Palm Tocotrienols

Building Bone: The Novel Role of Tocotrienols

An Interview With Professor Dr Ima-Nirwana Soelaiman, MBBS, PhD, Deputy Dean (Research and
Innovation) Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

Biography: The focus of Dr Ima-Nirwanas research is the impact of natural products on bone metabolism and osteoporosis,
with special emphasis on tocotrienols. Dr Ima-Nirwana has published 122 articles in scientific journals. Together with her team
she has presented her work at over a hundred local and international conferences. The results from her animal studies have
consistently shown that tocotrienols can prevent and reverse osteoporosis due to stressors, including menopause, estrogen and
androgen deficiency, steroid excess, nicotine exposure and oxidative stress and inflammation. She is currently planning clinical
trials on tocotrienols and osteoporosis in the USA and in Malaysia. She is a member of the Malaysian Osteoporosis Society and
the Malaysia Endocrine and Metabolic Society. She holds a patent within Malaysia for the use of tocotrienol for bone heal th in
humans.

Introduction: By the time most of us begin to think about our bones, we may have already suffered significant bone
loss. The early stages of osteoporosis can start by age 35. But osteoporosis is not merely the loss of bone structure
and strength. Bones are a valuable storehouse of minerals for the body, as well as red and white blood cells. And
skeletal tissue undergoes continuous remodelling throughout life, which makes it unique among all body tissues. The
bone-immune connection is profound. The field of osteo-immunology has begun to explore how chronic immune
system overexertion leads to bone loss. Dr Soelaimans decades of research on tocotrienols and osteoporosis
examines many facets of bone loss, including the ways in which it is driven by hormone deficiency, inflammation,
inflammatory cytokines, and free radical damage. Tocotrienols interrupt the degeneration to weak, thin bones in
several different ways, and show remarkable promise in helping prevent and reverse this process and contribute to
bone strength and healthy aging. They may provide a new and safe therapy to prevent bone loss.

Focus: You have produced a remarkable body of work spanning several decades, and of your 122 published studies,
forty-eight are on tocotrienols and bone health. Youve shown that tocotrienols can prevent osteoporosis caused by
estrogen deficiency, testosterone deficiency, nicotine, glucocorticoids, and even simple free radical damage. What
got you so interested in this subject?

Ima-Nirwana Soelaiman
(INS): My PhD thesis was on the antioxidant effects of tocotrienol-rich palm oil. As a young lecturer keen to focus
on a research area, I was encouraged by my PhD mentor to study the effects of tocotrienols on osteoporosis. Why
osteoporosis? I am interested in osteoporosis because it is a significant medical issue, with profound implications for
healthy aging. Around two hundred million people worldwide suffer from osteoporosis, and the United States alone
has 44 million. An additional 33.6 million individuals have osteopenia, or low bone mass, which can lead to
osteoporosis. In fact, osteoporosis is very serious, and the lifetime risk of fractures for men and women is on par
with the risk of cardiovascular disease. Another reason for my interest is that at that time the idea of using an
antioxidant to combat osteoporosis was very novel and tocotrienols from palm oil were the unknown siblings of the
more famous alpha-tocopherol.

My first research paper on the protective effects of vitamin E tocotrienols against osteoporosis induced by oxidative
stress was in 1998 (1). Little did I know that from one idea, many more flowered, leading to 20 years of passionate
research thus far. Palm oil-derived tocotrienol extract contains a mixture of gamma, delta, alpha, and beta
tocotrienol isomers as well as about 20% alpha tocopherol. I have been studying tocotrienols and bone health since
1994. The current strategies to preserve bone density include calcium, Vitamin D, bisphosphonate drugs, estrogen
replacement therapy, and selective estrogen receptor modulators. In addition, it has been shown that the statin
drugs, at high doses, increase bone density-but those doses are not well tolerated. What is interesting is that both


bisphosphonates and statins seem to help bone health by inhibiting a crucial pathway, the mevalonate pathway-and
so do tocotrienols.

Lets stop and consider how remarkable bone is. Its a specialized, dynamic, metabolizing connective tissue. We
dont usually think of it that way. It undergoes continuous replenishment throughout life by bone remodelling. This
process involves bone resorption by osteoclasts, and bone formation by osteoblasts. Remodelling allows our body to
replace old bone tissue with new, regulate calcium and phosphate levels, and provide adaptation to different
conditions of load and stress. Bone is a fascinating tissue. So, yes, I have been working on this for quite a long time.
We have over forty very-detailed studies in animals - all looking at how tocotrienols affect bone health. In the early
years, we used a vitamin E mixture from palm oil, which contained 80% tocotrienols and 20% tocopherol. In more
recent years, we have been able to study the impact of individual tocotrienol isomers as well as a palm oil blend. For
decades now, my colleagues and I have looked at everything from the impact of nicotine to sex hormones to vitamin
E deficient diets on bone, and studied how tocotrienols can help in each case. I am so pleased that over all this time,
and in so many different studies, our data is remarkably consistent. Tocotrienols increase bones microstructural
integrity. They increase bone calcium content and bone mechanical strength. They inhibit bone resorption and
increase bone formation. And they do this through several novel metabolic pathways, not just one. We are hoping
to embark on human studies soon and translate our findings into definitive clinical benefits. The Early Work: Vitamin
E Deficient Diets.

Focus: Lets start with your early research on the impact of tocotrienols on a vitamin-E deficient diet, one that
contributes to osteoporosis.

INS: We first set out to prove that vitamin E is needed for bone health. In early experiments, we fed animals a
vitamin E deficient diet, which impaired bone calcification and lead to bone loss (2,3). Then we supplemented the
experimental group with calcium and a vitamin E-tocotrienol mixture for nine months. We scanned with a bone
densitometry x-ray device that we had modified for small animals. I t took that long to see changes in the bone using
this device. We did find some significant changes in lumbar bone density, in terms of calcium deposition (4,5). And
when we fed normal rats gamma-tocotrienol isomer, they displayed better structural, static and dynamic bone
histomorphometry compared to rats not fed tocotrienols (6,7). We have since gone on to use more far more
sensitive measurements in all our work. Today we use dynamic histomorphometry in all our studies, which allows us
to make a sophisticated, quantitative measure of bone and bone changes with a computerized image analyser
system. It is not just observational histology as in the typical bone microscopy. We are also using biomechanical
strength testing to determine the strength of the bones of rats treated with tocotrienols. This is important to
confirm that the improved structure and density is translated to improved strength. And when we do this, we
inevitably find significant improvements with tocotrienols (8, 9, 10, 11).

Reversing Osteoporosis in Menopause
Focus: You have conducted many detailed studies on a post-menopausal animal model, looking at how hormone
status affects bone and how tocotrienols help prevent osteoporosis in this model. Can you review your findings?

INS: This is very important, because we know that post-menopausal osteoporosis is the most common cause of
fractures. Our studies have shown that vitamin E, especially the tocotrienols at a dose of 60 mg/kg/ day, provides
significant protection against osteoporosis in an animal model of menopause. The human dose calculated from the
animal dose has been demonstrated to be safe in both humans and animals. Conversion from human dose to animal
dose is not by simple multiplication. Metabolic rate of the human is about 7-10 times slower than the rat. Therefore
the calculated human dose per kg is about 7-10 times smaller than the animal dose per kg. It is a safe dose as shown
from our safety studies and the dose is comparable to efficacy doses in other clinical parameters (12,13).

In one study, we compared tocotrienols to estrogen, and measured histomorphometric changes in rats whose
ovaries had been removed, to mimic menopause in humans. We included sham operated rats, randomly divided
into two groups, so that we had a double- blind, controlled study. We treated the rats for two months with estrogen
or tocotrienols. Both groups showed improvement in dynamic markers, but the tocotrienol group showed better
effects than estrogen on most of those markers. Tocotrienol exhibits bone anabolic actions that actually build bone,
and reversed the harmful changes induced by menopause (8, 14, 15). We then compared tocotrienols with calcium


in post-menopausal rats, with ovaries removed. We looked at bone biomarkers and bone formation rate and
showed that palm tocotrienols significantly increased bone formation. We looked at many markers, including rate of
mineral deposit and increase in bone formation. These were increased by tocotrienols, but not by calcium alone (8).

Calcium is often recommended for osteoporosis, and its the most abundant mineral in the diet. It is essential for the
development and maintenance of strong bones and teeth. In adults with a baseline calcium intake of 500-900
mg/day, increasing or supplementing this intake by a further 500-1000 mg/ day has a beneficial effect on bone
mineral density. However, the relative risk reduction for osteoporotic fracture is likely to be no more than 10%-20%.
Although inadequate calcium intake is likely to be harmful to bone, calcium intake significantly above the
recommended level is unlikely to achieve substantive additional benefit for bone health, and high doses can increase
the risk of cardiovascular disease (16). I feel this is reflected perfectly in our animal study, which did not find
significant improvement in bone formation in rats supplemented with calcium. I should also note that the rats were
supplemented with tocotrienols or calcium only two weeks after their ovaries were removed. They were in an early
postmenopausal state (17). Since we have shown that tocotrienols increased bone density and bone strength in our
post-menopausal rat model, we then looked at the effect of palm oil tocotrienols and alpha-tocopherol on bone
fracture healing in post-menopausal rats with osteoporosis. Two months of supplementation with tocotrienol
allowed fractured bone to bear significantly more stress, compared to alpha-tocopherol.

Fracture healing is a complex process with three distinct phases, the reactive phase, reparative phase, and the
remodelling phase. In the reactive phase, inflammation and formation of granulation tissue occur immediately after
fracture. This is followed by the reparative phase, where callus is formed and lamellar bone is deposited. In the final
or remodelling phase, the bone will be remodelled back to its original bone contour. Osteoporosis can delay and
impair fracture healing. Our study found that the bone fractures of rats whose ovaries had been removed healed
poorly. We found that while alpha-tocopherol supplementation improved the speed of fracture healing it did not
increase strength and quality of the healed fracture. Tocotrienols did, however. We showed that tocotrienols
improved late-phase fracture healing by improving callus formation. In fact, supplementation with tocotrienols
actually allowed the bones to handle more stress than sham-operated female rats that had normal estrogen profiles
(18, 19, 20). That makes sense, since normal male rats supplemented with gamma tocotrienols have better bone
biomechanical strength that normal control rats (21). In addition, male rats put through andropause (testes
removed) also suffered bone loss, which was reversed by tocotrienols (22).

Oxidative Stress and Inflammation Destroy Bone
Focus: One of your most fascinating insights is that osteoporosis may be spurred by oxidative stress and the
resulting inflammation that occurs. We think of other bone conditions, such as rheumatoid arthritis, as due to
inflammation. But though we know osteoporosis is generally a disorder of aging, we dont necessarily treat it with
antioxidants and anti-inflammatories.

INS: Yes, our work has found that tocotrienols can quench both oxidative stress and inflammation and thereby
protect bone (11, 23). An obvious relationship between inflammation and osteoporosis is accepted in rheumatoid
arthritis, where pro-inflammatory cytokines cause bone loss around the affected joints. We also know there is a
higher incidence of osteoporosis in ankylosing spondylitis and systemic lupus, which are both driven by
inflammation. In fact, research has shown that the degree of osteoporosis is correlated with the extent of
inflammation in these diseases. But the role of oxidative stress and cytokines in osteoporosis is a fairly new view.
Weve begun to realize that elderly patients may be prone to osteoporosis in part because of an elevated level of
pro-inflammatory cytokines that comes with aging - called Inflamm-aging. We now have good evidence there is
indeed a link. If this seems astonishing, it actually opens a window into one means by which tocotrienols repair
bones: quenching oxidative stress (11). The osteoblast, which builds bone, is sensitive to oxidative stress. For
instance, if you expose an osteoblast to hydrogen peroxide, you reduce differentiation, proliferation, mineralization
and antioxidant defences. You actually stimulate molecules that lead to osteoblast death. Tocotrienols have potent
free radical scavenging activities, and may protect the osteoblast from oxidative stress (24).

Oxidative stress and inflammation are tightly linked, and we have abundant evidence that osteoporosis is at least in
part due to chronic inflammation as well (14). Free radicals activate one of the most important inflammatory
molecules and master switches in the body: NFKappaB. This leads to increases in two inflammatory cytokines,


Interleukin-1 and Interleukin-6. Both cause bone resorption. Several studies have shown that tocotrienols are able
to suppress these cytokines. In addition, tocotrienols suppress other cytokines (including an important one in
remodelling bone, called RANKL) that destroy bone. The level of C-reactive protein, a sensitive marker of systemic
inflammation, was also found to be associated with bone mineral density. Supplementation of palm tocotrienol (100
mg/kg) in normal male rats significantly increases antioxidant enzyme activities in the femur (25). Another indication
that oxidative stress and bone loss are related is the fracture rate of cigarette smokers. It has long been known that
cigarette smoking leads to osteoporosis. One in eight hip fractures is due to smoking. Among 60 year olds with hip
fractures, 17% are smokers. But among 80 year olds with hip fractures, 71% are smokers. One cause may be
nicotine, which creates oxidative stress. Nicotine reduces bone mineral density, inhibits osteoblasts and delays bone
healing (26,27,28). In our studies, tocotrienols reversed all the histomorphometric changes induced by nicotine, and
protected and restored bone (28, 29, 30). Another study we are doing is on the effects of tocotrienols on steroid-
induced osteoporosis. As is well known, osteoporosis is a complication of long-term steroid therapy. So far our early
results are promising (31). In conclusion, tocotrienols are both antioxidant and anti-inflammatory and uniquely able
to protect bone through both mechanisms.

Statins and Tocotrienols: Why Do Both Protect Bone?
Focus: Statins are controversial drugs these days, for many reasons (32). But they also offer protective health
effects. One of the pathways that tocotrienols work on is the same pathway that statins work on, and may offer
similar protective effects, without the downsides. Can you talk to us about statins, tocotrienols, bone health and the
pathway that they share?
INS: Statins, bisphosphonates and tocotrienols all work on a profoundly important and basic pathway in the body,
called the mevalonate pathway. That pathway is important for synthesizing many molecules, including hormones,
steroids, and cholesterol. Yes, statins often have serious side effects. But research also shows they also offer
protective effects against cardiovascular disease, cancer, diabetic dyslipidaemia, Alzheimers disease,
glomerulonephritis, vitiligo, macular degeneration, polycystic ovary syndrome, influenza, infection and sepsis,
rheumatoid arthritis and more. And of course, they work on osteoporosis, however, studies have been mixed, and
the doses required may not be tolerated. Nonetheless, the fact that statins affect this pathway and are so beneficial,
makes us take a closer look at tocotrienols, which also inhibit the pathway at a later step, and confer many benefits,
including bone health. We have found that statins improve bone health in both intact animals, and those with
ovaries removed - but at clinically intolerable doses. Even so, studies of women on long term statins do show better
bone density than those not on statins. However, in our animal studies, enhancements of bone formation, and
reduction of bone resorption, were best achieved by a combination of statins and tocotrienols. By adding
tocotrienols to statins, the adverse effects associated with high doses might be avoided, while the bone protective
effects might be preserved (33). This combination strategy might be useful for patients at risk of osteoporosis,
cardiovascular disease and high cholesterol. Our study is the only one I know of in the literature looking at both
together. Many patients are already on statins worldwide, and adding tocotrienols might enhance their benefit.

Focus: How would you summarize your decades of research on tocotrienols and bone health?
INS: Tocotrienols preserve bone health. They do this in several ways. They quench free radicals and oxidative stress.
They reduce inflammation. They work on the mevalonate pathway, which tends to increase osteoclast activity and
break down bone. Inhibiting this pathway protects individuals from high cholesterol, cardiovascular disease, and
bone loss. Tocotrienols are useful for bone loss triggered by menopause, andropause, and smoking. They help
repair fractures in osteoporotic bone at a faster rate. They also enhance the structure and strength of normal, non-
osteoporotic bone, increasing bone mass so that there is less risk of osteoporosis later in life. We are in the process
of translating our animal studies into human clinical trials. Our new insights into tocotrienols and the way they work
are leading us to design other, interesting studies. For instance, we think they may help treat arthritis, and will be
studying that soon.

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