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Discussion |
Sarah Stedman Center for Nutritional Studies, Duke University Medical Center and Durham VA Medical Center, Durham, North Carolina
Dr. Connie W. Bales.
Dr. Arjmandi reviewed ways in which phytoestrogens may specifically benefit bone, provided information about the bone-sparing effects of soy protein and/or soy isoflavones, and talked about potential effects of phytoestrogens on calcium uptake by intestinal cells. This is an important topic considering that the percentage of hormone replacement therapy users is low compared with the number of women who could benefit from this treatment. There is a great deal of interest in finding alternatives to hormone replacement therapy. Questions relate to the specific effects of isoflavones compared with those of soy proteins, the effect of longer term studies and studies using different doses, and the structural and functional stability of isoflavones. Dr. Arjmandi identified the need to explore the possibility of combination therapy of isoflavones, perhaps with hormone replacement therapy, and speculated about the potential beneficial effects of isoflavones on human cartilage.
Dr. Heaney reviewed current understanding of the most important nutrients (e.g., calcium, vitamin D, phosphorus, protein, magnesium) for maintenance of good bone density. This particular area is important because of the need to more systematically look at the presence of at least full calcium and vitamin D sufficiency in studies of bone-active pharmacologic agents. Key questions relate to problems of quantifying calcium intake and how to best meet calcium needs.
Dr. Watkins reported on his research on nutraceutical fatty acids, particularly as modulators of skeletal biology. Although this area is incompletely explored, it is important given that polyunsaturated fatty acids and conjugated linoleic acid (CLA) may modulate eicosanoid biosynthesis in a number of tissues and cells. Remaining questions relate to how specific fatty acids accomplish their effects on bone and other cells. Potential pharmaceutical applications or the nutraceutical applications of these fatty acids are of interest, as is their possible influence on inflammatory processes in bones and joints.
Dr. Heaney has talked about an area in which a vast amount of science-based information has accumulated over the years. Drs. Arjmandi and Watson reviewed some provocative information that needs to be confirmed by additional scientific investigations. It will be exciting to move these new emerging areas to the level of understanding that we now have with Dr. Heaney’s presentation.
Dr. David M. Klurfeld.
Dr. Arjmandi, you mentioned that soy protein increased serum insulin-like growth factor-1 (IGF-1) by 100%, which is good for bone. My concern is the effect of increased serum IGF-1 levels on risk for cancer. About 15 years ago, we published studies demonstrating that low calorie feeding inhibits mammary tumorigenesis in rats primarily through IGF-1 interactions. In fact, long-term aging studies with low-calorie feeding in nonhuman primates show small reductions in serum glucose and large reductions in serum insulin and IGF-1. Literally hundreds of articles report that IGF-1 is a potent mitogen for a variety of tumors. I am concerned that if higher serum IGF-1 levels are promoted to improve our bones, cancer risk may also increase.
Dr. Bahram H. Arjmandi.
IGF-1 is usually a surrogate measure for growth hormone. I agree with you that growth hormone has a lot to do with cell proliferation, but I suggest that IGF-1 is independent of growth hormone and that, in this case, growth hormone may not have been increased.
Dr. Bruce Watkins.
We originally started looking at prostaglandin E2 (PGE2) because of its effects on IGF and vice versa. The effects of IGF in the rat are different from those in humans. Further, in the rat model the story is incomplete because we have not finished our work with receptors for IGF and have just started work on mRNA for IGF-1.
Dr. Robert P. Heaney.
We recently reported that IGF-1 levels rise in normal human adults fed supplemental milk. We interpreted this finding in a positive sense. Previous research has shown that protein intake raises IGF-1 in an almost linear fashion up to a certain point. One could perhaps argue that the point at which IGF-1 can no longer be raised is the protein requirement for humans. We may have understated the protein requirement. I think the fact that IGF-1 is a growth factor is the basis for the concern about cancer.
Regarding Dr. Bales’ question about assessment of calcium status, assessment is extremely difficult because none of the indices are reliable. In fact, it may be a "nonquestion" in the future. As fortified foods become more and more common, it’s highly likely that the calcium problem will be solved. Then we will have to deal with all the other components of the bone osteoporosis problem, of which calcium is only one piece. In more than 500 balance studies in healthy middle-aged women, dietary calcium explains only about 10% of the variability in calcium balance. Most of the variability is explained by urinary calcium loss, and a substantially higher fraction than intake is explained by absorption efficiency. However, once calcium intake is 1500 mg/day or higher, calcium absorption is about the same for everyone. The problem related to assessing calcium status is explained by the lack of information on calcium absorption. Net calcium absorption can range from 5% to 45% in people who are otherwise identical. This is why controlled trials are so important. Regardless of calcium absorption, one group consumes more calcium than the other, and there is a difference even if absolute intake is unknown for either group.
Dr. Arjmandi.
Would you comment about the biphasic nature of the change in bone mass with time as a function of calcium supplementation?
Dr. Heaney.
Like any other resorption inhibitor, calcium shuts down some bone remodeling. In the process, bone that was being remodeled is recovered. So there is a transient increase in bone mineral density that has nothing to do with the steady state bone balance. Studies show that after that point, the slope is less on a high-calcium than on a low-calcium diet. So there is a residual effect of the extra calcium on the change in bone loss with age. Age-related bone loss cannot be stopped just with calcium because it’s due to so many other factors as well. All calcium can do is meet the calcium requirement—it can’t solve all the problems of aging.
Dr. Robert J. Nicolosi.
Have we resolved the issues of calcium bioavailability? What are the best sources of calcium?
Dr. Heaney.
The best source is milk because it is readily bioavailable, has a high content of calcium, is economical (costs less per calorie than other foods), and provides other nutrients for bone and overall health, such as phosphorus, protein, vitamin D, and potassium. Calcium bioavailability is generally about the same for calcium carbonate, calcium citrate, and other supplements.
Dr. Nicolosi.
I thought calcium from orange juice was very bioavailable.
Dr. Heaney.
There are some differences in calcium bioavailability, but they generally are small. Some food companies have juices such as orange and apple that are fortified with calcium citrate malate. That calcium is better absorbed from apple juice than from orange juice suggests that increased malic acid content, as found in apple juice, is important for the absorption of calcium. In general, differences in calcium absorption among different calcium supplements appear to be small, whereas large price differences exist. Therefore, price may be the deciding factor when selecting one calcium source over another. There are many good sources of calcium, and what suits one person may not suit another. Before we consider calcium supplements, I think we have to start with milk. It’s cost-effective at the checkout stand as well as in the emergency room.
Dr. Kenneth D. R. Setchell.
Paradoxically, high rates of hip fractures have been found in some countries with high calcium intakes. Nevertheless in the United States, the trend is toward increasing the level of recommended calcium intake. Clearly, there is more to the osteoporosis problem than calcium.
Regarding phosphate, I disagree with the notion that we do not have high phosphate intake in this country. Critical to bone and ultimately to the development of osteoporosis and hip fractures is bone mass acquired during development and puberty. When you look at current nutritional trends, children’s consumption of soda, which is high in sodium phosphate, is enormous. I think this may be leading to long-term detrimental effects on bone.
Dr. Heaney.
There is no doubt that bone accumulated early in life is the best protection against fractures in later years. The principal problem with soft drinks is not what they contain, but what they don’t contain. The phosphorus content is relatively small and its contribution to total phosphorus intake is nowhere near the level we feed our animals. Concern about phosphorus and bone health comes from studies of gross comparisons.
When comparisons are made across cultures, other major contributing factors are ignored. There are more data within populations with respect to calcium intake. Asians have half the hip fracture rate of Caucasians, not because of any differences in calcium intake, but because they have a different hip architecture. In fact, Japanese have about a 30% higher rate of spinal osteoporosis and spine fractures than do Caucasians.
Dr. Bales.
Could you elaborate on the dietary calcium/phosphorus ratio and bone health?
Dr. Heaney.
I have looked at diets with calcium/phosphorus ratios varying from 2:1 to 0.2:1 and have found no differences at all in calcium balance in healthy people.
Dr. David J. Strobl.
I wonder if the Asian population’s high intake of omega-3 fatty acids—not so much the architecture of their bone structure—provides Asians with protection against hip fractures. Also, at what point is the intake of calcium not beneficial or even harmful?
Dr. Heaney.
The Food and Nutrition Board published an upper limit of 2500 mg of calcium, which was aimed solely at the supplement and fortification industry. There has never been a report of any calcium intoxication from food sources of calcium, even among the Pastoralist peoples who consume nothing but milk for their total energy supply. Despite the very high intake of calcium by the Masai in East Africa, who consume 5 to 6 quarts of milk per day, no calcium intoxication has been reported. The problem with calcium supplements may relate, in part, to the extra carbonate and the very mild alkalosis produced. It is conceivable that, with other physiologic impairments superimposed, calcium intoxication may occur. However, this situation is unusual.
Dr. Nicolosi.
The latest nutrition textbooks all provide the same information about the adverse effects of high intakes of phosphorus and protein on calcium and bone health. If this information is inaccurate, it should be corrected.
Dr. Heaney.
Updating current understanding of the research is one of the advantages of conferences such as this. All the evidence about protein that I am aware of supports a positive effect on bone. In contrast to protein, the phosphorus literature is sparse. Studies indicate that if people consume a high-phosphorus, low-calcium diet, parathyroid hormone level rises. However, if people consume the same high-phosphorus diet, but the diet also is high in calcium, parathyroid hormone level does not rise. The decrease in calcium is responsible for the increase in parathyroid hormone. Organ culture studies have found that osteoclasts are extremely sensitive to the ambient phosphorus concentration. When phosphorus concentration increases, bone-absorbing activity declines dramatically because the phosphorus blocks osteoclast bone resorption, as evidenced by bone resorption markers. Instead of the bone resorption markers increasing, as one would expect with the high parathyroid hormone, they decline. The parathyroid hormone level increases to release calcium. So, in a sense, bone is protected by high phosphorus. There is relatively little evidence regarding the effect of phosphorus on bone health; this area needs to be explored.
Dr. Michael B. Zemel.
Balance studies from the 1970s show that adding elemental phosphorus to a calcium-rich diet clearly enhanced calcium balance.
With regard to Dr. Arjmandi’s calcium absorption data with soy protein, in ovariectomized animals there was no change in calcium absorption. But when the animals were fed a diet high in soy protein, calcium absorption doubled. Does this mean that calcium absorption increased in vivo or decreased in vivo because this is an ex vivo model?
Dr. Arjamandi.
A study by a Japanese group that gave soy meal to rats reported that soy meal increased calcium absorption. This was an in vitro study, but the treatments were given in vivo.
Dr. Heaney.
It’s interesting that calcium was absorbed in the distal bowel. Interest has grown during the last few years in the possibility that inulin and the fructooligosaccharides may increase colonic absorption of calcium. Normally in a typical adult human, less than 5% of calcium is absorbed in the colon. There is potential for increased absorption in the colon, as suggested by rat data with oligosaccharides.
Dr. Bales.
Dr. Strobl, what are some practical alternatives to estrogen replacement therapy for postmenopausal women?
Dr. Strobl.
From a cardiologist’s viewpoint, I think that hormonal supplements are underutilized by postmenopausal women, in large part, because of fear of breast or uterine cancer. Also, some physicians may be hesitant to recommend estrogen replacement therapy because of fear of introducing some pathology when in fact they are trying to treat a condition. This is a dilemma for preventive medicine. In my practice, if a postmenopausal woman has a favorable blood lipid profile, I recommend that she consult with her primary care physician regarding hormonal replacement therapy. On the other hand, if a postmenopausal woman has a strong family history of breast or uterine cancer, I look for alternatives to hormonal replacement. As you know, some recent studies, including the HERS trial and others, have cast doubt on the safety of estrogen replacement therapy. There is a difference between having people follow a treatment for most of their adult life and instituting treatment at a time of crisis. The disappointing finding of the HERS study was that the women who already had an acute ischemic event and who were then placed on hormonal supplements subsequently experienced more problems. In contrast, healthy women on hormonal replacement therapy did well throughout the study period. Whether this same finding holds true for soy products is unknown.
Dr. Setchell.
Treatment and prevention are different categories. When you have an advanced ongoing disease, it becomes quite difficult to expect dramatic effects from a dietary intervention. One problem with the FDA’s recent health claim for soy protein and reduced risk for coronary heart disease is the recommendation for 25 g/day of soy protein. Nobody consumes 25 g/day of soy protein, not even in Asia. The health claim states that soy reduces the risk for cardiovascular disease by lowering blood cholesterol. This claim assumes a treatment with soy protein. Data from Asia on serum cholesterol levels show a strong inverse relationship between serum cholesterol levels and soy protein consumption. The majority of adults in Japan do not have elevated blood cholesterol levels and, therefore, by definition are at much lower risk for coronary heart disease. I believe that dietary modification is important in the prevention of disease when it is introduced very early, beginning in childhood.
Dr. Heaney.
Dr. Strobl, I agree with your point about the HERS study, which was a treatment study in secondary prevention. But, what about the caution that came out of the Women’s Health Initiative study, which seemed to say the same thing for women who had not had a prior ischemic event?
Dr. Strobl.
That’s a good point and a problem when you focus on a single study. I think the information was contradictory to some degree. One of the problems is that we are trying to make blanket recommendations for the general public. We have to deal with subsets of the population. Medicine is practiced on individuals, not on populations.
Dr. Heaney.
It’s realistic for women to be afraid of breast cancer, particularly considering the statistics indicating that this disease is the principal cause of years of life lost before age 75 for North American women today. The coronary events that lead to the principal cause of death tend to take life away after age 75.
Dr. Bales.
Dr. Watkins, regarding your nutraceutical approaches to bone and inflammatory joint diseases, which do you see as the most promising in the near future?
Dr. Watkins.
That’s a difficult question to answer. When you look at the overall diet, identifying an optimal dietary ratio of omega-6 (n-6) to omega-3 (n-3) offers the most promise, although some groups are advocates of CLA. Decades of research support the benefits of long-chain n-3 fatty acids on cardiovascular disease and cardiac arrhythmias and have identified how these fatty acids modify eicosanoid production, which influences the cardiovascular system. Other research has focused on n-3 fatty acids and cancer prevention. In terms of humans, at some point we are going to have to make a dietary recommendation for n-3 fatty acids. Although most of our work on n-3 fatty acids and bone has not been done in human models, our findings support those in humans identified by other investigators. We need to carry out clinical trials of n-3 fatty acids to determine their efficacy in bone and joint disease in humans. Other laboratories have found that n-3 and n-6 fatty acids affect transcription factors involved in carbohydrate and lipid metabolism. If we look at our food supply over the last 100 years, there is now more n-6s than n-3s, not only in fish and vegetables, but also in animal foods because of the way food animals are raised. In the past, fishmeal was added to poultry and swine rations. Today, there are fewer n-3s in poultry and swine. For this reason, people are developing foods, such as eggs, with extra n-3s to reduce the risk for cancer, cardiovascular disease, and now possibly bone disease.
Dr. Nicolosi.
You said that the ratio of n-6/n-3 in the Western diet is about 20:1. I’ve heard that it should be reduced to 4:1. Is this reduction too extreme? What is a reasonable ratio according to the literature?
Dr. Watkins.
According to a recent article by Etherton a reasonable ratio for n-6/n-3 is closer to 10:1.
Dr. Nicolosi.
Is it true that in the United States, infant formulas cannot contain n-3s?
Dr. Mark L. Masor.
Right now the FDA does not allow the addition of long-chain polyunsaturated fatty acids in infant formula. The same is true in Canada.
Dr. Kevin L. Fritsche.
You can use canola oil and have a 2:1 ratio of n-6 to n-3.
Dr. Masor.
Canola oil is not allowed in infant formula in the United States or Canada. Some studies in humans have associated intake of canola oil with cardiac fatty infiltration. More recently, some studies using hypertensive rats have shown that intake of canola oil increases hypertensive events in these animals.
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