstract Mechanisms of action of statins and their pleiotropic effects. Davignon J, Mabile L. Ann Endocrinol (Paris) 2001 Feb;62(1 Pt 2):101-12. This brief review and update considers a few aspects of the mechanisms of action of statins, especially those related to some of the pleiotropic effects that have clinical relevance. The beneficial effect on endothelial dysfunction is a class effect that is related not only to the lowering of plasma LDL-cholesterol but also to a direct effect on nitric oxide (NO) production. It is an early and sustained effect, linked to oxidative processes, that deserves particular attention since endothelial dysfunction is intimately linked to atherogenesis. Awareness of the anti-inflammatory effect came about following the observation that statin administration in humans reduces markers of inflammation in the circulation. The importance of these observations is ascribable to the fact that atherosclerosis is an inflammatory disease, that the inflammatory process in a coronary artery is now measurable in vivo in humans, that it contributes to the progression and the destabilization of the plaque, and also, because statins exert a number of effects that tend to stabilize it. Statins, and particularly lipophilic statins, in general inhibit cell proliferation, seemingly by multifaceted mechanisms. These include inhibition of cell cycle progression, induction of apoptosis, reduction of cyclooxygenase-2 activity and an enhancement of angiogenesis. This effect has been used to show that statins are anticarcinogenic in vitro and in animals. The clinical relevance of such a property remains to be proven but is supported by promising observations in animals and in humans which are detailed in this review. Finally, the ability of lipophilic statins to increase the production of bone morphogenetic protein-2 (BMP-2), and to enhance osteogenesis in animals combined with the results of several clinical studies should stimulate physicians to seriously consider an eventual indication of statins for the treatment of osteoporosis.

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