Progress 02/22/02 to 07/31/05
Outputs
1. What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? What does it matter? Osteoporosis is a prevalent and costly bone disease that causes at least one bone fracture in one out of every two women and one out of eight men in their lifetimes. The annual cost of healthcare related to osteoporosis is estimated at $14 billion. In the elderly, hip fractures are associated with mortality in up to 20% of the cases. Osteoporosis is a multifactorial disease process directed by several factors. These risk factors include environment (i.e., nutrition, physical activity), genetics, endogenous hormones (estrogen and androgen deficiencies), and age. Behavior modification and pharmacologic intervention (e.g., hormone replacement therapy [HRT]) are the common complementary approaches used to prevent bone loss in asymptomatic women. However, only 12-20% of US postmenopausal women
currently use HRT. Thus, nutrition is, arguably, one of the most important modifiable factors and represents a primary approach in prevention of this debilitating disease. For this reason, all significant nutritional factors must be identified that maximize peak bone mass during development and maintain bone mass and strength during aging. There is consensus that adequate calcium intake continuous from childhood is critical for the formation and maintenance of a healthy skeleton. Thus, dietary calcium supplementation is considered as both a treatment and prophylaxis for osteoporosis. However, there is no current recommended daily allowance (RDA) for this important nutrient because experimental data are not available to assess adequately the physiological adaptation to changes in calcium intake over time. Furthermore, calcium metabolism is known to be modified by many other dietary factors including dietary protein sources (vegetable and animal), trace minerals (e.g., copper, zinc,
and boron), and prebiotics (e.g., inulin). However, to date, the interaction of these factors with calcium is at best ill-defined. Therefore, this project had two specific goals: 1) titration of the calcium intake needed to optimize bone health and prevent bone loss in postmenopausal women and 2) determination of the roles of key dietary factors (protein, selected trace elements, and prebiotics) on the utilization of dietary calcium. Animal and human experiments were conducted with the goal of establishing the calcium requirement and characterizing the modifying roles of animal proteins (in meat and milk), and zinc, copper, magnesium, and boron (as trace elements) on that requirement. Postmenopausal women and appropriate animal models (e.g., ovariectomized female rats) consumed varying amounts (low, adequate, and/or supranutritional) of calcium and the identified dietary factors while all other components of the diet remained constant. The response of the animals and humans to the
dietary manipulations was ascertained by evaluating appropriate biochemical, physiological, and anatomical variables. The research undertaken fell under National Program 107, Human Nutrition, and addressed goal 3.1.1 (Human Nutrition Requirements). The challenge of this component is to identify essential nutrients, determine their effects on reproduction, development, function and longevity, and to provide information that will be used to develop standards to optimize human health, well-being, and genetic potential throughout the life cycle. All priority objectives, especially mechanism of action, biomarkers, function and performance, and nutrient interactions apply to the research program. Outcomes of the research was knowledge that will facilitate establishment of an RDA for calcium with due consideration of the dietary factors that have significant potential to modify that requirement. 2. List the milestones (indicators of progress) from your Project Plan. Because this project
plan was under development, no formal milestones were in place. The review process was completed and this project was replaced by another project plan (5450-51000-039-00D, Mineral Intakes for Optimal Bone Development and Health) that continues work in a similar area and was initiated 08/01/2005. Milestones from the new approved plan are listed below: FY 2005: Enroll subjects and conduct study on estimating the Ca requirement by titration Conduct the first of a three year study on bone health and copper and zinc supplementation Complete in utero phase of boron essentiality study Initiate growth phase of three study of boron essentiality FY 2006: Complete data analyses from study on estimating the Ca requirement by titration Enroll subjects and conduct study on bone health during weight loss Conduct the second of a three year study on bone health and copper and zinc supplementation Report findings from in utero phase of boron essentiality study Conduct the second of a three year study
of boron essentiality Conduct study on whether dietary boron affects calcium absorption Enroll subjects and conduct study on whether dietary inulin affects calcium absorption FY 2007: Report on study on estimating the Ca requirement by titration Complete analyses from study on bone health during weight loss Conduct the third of a three year study on bone health and copper and zinc supplementation Conduct the third of a three year study of boron essentiality Conduct post-growth phase of boron essentiality study Enroll subjects and conduct study on whether magnesium status affects calcium retention and bone resorption Complete analyses from study on whether dietary inulin affects calcium absorption FY 2008: Report on study of whether bone health is affected by weight loss Complete analyses on study on bone health and copper and zinc supplementation Report findings from growth phase of boron essentiality study Report findings from post-growth phase of boron essentiality study Complete
analyses on study whether magnesium status affects calcium retention and bone resorption Report findings from dietary inulin and calcium absorption study 3a List the milestones that were scheduled to be addressed in FY 2005. For each milestone, indicate the status: fully met, substantially met, or not met. If not met, why. 1. Conduct the second of a three year study to determine whether dietary copper and/or zinc enhance the ability of calcium to attenuate bone loss Milestone Fully Met 2. Complete in utero phase of boron essentiality study Milestone Fully Met 3. Initiate growth phase of boron essentiality study Milestone Fully Met 4. Enroll recruitment of subjects and conduct study on estimating the Ca requirement by titration Milestone Not Met Critical SY Vacancy 3b List the milestones that you expect to address over the next 3 years (FY 2006, 2007, and 2008). What do you expect to accomplish, year by year, over the next 3 years under each milestone? Development of this project
was completed and replaced by another project plan (5450-51000-039-00D, Mineral Intakes for Optimal Bone Development and Health) that continues work in a similar area and was initiated 08/01/2005. Milestones from the new approved plan are listed. FY 2006: Complete data analyses from study on estimating the Ca requirement by titration. A study to determine the amount of dietary calcium needed to maximize calcium retention and minimize bone resorption in postmenopausal women has been delayed because of a critical SY vacancy. Because existing experimental data are not adequate to assess physiological adaptation(s) to changes in calcium intake over time, the information from this study will be useful to Dietary Reference Committees in establishing a Recommended Daily Allowance for calcium in postmenopausal women. Enroll subjects and conduct study on bone health during weight loss. A study will be planned and initiated to determine whether a balanced, high protein diet, one providing
moderate amounts of carbohydrate, is adequate to maintain calcium homeostasis. Because changes in dietary patterns are needed to combat the American epidemic of obesity, rigorous tests of weight loss strategies (consumption of high protein diets) on calcium retention are needed. The tests will be useful in helping develop guidelines that will protect against bone loss. Conduct the second of a three year study on bone health and copper and zinc supplementation A three year study is underway to determine whether dietary supplements of copper and/or zinc enhance the ability of calcium to attenuate bone loss in postmenopausal women. Because osteoporosis is a multifactorial disease not prevented by adequate calcium and vitamin D nutrition alone, this research will characterize the interactions of calcium with zinc and copper, two elements that show special promise in affecting bone calcification. Report findings from in utero phase of boron essentiality study. Findings will be reported
from a study to determine whether or not boron affects the quantitative need for calcium and is essential for bone health during the in utero phase of development. Because adequate calcium intake continuous from development is considered critical for the formation and maintenance of a healthy skeleton, this research will characterize some of the interactions of calcium with boron, an element that benefits bone calcification. Conduct the second of a three year study of boron essentiality during growth. A three year study is underway to determine whether or not boron affects the quantitative need for calcium and is essential for bone health during the postnatal phase of development. Because adequate calcium intake continuous from development is considered critical for the formation and maintenance of a healthy skeleton, this research will characterize some of the interactions of calcium with boron, an element that benefits bone calcification. Conduct study on whether dietary boron
affects calcium absorption. A study will be completed on whether dietary boron deprivation impairs calcium absorption especially at marginal calcium intakes. Because osteoporosis is a multifactorial disease not prevented by adequate calcium and vitamin D nutrition alone, this research will characterize the interactions of calcium with boron, an element that benefits bone calcification. Enroll subjects and conduct study on whether dietary inulin affects calcium absorption. A study will be conducted with healthy postmenopausal women to determine whether inulin, a prebiotic, sufficiently enhances calcium absorption to be of practical significance for bone health. Because osteoporosis is a multifactorial disease of unknown etiology, this research will characterize specific health effects of inulin, a natural nondigestible carbohydrate with apparent potential to enhance calcium absorption. FY 2007: Report on study on estimating the Ca requirement by titration. A study to determine the
amount of dietary calcium needed to maximize calcium retention and minimize bone resorption in postmenopausal women has been delayed because of a critical SY vacancy. Because existing experimental data are not adequate to assess physiological adaptation(s) to changes in calcium intake over time, the information from this study will be useful to Dietary Reference Committees in establishing a Recommended Daily Allowance for calcium in postmenopausal women. Complete analyses from study on bone health during weight loss. Data analyses will be completed on a study to determine whether a balanced, high protein diet, one providing moderate amounts of carbohydrate, is adequate to maintain calcium homeostasis. Because changes in dietary patterns are needed to combat the American epidemic of obesity, rigorous tests of weight loss strategies (consumption of high protein diets) on calcium retention are needed. The tests will be useful in helping develop guidelines that will protect against
bone loss. Conduct the third of a three year study on bone health and copper and zinc supplementation. A three year study is underway to determine whether dietary supplements of copper and/or zinc enhance the ability of calcium to attenuate bone loss in postmenopausal women. Because osteoporosis is a multifactorial disease not prevented by adequate calcium and vitamin D nutrition alone, this research will characterize the interactions of calcium with zinc and copper, two elements that show special promise in affecting bone calcification. Conduct the third of a three year study of boron essentiality during growth. A three year study is underway to determine whether or not boron affects the quantitative need for calcium and is essential for bone health during the postnatal phase of development. Because adequate calcium intake continuous from development is considered critical for the formation and maintenance of a healthy skeleton, this research will characterize some of the
interactions of calcium with boron, an element that benefits bone calcification. Conduct post-growth phase of boron essentiality study. A study will be completed on whether dietary boron affects the quantitative need for calcium and is essential for bone health during the post-growth phase of the life cycle. Because osteoporosis is a multifactorial disease not prevented by adequate calcium and vitamin D nutrition alone, this research will characterize the interactions of calcium with boron, an element that benefits bone calcification. Enroll subjects and conduct study on whether magnesium status affects calcium retention and bone resorption. A study will be planned and initiated to determine whether marginal magnesium status increases bone resorption and changes calcium needs in postmenopausal women. Because osteoporosis is a multifactorial disease not prevented by adequate calcium and vitamin D nutrition alone, this research will characterize the interactions of calcium with
magnesium, an element that may be a risk factor for osteoporosis. Complete analyses from study on whether dietary inulin affects calcium absorption. Data analyses will be completed from a study conducted with healthy postmenopausal women to determine whether inulin, a prebiotic, sufficiently enhances calcium absorption to be of practical significance for bone health. Because osteoporosis is a multifactorial disease of unknown etiology, this research will characterize specific health effects of inulin, a natural nondigestible carbohydrate with apparent potential to enhance calcium absorption. FY 2008: Report on study of whether bone health is affected by weight loss. Findings will be reported from a study to determine whether a balanced, high protein diet, one providing moderate amounts of carbohydrate, is adequate to maintain calcium homeostasis. Because changes in dietary patterns are needed to combat the American epidemic of obesity, rigorous tests of weight loss strategies
(consumption of high protein diets) on calcium retention are needed. The tests will be useful in helping develop guidelines that will protect against bone loss. Complete analyses on study on bone health and copper and zinc supplementation Data analysis will be completed from study to determine whether dietary supplements of copper and/or zinc enhance the ability of calcium to attenuate bone loss in postmenopausal women. Because osteoporosis is a multifactorial disease not prevented by adequate calcium and vitamin D nutrition alone, this research will characterize the interactions of calcium with zinc and copper, two elements that show special promise in affecting bone calcification. Information from this study will be useful to Dietary Reference Committees in establishing a Recommended Daily Allowance for calcium in postmenopausal women. Report findings from growth phase of boron essentiality study. Findings will be reported from a study on whether or not boron affects the
quantitative need for calcium and is essential for bone health during the postnatal phase of development. Because adequate calcium intake continuous from development is considered critical for the formation and maintenance of a healthy skeleton, this research will characterize some of the interactions of calcium with boron, an element that benefits bone calcification. This information is needed by Dietary References Committees to help establish an adequate intake of boron in adolescents. Report findings from post-growth phase of boron essentiality study. Findings will be reported from a study on whether dietary boron affects the quantitative need for calcium and is essential for bone health during the post-growth phase of the life cycle. Because osteoporosis is a multifactorial disease not prevented by adequate calcium and vitamin D nutrition alone, this research will characterize the interactions of calcium with boron, an element that benefits bone calcification. This information
is needed by Dietary References Committees to help establish an adequate intake of boron in mature adults. Complete analyses on study whether magnesium status affects calcium retention and bone resorption. Data analyses will be completed for a study to determine whether marginal magnesium status increases bone resorption and changes calcium needs in postmenopausal women. Because osteoporosis is a multifactorial disease not prevented by adequate calcium and vitamin D nutrition alone, this research will characterize the interactions of calcium with magnesium, an element that may be a risk factor for osteoporosis. The information is needed by Dietary References Committees to refine the Recommended Daily Allowance for magnesium in postmenopausal women. Report findings from dietary inulin and calcium absorption study. Findings will be reported from a study with healthy postmenopausal women to determine whether inulin, a prebiotic, sufficiently enhances calcium absorption to be of
practical significance for bone health. Because osteoporosis is a multifactorial disease of unknown etiology, this research will characterize specific health effects of inulin, a natural nondigestible carbohydrate with apparent potential to enhance calcium absorption. This information is needed to determine whether inulin, a prebiotic, sufficiently enhances calcium absorption to be of practical significance for bone health. 4a What was the single most significant accomplishment this past year? Boron Reduces Inflammation Signals From Cells Involved in Inflammation: There is evidence that dietary boron helps control the normal inflammatory process and thereby helps prevent development of bone diseases such as rheumatoid arthritis. Scientists at the Grand Forks Human Nutrition Research Center, in cooperation with scientists at the University of North Dakota, Grand Forks, ND, used immune function cells taken from mice to determine how boron prevents inflammatory disease. The cells were
grown in a culture solution that was low in boron or was supplemented with boron. When the cells were stimulated with an agent to produce inflammatory signal molecules, gene expression of those signal molecules was suppressed in those cells supplied with boron. This accomplishment is important because it shows a likely mechanism by which dietary boron keeps the normal inflammatory system in check. 4b List other significant accomplishments, if any. Boron and Fish Oil Act Synergistically to Enhance Bone Strength: Boron deprivation and a diet with safflower oil as the fat source resulted in long bone strength that was increased synergistically by both boron supplementation and providing fish oil instead of safflower oil in the diet. The increase in bone strength may have been the result of improved bone microarchitecture because boron supplementation increased vertebra trabecular thickness and fish oil increased trabecular bone volume. Some studies show that, compared to diets high
in omega-6 polyunsaturated fatty acids (PUFA), diets high in omega-3 PUFA promote bone accretion and strength, but other studies show no marked effects. The inconsistency may be the result of different intakes of another nutrient, such as boron, shown to affect similar functions as the long chain omega-3 PUFA. This accomplishment is important because it shows that the beneficial effects of fish oil or omega-3 fatty acids on bone health may be maximized with a diet containing boron-rich foods (fruits, vegetables and pulses). High Protein Intake Enhances Calcium Retention From A Low Calcium Diet: A controlled feeding study with healthy postmenopausal women was conducted to determine whether dietary protein and calcium interact to affect calcium retention and thus bone health. The subjects were fed a series of diets that were low in Ca (600 mg/d) or high in Ca (1500 mg/d) and low protein or high in protein (10% and 20% of energy mostly as meat protein, respectively). The four diets
were fed for 7 weeks each in random order. After 3 weeks of equilibration, the menu was labeled with a tracer dose of radioactive calcium to monitor how long the calcium stayed in the body. Regardless of how much calcium was consumed, a high protein diet increased the amount of calcium in the urine. When calcium intake was low, a high protein diet, compared to a low protein diet, enhanced the initial absorption of calcium and also increased calcium retention. As expected, a high calcium intake, compared to a low calcium intake, reduced the fractional amount of calcium retained. A high protein intake also decreased bone resorption, as indicated by the amount of a bone marker found in urine. This accomplishment is important because it shows that, in postmenopausal women, a moderately high protein diet may be beneficial to bone health, especially when calcium intake is low. Antirachitic Properties of Dietary Calcium: A 13 mo. long, double-blind, clinical trial was conducted in 1-5
yr. old children at risk to developing rickets in a rickets-endemic part of Bangladesh. Subjects were randomized to four treatments consisting of a milk powder-based dietary supplement providing graded levels of calcium (Ca) with or without multi-vitamins and minerals. When 183 healthy children presenting with no rachitic leg signs but serum alkaline phosphatase activities in the upper decile were re-screened after a 7 mo. pre-trial period, 23 (12.6%) showed rachitic leg signs, suggesting an annual risk of 21.5% in this cohort. Of those still not presenting with leg signs after the pre-trial period and completing 13 mos. of dietary intervention, none showed rachitic leg signs and all showed carpal ossification normal for age after that intervention. At that time, however, 18 subjects (16%) showed modest radiographic knee deformations (<168 degrees) without significant differences between treatment groups. This accomplishment is important because it shows that even very small
supplements of calcium (50 mg/d) are useful in supporting normal bone development in this high-risk population. Dietary Boron Reduces Serum Insulin Concentrations Regardless of Vitamin D Status: There is evidence that dietary boron helps control the normal levels of insulin in blood. Scientists at the Grand Forks Human Nutrition Research Center, in cooperation with scientists at North Dakota State University, Fargo, ND, determined whether dietary boron works through vitamin D to affect serum insulin levels. As expected, dietary boron lowered insulin levels when vitamin D status was adequate. Also, as expected, severe vitamin D deficiency lowered insulin levels in the blood far below the normal range but adding boron to the diet did not change that effect. The results suggest that dietary boron affects blood insulin concentrations independent of vitamin D status. Because dietary boron reduces circulating insulin concentrations while maintaining serum glucose concentrations within
the normal range, dietary boron might help prevent pancreatic exhaustion caused by chronic hyperinsulinemia. 5. Describe the major accomplishments over the life of the project, including their predicted or actual impact. High Protein Diets May Not Adversely Affect Bone Health in Healthy Postmenopausal Women: To determine whether animal protein intake is a risk for the development of osteoporosis, a carefully controlled feeding study of several weeks duration was conducted in postmenopausal women at the Grand Forks Human Nutrition Research Center. Findings from this study indicate that a high protein diet (20% of energy mostly provided as meat) may not increase calcium loss and or adversely affect bone health in healthy postmenopausal women. On the contrary, a significant improvement in calcium retention was observed in women with low calcium intake. These findings, which contradict prevalent assumptions about the effects of meat consumption on calcium retention, will improve the
quality and nature of the advice given to the public regarding the effects of dietary protein, especially meat protein, on bone health. This accomplishment was conducted under National Program 107 Human Nutrition; ARS Strategic Plan goal 4 of IMPROVING THE NATIONS NUTRITION AND HEALTH; and part of performance standard 4.1.2 related to defining interactions for known classes of nutrients. High Protein Diets May Be Protective Against Bone Loss: A study to determine the effects of high-isoflavone soy protein versus beef on calcium retention and biomechanical properties of bones was conducted at the Grand Forks Human Nutrition Research Center in collaboration with the University of North Dakota, Grand Forks, ND. In this study with ovarioectomized rats (estrogen-deficient), the findings indicated that calcium retention was significantly improved when protein intake was high (20%) and it was higher in the animals consuming beef versus soy protein. Serum IGF-1, a growth factor needed for
bone health, was also higher in the animals consuming the high protein diets (20% soy or beef). These results are consistent with our findings from human studies and indicate that a high protein diet may be protective against bone loss in postmenopausal women rather than harmful. This accomplishment was conducted under National Program 107 Human Nutrition; ARS Strategic Plan goal 4 of IMPROVING THE NATIONS NUTRITION AND HEALTH; and part of performance standard 4.1.2 related to defining interactions for known classes of nutrients. Dietary Silicon May Have a Role in Bone Formation: An experiment was performed at the Grand Forks Human Nutrition Research Center to determine whether silicon deficiency in mature rats would exacerbate bone loss induced by ovariectomy (a model of osteoporosis). Silicon deprivation did not affect calcified bone changes induced by ovariectomy, but independently changed blood markers of bone metabolism and bone composition associated with the organic matrix.
The findings suggest that silicon is a bioactive food component that is involved in the proper formation of the organic scaffold upon which calcified bone is formed. This accomplishment was conducted under National Program 107 Human Nutrition; ARS Strategic Plan goal 4 of IMPROVING THE NATIONS NUTRITION AND HEALTH; and part of performance standard 4.1.2 related to defining functions for emerging classes of nutrients. Boron in Breast Milk May be Under Homeostatic Control: To determine whether the amount of boron in human milk is regulated, scientists at the Grand Forks Human Nutrition Research Center, in cooperation with scientists at the University of Manitoba, Winnipeg, Canada, and the USDA/ARS Childrens Nutrition Research Center, Baylor College of Medicine, Houston, TX, obtained definitive data on the concentration of boron in human milk during the first four months of lactation. Boron milk concentrations were remarkably similar between the separate populations and stable over
four months of lactation. This accomplishment is important because it clearly shows that boron concentrations are similar in separate populations and therefore probably under homeostatic control. This accomplishment was conducted under National Program 107 Human Nutrition; ARS Strategic Plan goal 4 of IMPROVING THE NATIONS NUTRITION AND HEALTH; and part of performance standard 4.1.2 related to defining functions for emerging classes of nutrients. Dietary Boron May Provide Resistance to Rheumatoid Arthritis: Studies were conducted at the Grand Forks Human Nutrition Research Center in collaboration with the University of North Dakota to characterize further the effect of dietary boron on the onset of collagen-induced arthritis (an animal model of polyarthritis similar to human rheumatoid arthritis). Similar to our previous studies, mice weaned onto low-, adequate-, or luxuriant-boron diets exhibited a 54, 29, and 13% incidence of arthritis respectively. The findings indicate that
dietary boron provides resistance to clinical signs in this animal model of rheumatoid arthritis. This accomplishment was conducted under National Program 107 Human Nutrition; ARS Strategic Plan goal 4 of IMPROVING THE NATIONS NUTRITION AND HEALTH; and part of performance standard 4.1.2 related to defining functions for emerging classes of nutrients. Very High Amounts of Calcium May Compromise Iron Status of Some Individuals: A study was conducted with growing female rats to determine whether an interaction between calcium and iron affects the biomechanical and biochemical properties of bone. The findings from this study, done in collaboration with the University of North Dakota, indicate that higher than adequate calcium intakes reduced both iron status and bone quality. These findings indicate that very high calcium intakes, as may result from indiscriminate supplementation and fortification of foods with calcium, may compromise the iron status of vulnerable segments of the
population without offering additional benefits to bone health. This accomplishment was conducted under National Program 107 Human Nutrition; ARS Strategic Plan goal 4 of IMPROVING THE NATIONS NUTRITION AND HEALTH; and part of performance standard 4.1.2 related to defining interactions for known classes of nutrients. Consuming Foods High in Magnesium and Nickel May Benefit Bone Health: A study was conducted to determine whether bone health is impaired by a combined lack of dietary nickel and magnesium, two minerals generally supplied by the same foods. The combined marginal deficiency of magnesium and nickel resulted in increased prostaglandin E-2 excretion and changed the mineral composition of bone. The findings indicate that consuming foods high in both magnesium and nickel, including leafy green vegetables, legumes, whole grains and nuts, is beneficial to bone health, and that the beneficial effects possibly occur through these minerals influencing the metabolism of lipids to
prostaglandins that promote bone formation. This accomplishment was conducted under National Program 107 Human Nutrition; ARS Strategic Plan goal 4 of IMPROVING THE NATIONS NUTRITION AND HEALTH; and part of performance standard 4.1.2 related to defining functions for emerging classes of nutrients. Full Substitution of Soy Protein for Meat Protein May Reduce Calcium Retention: A high meat intake is often cited as a risk factor for development of osteoporosis, and soy protein is thought to have a beneficial effect on bone health. However, new reported findings indicate that partial substitution of soy protein (with high isoflavones) for meat protein does not improve calcium retention in postmenopausal women. In a follow-up study with ovarioectomized rats, complete substitution of meat protein by soy protein isolate with high isoflavone content reduced calcium retention by about 30%. Assuming that the findings in rats are applicable to humans, these combined results indicate that,
contrary to popular belief, meat protein intake does not adversely affect bones and that while a partial substitution of soy protein for meat protein may not reduce calcium retention, full replacement may adversely affect calcium retention. This accomplishment was conducted under National Program 107 Human Nutrition; ARS Strategic Plan goal 4 of IMPROVING THE NATIONS NUTRITION AND HEALTH; and part of performance standard 4.1.2 related to interactions functions for known classes of nutrients. A Diet Low in Silicon May Impair Bone Mineralization: A series of experiments with rats performed both in-house and with collaborators at the University of Wisconsin-Stout, Stout, WI, and the University of Buenos Aires have shown that silicon deprivation is detrimental to bone physical characteristics and repair apparently through changing collagen and glycosaminoglycan metabolism during development and maturation of the organic matrix upon which bone mineralization occurs. The findings have
resulted in increased interest from other scientists to determine whether low dietary silicon may contribute to decreased bone strength and increased risk to fractures, and to delayed bone healing or repair. The findings also have stimulated the appearance of nutritional supplements that contain silicon. This accomplishment was conducted under National Program 107 Human Nutrition; ARS Strategic Plan goal 4 of IMPROVING THE NATIONS NUTRITION AND HEALTH; and part of performance standard 4.1.2 related to defining functions for emerging classes of nutrients. Substitution of Soy Protein for Meat Protein Did Not Improve Bone Health in Postmenopausal Women: The US Food and Drug Administration has approved a health claim that a daily consumption of 25 g of soy protein is beneficial to heart health. However, the effects of this dietary practice on bone health are unknown. A controlled feeding trial with postmenopausal women, using sensitive whole body counting methodology, demonstrated that
when 25 g of soy protein is substituted for an equal weight of meat protein, on a daily basis for 8 weeks, the amount of calcium that the body retains does not change. Furthermore, urinary and blood biomarkers of bone formation and breakdown did not change. These findings indicate that the common practice of substitution of soy protein for meat protein does not provide any additional benefits (associated with phytoestrogens) or risks (associated with phytate) with regards to calcium retention or bone health in postmenopausal women and that the effects of vegetable proteins versus animal proteins on bone health deserve further investigations. This accomplishment was conducted under National Program 107 Human Nutrition; ARS Strategic Plan goal 4 of IMPROVING THE NATIONS NUTRITION AND HEALTH; and part of performance standard 4.1.2 related to defining interactions for known classes of nutrients. Dietary Boron May Help Reduce The Amount of Insulin Needed to Maintain Blood Glucose: Two
separate studies with healthy rats and a third with chicks were conducted to determine whether boron, a natural substance in the diet, helps regulate the level of insulin in the blood. Results from the rat studies demonstrated that a diet with normal physiological amounts of boron reduced blood insulin levels without affecting glucose levels. In chicks given glucose through a vein injected, boron decreased peak pancreatic insulin release. These results suggest that dietary boron, found in higher concentrations in fruits, vegetables, nuts, and legumes, may help reduce the amount of insulin needed to maintain blood glucose. This accomplishment was conducted under National Program 107 Human Nutrition; ARS Strategic Plan goal 4 of IMPROVING THE NATIONS NUTRITION AND HEALTH; and part of performance standard 4.1.2 related to defining functions for emerging classes of nutrients. 6. What science and/or technologies have been transferred and to whom? When is the science and/or technology
likely to become available to the end- user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? Information about the nutritional of beneficial aspects of ultratrace and trace elements as it became available was routinely transferred to a variety of customers. The customers included nutritional risk assessment groups through direct contact or organized meetings and workshops; the public through web pages of professional organizations, via the popular media; and other scientists through presentations at national and international meetings and professional publications. 7. List your most important publications in the popular press and presentations to organizations and articles written about your work. (NOTE: List your peer reviewed publications below). Information was transferred to the public through the local newspaper (Grand Forks Herald) that was also placed on the Grand Forks Human Nutrition
Research Center Home Page. Dr. Roughead wrote an article entitled, "Vitamin D: you need it for good bones." Dr. Nielsen wrote an article entitled, "Don't overlook benefits of diet that contain fish."
Impacts
(N/A)
Publications
- Hunt, C. 2005. Boron. In: P.M. Coates, M.R. Blackman, G. Cragg, M. Levine, J. Moss, J. White, editors. Encyclopedia of Dietary Supplements. New York: Marcel Dekker/Taylor and Francis Group. p. 55-63.
- Roughead, Z.K., Hunt, J.R., Johnson, L.K., Badger, T.M., Lykken, G.I. 2005. Controlled substitution of soy protein for meat protein: effects on calcium retention, bone, and cardiovascular health indices in postmenopausal women. Journal of Clinical Endocrinology and Metabolism. 90(1):181-9.
- Nielsen, F.H. 2004. The effect of nickel deprivation on bone strength and shape and urinary phosphorus excretion is not enhanced by a mild magnesium deprivation in rats. In: Anke, M., Flachowsky, G., Kisters, K., Schafer, U. , Schenkel, H., Seifert, M., Stoeppler, M., editors. Proceedings of the Macro and Trace Elements 22nd Workshop, September 24-25, 2004, Jena, Germany. 2:965-70.
- Roughead, Z.K. 2004. Member Spotlight. The Digest. Newsletter of the Research Dietetic Practice Group of the American Dietetic Association. 39(4):8-9.
- Combs Jr., G.F., Hassan, N., Hunt, C.D., Watts, J. 2005. Apparent efficacy of food-based calcium supplementation in preventing rickets in Bangladesh [abstract]. The Federation of American Societies for Experimental Biology Journal. 19(5):A1462.
- Durick, K.A., Tomita, M., Hunt, C., Bradley, D. 2005. Evidence that boron down-regulates inflammation through the NF-KB pathway [abstract]. The Federation of American Societies for Experimental Biology Journal. 19(5) :A1705.
- Durick, K.A., Hunt, C., Bradley, D. 2005. Evidence for anti-inflammatory properties of dietary boron in collagen-immunized B10.T(6R), an animal model of polyarthritis [abstract]. The Federation of American Societies for Experimental Biology Journal. 19(4):A915.
- Hunt, C. 2004. Dietary boron as a factor in glucose and insulin metabolism [abstract]. The Journal of Trace Elements in Experimental Medicine. 17(4) :258.
- Hunt, C.D., Butte, N.F. 2005. Boron concentrations remain stable in milk from mothers of full-term exclusively breast-fed infants during the first four months of lactation [abstract]. The Federation of American Societies for Experimental Biology Journal. 19(5):A1704.
- Nielsen, F.H. 2004. Essentiality of copper, zinc, magnesium, boron and silicon in bone development and function [abstract]. The Journal of Trace Elements in Experimental Medicine. 17(4):263-4.
- Nielsen, F.H. 2005. Fish oil instead of safflower oil as the dietary fat source modifies the oxidative stress response to boron deficiency in rats [abstract]. The Federation of American Societies for Experimental Biology Journal. 19(5):A1705.
- Stoecker, B.J., Nielsen, F.H. 2005. Dietary fatty acid composition, dietary boron, and ovariectomy affect bone strength and microarchitecture [abstract]. The Federation of American Societies for Experimental Biology Journal. 19(4):A57.
- Rhee, Y., Hunt, C., Idso, J.P. 2004. Dietary boron reduces serum insulin concentrations regardless of vitamin d status in rats [abstract]. The Journal of Trace Elements in Experimental Medicine. 17(4):208.
- Roughead, Z.K., Johnson, L.K., Lykken, G.I. 2004. The effects of interaction of dietary protein and calcium on calcium retention: a controlled feeding study [abstract]. Journal of Bone and Mineral Research. 19(sup1):S302.
- Roughead, Z.K. 2004. Dairy protein and bone health [abstract]. International Dairy Federation (IDF) World Dairy Summit. p.47.
- Roughead, Z.K., Johnson, L.K., Lykken, G.I. 2005. A high protein intake enhances calcium retention from a low calcium diet in healthy postmenopausal women: A controlled feeding study [abstract]. The Federation of American Societies for Experimental Biology Journal. 19(5) :A1463.
- Sattler, J.A., Soule, M.R., Hillegonds, D.J., Roughead, Z.K., Wagner, J.L. 2005. Whole body versus skeletal calcium (Ca) retention in rats: Short and long term comparisons using 47CA and 41Ca tracers [abstract]. The Federation of American Societies for Experimental Biology Journal. 19(4) :A60.
- Guglielmotti, M.B., Gorustovich, A., Krieger, L., Renou, S.J., Giglio, M.J. , Nielsen, F.H. 2005. Bone healing under a silicon-deficient diet: a histomorphometric study in rats [abstract]. Presented at the Annual Meeting of the International Association for Dental Research, Baltimore, MD. March 9 - 12, 2005. Journal Dental Research 84(Spec Iss A):abstract 2157.
- Hunt, C., Friel, J.K., Johnson, L.K. 2004. Boron concentrations in milk from mothers of full-term and premature infants. American Journal of Clinical Nutrition. 80:1327-33.
- Nielsen, F.H., Poellot, R.A. 2004. Dietary silicon affects bone turnover differently in ovariectomized and sham-operated growing rats. Journal of Trace Elements in Experimental Medicine. 17:137-149.
- Nielsen, F.H. 2004. Dietary fat composition modifies the effect of boron on bone characteristics and plasma lipids in rats. Biofactors. 20(3):161- 71.
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Progress 10/01/03 to 09/30/04
Outputs
1. What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? What does it matter? Osteoporosis is a prevalent and costly bone disease that causes at least one bone fracture in one out of every two women and one out of eight men in their lifetimes. The annual cost of healthcare related to osteoporosis is estimated at $14 billion. In the elderly, hip fractures are associated with mortality in up to 20% of the cases. Osteoporosis is a multifactorial disease process directed by several factors. These risk factors include environment (i.e., nutrition, physical activity), genetics, endogenous hormones (estrogen and androgen deficiencies), and age. Behavior modification and pharmacologic intervention (e.g., hormone replacement therapy [HRT]) are the common complementary approaches used to prevent bone loss in asymptomatic women. However, only 12-20% of US postmenopausal women
currently use HRT. Thus, nutrition is, arguably, one of the most important modifiable factors and represents a primary approach in prevention of this debilitating disease. For this reason, all significant nutritional factors must be identified that maximize peak bone mass during development and maintain bone mass and strength during aging. There is consensus that adequate calcium intake continuous from childhood is critical for the formation and maintenance of a healthy skeleton. Thus, dietary calcium supplementation is considered as both a treatment and prophylaxis for osteoporosis. However, there is no current recommended daily allowance (RDA) for this important nutrient because experimental data are not available to assess adequately the physiological adaptation to changes in calcium intake over time. Furthermore, calcium metabolism is known to be modified by many other dietary factors including dietary protein sources (vegetable and animal), trace minerals (e.g., copper, zinc,
and boron), and prebiotics (e.g., inulin). However, to date, the interaction of these factors with calcium is at best ill-defined. Therefore, this project has two specific goals: 1) titration of the calcium intake needed to optimize bone health and prevent bone loss in postmenopausal women and 2) determination of the roles of key dietary factors (protein, selected trace elements, and prebiotics) on the utilization of dietary calcium. Animal and human experiments are and will be conducted with the goal of establishing the calcium requirement and characterizing the modifying roles of inulin (a prebiotic), animal proteins (in meat and milk), and zinc, copper, and boron (as trace elements) on that requirement. Postmenopausal women and appropriate animal models (e.g., ovariectomized female rats) consumed varying amounts (low, adequate, and/or supranutritional) of calcium and the identified dietary factors while all other components of the diet remained constant. The response of the
animals and humans to the dietary manipulations was ascertained by evaluating appropriate biochemical, physiological, and anatomical variables. The research to be undertaken falls under National Program 107, Human Nutrition, and addresses goal 3.1.1 (Human Nutrition Requirements). The challenge of this component is to identify essential nutrients, determine their effects on reproduction, development, function and longevity, and to provide information that will be used to develop standards to optimize human health, well-being, and genetic potential throughout the life cycle. All priority objectives, especially mechanism of action, biomarkers, function and performance, and nutrient interactions apply to the research program. Outcomes of the research will be knowledge that will facilitate establishment of an RDA for calcium with due consideration of the dietary factors that have significant potential to modify that requirement. 2. List the milestones (indicators of progress) from your
Project Plan. Because this project plan is under development, no formal milestones are in place. The Project Plan for FY 2004 -9 recently completed an ad hoc review (Composite Action Class: Major Revision) and is being revised. 3. Milestones: A. Research activities for FY 2004. Studies planned for and executed in FY 2004 are listed below: Study 1. The hypothesis that silicon is an essential nutrient involved in the formation or function of bone matrix components including collagen and glycosaminoglycans which, if suboptimal, increases the risk for osteoporosis will be tested by using a SASo-2 cell culture system to ascertain the effect of silicon at the molecular level. OUTCOME: A SASO- 2 cell culture system was established in an attempt to determine the role of silicon in bone matrix formation. Study 2. An experiment will be performed with experimental animals to determine whether urinary and blood markers of bone turnover are altered by relationship between boron and the
omega-3 fatty acids that could be used as a basis for a human study to ascertain the influence of these dietary substances on the susceptibility or prevention of osteoporosis. OUTCOME: The animal portion of the study was completed and biochemical and bone morphological determinations are partially completed. Study 3. An experiment will be performed in collaboration with the University of Buenos Aries to determine whether silicon status affects the formation of bone around dental and bone implants. OUTCOME: The animal portion of the study was completed and biochemical and bone histological determinations are partially completed. Study 4. An experimented will be completed that determines whether dietary silicon helps prevent bone loss in an animal model of osteoporosis (ovarioectomized adult rats). OUTCOME: Study was completed. Study 5. The previously initiated three-year, double-blind placebo- controlled supplementation trial will continue to compare the effects of calcium
supplementation with and without copper and zinc supplementation on bone loss in postmenopausal women. OUTCOME: Recruitment and data collection for this previously initiated study continues. A total of 220 women are needed. Currently, we have successfully recruited 179 women into the study. Study 6. Controlled feeding studies designed to test the effects of interaction between meat protein and dietary calcium on calcium retention and bone metabolism will be conducted. OUTCOME: The feeding phase of this study is complete and sample analysis is in progress. Study 7. Animal studies investigating the interaction of meat protein and dietary calcium on calcium retention and biomechanical and biochemical properties of bone as well as the IGF-1 proteins will be conducted in ovarioectomized rats. OUTCOME: This study has been completed. Study 8. Studies will be initiated to test the feasibility of use of calcium-41 combined with accelerated mass spectrometry in nutrition research, with
emphasis on bone metabolism. OUTCOME: A pilot study was completed, in collaboration with the Lawrence Livermore National Laboratory, using archived human urine samples from a previous study. The results, which were presented this year in a workshop held in Zurich Switzerland and at the Experimental Biology 2004 meeting in Washington, DC, indicate that we can successfully measure Ca-41 in the human samples in very small quantities using accelerated mass spectrometry. Study 9. Controlled feeding studies designed to compare calcium retention from soy milk versus dairy milk will be conducted. OUTCOME: This study was not conducted because a grant application for support from the National Dairy Council was not funded. Study 10. Because boron in the diets has many beneficial effects on human and animal physiology, an experiment will be designed and initiated to examine the uptake and retention of boron from a common food source in healthy volunteers. OUTCOME: In preparation for a human
study, broccoli (a good source of dietary boron) samples were analyzed for boron content to determine whether boron content is affected by geographical location, fertilizer method (conventional versus organic), organic fertilizer source (fish meal, phytamin, compost, or guano) and water stress (80, 100, and 150% of water requirement). The samples were provided as part of a collaboration with Dr. John Finley who designed the broccoli production experiment. Study 11. Boron deprivation is known to affect inflammation in humans and animal models. A study initiated previously will be continued to determine the effects of boron deprivation on manifestation of rheumatoid arthritis in human subjects with an emphasis on measuring variables that will indicate whether low boron nutriture, not uncommon in the United States, is a factor in the prevalence and severity of rheumatoid arthritis. OUTCOME: Per development of the Project Plan, this study was not continued. Study 12-13. Studies will
be initiated to elucidate the induction mechanism whereby boron increases the concentration of natural killer cells in the serum of animal models with experimental rheumatoid arthritis. Animal studies will be conducted to determine why a semi- purified diet based on ground corn and supplemental with boron protect better against experimental arthritis than does a commercial rodent chow with ample boron. OUTCOME: Per development of the Project Plan, a series of alternate studies were designed in collaboration with Dr. David Bradley at the University of North Dakota to determine whether physiological levels of boron prevent or ameliorate collagen-induced arthritis, an animal model of polyarthritis similar to human rheumatoid arthritis (RA). The studies were completed. Study 14. Boron analysis of human milk samples from mothers living in Houston, TX, were analyzed for boron content to confirm previous findings from this laboratory that the boron content of milk remains constant
through the first 4 months of lactation. Study 15. An animal study was designed and completed to extend our previous finding that boron affects plasma insulin levels during conditions of vitamin D deficiency. Study 16. An animal study was designed and is in progress to determine the effect of consuming a boron low in on plasma insulin concentrations in those animals that have an impaired glucose tolerance response early in life. B. Research Plans for FY 2005, 2006, and 2007 FY 2005: Continue recruitment and data collection for the previously initiated three-year, double-blind placebo-controlled supplementation trial designed to compare the effects of calcium supplementation with and without copper and zinc supplementation on bone loss in postmenopausal women. Complete sample and statistical analyses and report the results for the recently conducted controlled feeding study designed to test the effects of interaction between meat protein and dietary calcium on calcium retention and
bone metabolism. Continue method development for the use of Ca-41 and accelerated mass spectrometry in determination of bone resorption in human subjects. Conduct controlled feeding studies, using calcium-41/accelerated mass spectrometry methodology, to test the effects of high protein weight loss diets on calcium retention and bone health in postmenopausal women. Conduct animal studies to determine the effects and mechanisms of action of interaction of trace minerals with calcium on the IGF-1 proteins, calcium retention and bone status in growing and ovarioectomized rats. Conduct studies with growing and ovariectomized mature rats to determine whether lifelong dietary boron deprivation will exacerbate the decline in tibial trabecular plate density and bone strength during postmenopausal osteoporosis. FY 2006: Conduct controlled feeding study to determine the effects of non- digestible carbohydrates, specifically inulin, on calcium retention in postmenopausal women. Complete sample
and statistical analyses and report the results for the recently conducted controlled feeding study designed to test the effects of high protein weight loss diets on calcium retention and bone health. Conduct animal studies to determine whether uncomplicated boron deficiency retards maturation of the epiphysial plate proliferative zone and induces distortion of the marrow sprouts. Conduct animal studies to determine whether dietary boron improves calcium absorption especially when calcium intakes are marginal. FY 2007: Conduct controlled feeding study to determine the effects of isolated milk proteins versus meat protein on calcium retention will be conducted. Complete sample and statistical analyses and report the results for the recently conducted controlled feeding study designed to test to determine the effects of non-digestible carbohydrates on calcium retention. Conduct controlled feeding studies, using calcium-41/accelerated mass spectrometry, to test the effects of graded
intakes of calcium on bone resorption with the goal of defining calcium requirements in postmenopausal women. Conduct animal studies to determine whether uncomplicated boron deprivation in utero will affect soft tissue structure of developing long bones and/or peak bone mass during adolescence. 4. What were the most significant accomplishments this past year? A. Single Most Significant Accomplishment during FY 2003: To determine whether animal protein intake is a risk for the development of osteoporosis, a carefully controlled feeding study of several weeks duration was conducted in postmenopausal women at the Grand Forks Human Nutrition Research Center. Findings from this study indicate that a high protein diet (20% of energy mostly provided as meat) may not increase calcium loss and or adversely affect bone health in healthy postmenopausal women. On the contrary, a significant improvement in calcium retention was observed in women with low calcium intake. Impact: These findings,
which contradict prevalent assumptions about the effects of meat consumption on calcium retention, will improve the quality and nature of the advice given to the public regarding the effects of dietary protein, especially meat protein, on bone health. B. Other Significant Accomplishment(s): A study to determine the effects of high-isoflavone soy protein versus beef on calcium retention and biomechanical properties of bones was conducted at the Grand Forks Human Nutrition Research Center in collaboration with Dr. Wagner at the University of North Dakota. In this study with ovarioectomized rats (estrogen-deficient), the findings indicated that calcium retention was significantly improved when protein intake was high (20%) and it was higher in the animals consuming beef versus soy protein. Serum IGF-1, a growth factor needed for bone health, was also higher in the animals consuming the high protein diets (20% soy or beef). Impact: These results are consistent with our findings
from human studies and indicate that a high protein diet may be protective against bone loss in postmenopausal women rather than harmful. Studies were conducted with rats to determine whether silicon affects collagen formation at the Grand Forks Human Nutrition Research Center in collaboration with Drs. Carol Seaborn and Scott Zimmerman at the University of Wisconsin, Stout. Silicon deprivation increased activity of a gene associated with type I collagen synthesis. Impact: The changes suggest that dietary silicon may have a role in collagen synthesis. An experiment was performed at the Grand Forks Human Nutrition Research Center to determine whether silicon deficiency in mature rats would exacerbate bone loss induced by ovariectomy (a model of osteoporosis). Silicon deprivation did not affect calcified bone changes induced by ovariectomy, but independently changed blood markers of bone metabolism and bone composition associated with the organic matrix. Impact: The findings suggest
that the effects of ovariectomy are mostly on the calcified portion of bone, while the effects of silicon are mostly on the organic matrix. To characterize further boron concentrations in human milk, a study was conducted at the Grand Forks Human Nutrition Research Center in collaboration with Dr. Nancy Butte (Baylor College of Medicine, Houston, TX). Similar to the findings of a previous study conducted at the Center with milk samples from St. John's, Newfoundland, the average concentration of boron in milk from nursing mothers living in Houston, TX, is 0.03 milligrams per liter and, similar to calcium, remains stable during the first 12 weeks of lactation. Impact: These findings extend the available data on boron contents of human milk making it possible to impute boron intakes of nursing infants. Studies were conducted at the Grand Forks Human Nutrition Research Center in collaboration with Dr. David Bradley (University of North Dakota) to characterize further the effect of
dietary boron on the onset of collagen-induced arthritis (an animal model of polyarthritis similar to human rheumatoid arthritis). Similar to our previous studies, mice weaned onto low-, adequate-, or luxuriant-boron diets exhibited a 54, 29, and 13% incidence of arthritis respectively. Impact: The findings indicate that dietary boron provides resistance to clinical signs in this animal model of rheumatoid arthritis. C. Other significant accomplishments(s), if any. None D. Progress Report opportunity to submit additional programmatic information to your Area Office and NPS (optional for all in-house ("D") projects and the projects listed in Appendix A; mandatory for all other subordinate projects. None 5. Describe the major accomplishments over the life of the project, including their predicted or actual impact. A study was conducted with growing female rats to determine whether an interaction between calcium and iron affects the biomechanical and biochemical properties of bone.
The findings from this study, done in collaboration with Dr. John Wagner (University of North Dakota), indicate that higher than adequate calcium intakes reduced both iron status and bone quality. Impact: These findings indicate that very high calcium intakes, as may result from indiscriminate supplementation and fortification of foods with calcium, may compromise the iron status of vulnerable segments of the population without offering additional benefits to bone health. Studies were conducted with rats to determine whether dietary silicon affects collagen turnover in bone. Low dietary silicon increased the urinary excretion of two bone-collagen breakdown products and a plasma protein involved in bone turnover. Impact: The changes in these products indicate dietary silicon may have a role in bone and joint collagen turnover. A study was conducted to determine whether bone health is impaired by a combined lack of dietary nickel and magnesium, two minerals generally supplied by the
same foods. The combined marginal deficiency of magnesium and nickel resulted in increased prostaglandin E-2 excretion and changed the mineral composition of bone. Impact: The findings indicate that consuming foods high in both magnesium and nickel, including leafy green vegetables, legumes, whole grains and nuts, is beneficial to bone health, and that the beneficial effects possibly occur through these minerals influencing the metabolism of lipids to prostaglandins. A high meat intake is often cited as a risk factor for development of osteoporosis, and soy protein is thought to have a beneficial effect on bone health. However, new reported findings indicate that partial substitution of soy protein (with high isoflavones) for meat protein does not improve calcium retention in postmenopausal women. In a follow-up study with ovarioectomized rats, complete substitution of meat protein by soy protein isolate with high isoflavone content reduced calcium retention by about 30%. Impact:
Assuming that the findings in rats are applicable to humans, these combined results indicate that, contrary to popular belief, meat protein intake does not adversely affect bones and that while a partial substitution of soy protein for meat protein may not reduce calcium retention, full replacement may adversely affect calcium retention. We collaborated with Dr. James Friel at the University of Manitoba, Canada, to determine the concentration of boron in human milk from mothers of full-term and premature infants living in St. John's, Newfoundland, Canada. The findings indicate that the average concentration of boron in milk from nursing mothers from this locale is 0. 03 milligrams per liter, is not affected by infant prematurity and, similar to calcium, remains stable during the first 12 weeks of lactation. Impact: The findings provide the first data available to impute boron intakes of nursing infants. The US Food and Drug Administration has approved a health claim that a daily
consumption of 25 g of soy protein is beneficial to heart health. However, the effects of this dietary practice on bone health are unknown. A controlled feeding trial with postmenopausal women, using sensitive whole body counting methodology, demonstrated that when 25 g of soy protein is substituted for an equal weight of meat protein, on a daily basis for 8 weeks, the amount of calcium that the body retains does not change. Furthermore, urinary and blood biomarkers of bone formation and breakdown did not change. Impact: These findings indicate that the common practice of substitution of soy protein for meat protein does not provide any additional benefits (associated with phytoestrogens) or risks (associated with phytate) with regards to calcium retention or bone health in postmenopausal women and that the effects of vegetable proteins versus animal proteins on bone health deserve further investigations. We conducted two separate studies with healthy rats and a third with chicks
to determine whether boron, a natural substance in the diet, helps regulate the level of insulin in the blood. Results from the rat studies demonstrated that a diet with normal physiological amounts of boron reduced blood insulin levels without affecting glucose levels. In chicks given glucose through a vein injected, boron decreased peak pancreatic insulin release. Impact: These results suggest that dietary boron, found in higher concentrations in fruits, vegetables, nuts, and legumes, may help reduce the amount of insulin needed to maintain blood glucose. 6. What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end- user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? Information about the nutritional of beneficial aspects of ultratrace and trace elements as it became available was routinely transferred to a
variety of customers. The customers included nutritional risk assessment groups through direct contact or organized meetings and workshops; the public through web pages of professional organizations, via the popular media; and other scientists through presentations at national and international meetings and professional publications. 7. List your most important publications in the popular press and presentations to organizations and articles written about your work. Information was transferred to the public through the local newspaper (Grand Forks Herald) that was also placed on the Grand Forks Human Nutrition Research Center Home Page. Dr. Roughead wrote two articles entitled, "Protein and calcium: Friends or Foes?" and "Vitamin D: It's good for your bones." Dr. Hunt wrote an article entitled, "Metabolic Syndrome: You may already have it." Dr. Roughead provided information regarding nutrition and bone health in a North Dakota Public Radio broadcast entitled, "Hear It Now." Dr.
Roughead's recent findings regarding the effects of dietary protein and the role of acid-base balance on bone health were featured in the LA Times and Vogue magazines. Roughead, Z.K. 2004. Trace Minerals and Bone Health. Presentation given at the Optimist Club, March 17, 2004. Grand Forks, ND. Roughead, Z.K. 2004. Nutrition for Bone Health. Presentation given at the Lions Club. April 7, 2004, Grand Forks, ND.
Impacts
(N/A)
Publications
- Roughead, Z.K. 2004. Dietary protein and calcium: friends or foes? Invited Commentary. Soy Connection 12:4-8 in Journal of American Dietetic Association. 104(7).
- Roughead, Z.K., Hunt, J.R., Lykken, G.I., Johnson, L.K. 2003. Effects of daily substitution of soy protein for meat protein on calcium retention and biomarkers of bone and cardiovascular health in postmenopausal women [abstract]. Presented at the 5th International Symposium on the Role of Soy in Preventing and Treating Chronic Disease, Orlando, FL, September 21 - 25 , 2003.
- Beuchler, J.L., Roughead, Z.K. 2004. Do meat and calcium interact to affect calcium retention and bone density in ovarioectomized rats? Poster presentation at the Frank Low Research Day, School of Medicine and Health Sciences, University of North Dakota. April 15, 2004.
- Roughead, Z.K. 2004. Radiotracer and whole body scintillation counting methodology: the gold standard for mineral bioavailability studies [abstract]. Presentation given at the Research Day held at Missouri University, Columbia, MO, May 12, 2004. (Invited)
- Bakken, N.A., Hunt C.D. 2003. Dietary boron decreases peak pancreatic in situ insulin release in chicks and plasma insulin concentrations in rats regardless of vitamin D or magnesium status. Journal of Nutrition. 133:3577-3583.
- Nielsen, F.H., Milne, D.B. 2004. A moderately high intake compared to a low intake of zinc depresses magnesium balance and alters indices of bone turnover in postmenopausal women. European Journal of Clinical Nutrition. 58:703-710.
- Ralston, N.V., Hunt, C. 2004. Transmembrane partitioning of boron and other elements in RAW 264.7 and HL60 cell cultures. Biological Trace Element Research. 98(2):181-192.
- Hunt, C.D. 2003. Dietary boron: An overview of the evidence for its role in immune function. Journal of Trace Elements in Experimental Medicine. 16:291-306.
- Roughead, Z.K., Hunt, J.R. 2003. Letter to Editor. Reply to Sebastian and Remer and Manz. Journal of Nutrition. 133:3240.
- Hillegonds, D.J., Roughead, Z.K., Vogel, J.S. 2004. Ultra low dose 41ca: testing the detection limits of accelerator mass spectrometry-based analysis in nutrition research [abstract]. Federation of American Societies for Experimental Biology Journal. 18:A925.
- Hunt, C.D., Friel, J. 2004. Boron concentrations in milk from mothers of full-term, but not premature, breast-fed infants remain stable during the first three months of lactation while copper, iron, selenium, and zinc concentrations decrease regardless of gestational length [abstract]. The Federation of American Societies for Experimental Biology Journal. 18:A492.
- Hull, S.C., Burrack, A., Ek-Pangerl, K.E., Nardini, D.M., Hopps, J.L., Seaborn, C., Zimmerman, S.D., Nielsen, F.H. 2004. Low dietary silicon increases tnf-a and collagen gene promoter activity in mice [abstract]. Federation of American Societies for Experimental Biology Journal. 18:A527.
- Nielsen, F.H., Stoecker, B. 2004. Nutritional intakes of silicon affect vertebral trabecular microarchitecture and strength, but not femoral or vertebral strength changes induced by ovariectomy, in rats [abstract]. Federation of American Societies for Experimental Biology Journal. 18:A919.
- Roughead, Z.K., Johnson, L.K., Wagner, J.L. 2003. Dietary iron and calcium interact to affect iron status and bone health in a response surface study of growing female rats [abstract]. Journal of Bone and Mineral Research. 16:S155.
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Progress 10/01/02 to 09/30/03
Outputs
1. What major problem or issue is being resolved and how are you resolving it? Bone and joint diseases are major causes of illness in the US. For example, one out of every two women and one out of eight men over age 50 will have an osteoporosis-related fracture in their lifetime. However, the causes of osteoporosis and many of the rheumatic diseases (e.g., osteoarthritis and rheumatoid arthritis) are unknown with the notable exception of those determined to have a nutritional (e.g., rickets) or a heritable (e.g., osteogenesis imperfecta) basis. Although it is generally agreed that these diseases (e.g., osteoporosis and arthritis) are of complex etiology with genetic, nutritional and hormonal factors, no effective prevention strategies are known. The treatments available for osteoporosis, osteoarthritis, or rheumatoid arthritis are characterized by either limited therapeutic value or pharmacologic intervention with significant potential for undesirable side effects.
Adequate trace element nutriture is a promising but meagerly examined candidate for helping prevent or ameliorate these bone diseases. For example, several recent findings are consistent with the hypothesis that nutritional copper and zinc deficiencies contribute to the occurrence of bone fractures by reducing bone strength in adults. Physiologic amounts of dietary boron correct manifestations of experimental rheumatoid arthritis in animal models, and improve subjective measures of osteoarthritis in volunteers with the disease. Thus, there is ample reason to determine whether acquired adult trace element deficiencies play a role in the pathogenesis or treatment of osteoarthritis, rheumatoid arthritis, and osteoporosis. Animal and human experiments are and will be conducted to define the biochemical and physiological roles of various ultratrace (including boron, nickel, and silicon), trace (including copper and zinc), and macro (including magnesium and calcium) elements for optimal
bone and joint development and health. The basic approach was to feed experimental animals and human volunteers diets that contained low, adequate, and/or supranutritional amounts of specific trace elements and other selected nutrients and non-nutrients (postulated to affect the metabolism and utilization of specific trace elements). The experimental designs typically simulated specific characteristics of the target population (e. g., ovariectomized rats are used to simulate the postmenopausal state; an injected antigen in rats simulated rheumatoid arthritis). The response of the animals and humans to the dietary manipulations was ascertained by evaluating appropriate biochemical, physiological, and anatomical variables. 2. How serious is the problem? Why does it matter? It has been estimated that the lifetime risk of fracture exceeds 40% for women and 13% for men. In the elderly, hip fractures are associated with mortality in up to 20% of the cases, with costly long-term nursing
home care required for most survivors. Osteoarthritis and osteoporosis alone currently cost more than $50 billion each year in medical costs and lost wages. The annual cost of healthcare related to osteoporosis is estimated at $14 billion. The lifetime cost of rheumatoid arthritis for an individual patient can be as much as $250,000. As the US population ages, the economic cost of osteoporosis alone is projected to reach $50 billion by the year 2040. In addition to the direct costs, diseases of bones and joints reduce personal independence and quality of life. Dietary modification is a sensible, practical and economically feasible approach to the prevention of osteoporosis and arthritis. As trace minerals are known to be essential for bone health, it is important that we determine their specific role in prevention of these devastating diseases. 3. How does it relate to the National Program(s) and National Program Component(s) to which it has been assigned? The research program relates
to the National Program 107, Human Nutrition, and emphasizes the Program Component Performance Goal 3.1.1- Human Nutrition Requirements. The challenge of this component is to identify essential nutrients, determine their effects on reproduction, development, function and longevity, and to provide information that will be used to develop standards to optimize human health, well-being, and genetic potential throughout the life cycle. All priority objectives, especially mechanism of action, biomarkers, function and performance, and nutrient interactions apply to the research program. Outcomes of the research will be knowledge that will facilitate the detection and prevention of biochemical, structural, physiological and psychological dysfunctions caused by the deficiency or imbalance of specific trace elements, and will define requirements and safe intakes of specific trace elements for health and well-being throughout the life cycle. 4. What were the most significant accomplishments
this past year? A. Single Most Significant Accomplishment during FY 2003: Diabetes mellitus, a disease caused by a deficiency of insulin, results in many severe health problems including osteoporosis. The Grand Forks Human Nutrition Research Center conducted studies with healthy rats to determine whether boron, a natural substance in the diet, helps regulate the level of insulin in the blood. The studies demonstrated that a diet with normal physiological amounts of boron reduced blood insulin levels without affecting glucose levels. Impact: These results suggest that dietary boron, found in higher concentrations in fruits, vegetables, nuts, and legumes, may help reduce the amount of insulin needed to maintain blood glucose and thus protect the insulin-secreting cells from "exhaustion" and development of diabetes mellitus. B. Other Significant Accomplishment(s): The concerns about inadequate intakes of calcium and iron have led to extensive fortification of both minerals in the US food
supply, but the effects of the interaction of these nutrients on bone health are poorly understood. The Grand Forks Human Nutrition Research Center, in collaboration with Dr. John Wagner at the University of North Dakota, conducted a study with growing female rats to determine whether an interaction between calcium and iron affects the biomechanical and biochemical properties of bone. The findings from this study indicate that higher than adequate calcium intakes reduced both iron status and bone quality. Impact: These findings indicate that very high calcium intakes, as may result from indiscriminate supplementation and fortification of foods with calcium, may compromise the iron status of vulnerable segments of the population without offering additional benefits to bone health. There is emerging evidence from human and animal experiments that silicon supplementation might be a nutrient that is beneficial to bone formation and maintenance, but the biochemical indicators needed to
ascertain such effects in humans have not been established. In an experiment performed at the Grand Forks Human Nutrition Research Center, urine and blood were collected from 3-month-old rats that were fed diets containing low or physiologically normal amounts of silicon starting after weaning. Low dietary silicon increased the urinary excretion of two bone-collagen breakdown products and a plasma protein involved in bone turnover. Impact: The changes in these products indicate that they are useful indicators in determining the nutritional effects of silicon on bone health in humans and that silicon has a function that affects bone and joint collagen turnover. Because dietary nickel and magnesium, two minerals generally supplied by the same foods, affect the metabolism of prostaglandin E-2 which influences bone formation, a combined lack of these minerals possibly could be detrimental to bone health. In an experiment performed at the Grand Forks Human Nutrition Research Center, urine
was collected at 8 and 12 weeks, and bones were obtained at 13 weeks after weanling rats were placed on diets either marginally deficient or adequate in magnesium, and containing low or physiologically normal amounts of nickel. The combined marginally deficient magnesium and low nickel diet resulted in increased prostaglandin E-2 excretion and changed the mineral composition of bone, but did not enhance changes in bone breaking characteristics induced by low nickel or magnesium deficiency alone. Impact: The findings indicate that consuming foods high in both magnesium and nickel, including leafy green vegetables, legumes, whole grains and nuts, is beneficial to bone health, and that the beneficial effects possibly occur through these minerals influencing the metabolism of lipids to prostaglandins. A high meat intake is often cited as a risk factor for development of osteoporosis, and soy protein is thought to have a beneficial effect on bone health. However, new reported findings from
a human study at the Grand Forks Human Nutrition Research Center indicate that partial substitution of soy protein (with high isoflavones) for meat protein does not improve calcium retention in postmenopausal women. In a follow-up study with ovarioectomized rats, complete substitution of meat protein by soy protein isolate with high isoflavone content reduced calcium retention by about 30%. Impact: Assuming that the findings in rats are applicable to humans, these combined results indicate that, contrary to popular belief, meat protein intake does not adversely affect bones and that while a partial substitution of soy protein for meat protein may not reduce calcium retention, full replacement may adversely affect calcium retention. Normal physiological amounts of boron are known to be essential or beneficial for the growth and development of several animal models of human nutrition but there is no information on the amount of boron supplied by human milk to the breast-fed infant. The
Grand Forks Human Nutrition Research Center, in collaboration with Dr. James Friel at the University of Manitoba, Canada, determined the concentration of boron in human milk from mothers of full-term and premature infants living in St. John's, Newfoundland, Canada. The findings indicate that the average concentration of boron in milk from nursing mothers from this locale is 0. 03 milligrams per liter, is not affected by infant prematurity and, in contrast to several other trace minerals, does not fall during the first 12 weeks of lactation. Impact: The findings indicate that, similar to calcium, the concentration of boron in human milk may be regulated. C. Significant Accomplishments/Activities that Support Special Target Populations. None. D. Progress Report. None. 5. Describe the major accomplishments over the life of the project, including their predicted or actual impact. The US Food and Drug Administration has approved a health claim that a daily consumption of 25 g of soy
protein is beneficial to heart health. However, the effects of this dietary practice on bone health are unknown. A controlled feeding trial conducted at the Grand Forks Human Nutrition Research Center (GFHNRC) with postmenopausal women, using sensitive whole body counting methodology, demonstrated that when 25 g of soy protein is substituted for an equal weight of meat protein, on a daily basis for 8 weeks, the amount of calcium that the body retains does not change. Furthermore, urinary and blood biomarkers of bone formation and breakdown did not change. Impact: These findings indicate that the common practice of substitution of soy protein for meat protein does not provide any additional benefits (associated with phytoestrogens) or risks (associated with phytate) with regards to calcium retention or bone health in postmenopausal women and that the effects of vegetable proteins versus animal proteins on bone health deserve further investigations. 6. What do you expect to accomplish,
year by year, over the next 3 years? FY2004 - The hypothesis that silicon is an essential nutrient involved in the formation or function of bone matrix components including collagen and glycosaminoglycans which, if suboptimal, increases the risk for osteoporosis will be tested by using a SASO-2 cell culture system to ascertain the effect silicon at the molecular level. An experiment will be performed with experimental animals to determine whether urinary and blood markers of bone turnover are altered by a relationship between boron and the omega-3 fatty acids that could be used as a basis for a human study to ascertain the influence of these dietary substances on the susceptibility or prevention of osteoporosis. An experiment will be performed in collaboration with the University of Buenos Aries to determine whether silicon status affects the formation of bone around dental and bone implants. An experiment will be completed that determines whether dietary silicon helps prevent bone
loss in an animal model of osteoporosis (ovariectomized adult rats). The previously initiated three-year, double-blind placebo-controlled supplementation trial will continue to compare the effects of calcium supplementation with and without copper and zinc supplementation on bone loss in postmenopausal women. Controlled feeding studies designed to test the effects of interaction between meat protein and dietary calcium on calcium retention and bone metabolism will be conducted. Animal studies investigating the interaction of meat protein and dietary calcium on calcium retention and biomechanical and biochemical properties of bone as well as the IGF-1 proteins will be conducted in ovarioectomized rats. Studies will be initiated to test the feasibility of use of calcium-41 combined with accelerated mass spectrometry in nutrition research, with emphasis on bone metabolism. Controlled feeding studies designed to compare calcium retention from soy milk versus dairy milk will be conducted.
Because boron in the diet has many beneficial effects on human and animal physiology, an experiment will be designed and initiated to examine the uptake and retention of boron from a common food source in healthy volunteers. Boron deprivation is known to affect inflammation in humans and animal models. A study initiated previously will be continued to determine the effects of boron deprivation on manifestations of rheumatoid arthritis in human subjects with an emphasis on measuring variables that will indicate whether low boron nutriture, not uncommon in the United States, is a factor in the prevalence and severity of rheumatoid arthritis. Studies will be initiated to elucidate the induction mechanism whereby dietary boron increases the concentration of natural killer cells in the serum of animal models with experimental rheumatoid arthritis. Animal studies will be conducted to determine why a semi-purified diet based on ground corn and supplemented with boron protects better against
experimental arthritis than does a commercial rodent chow with ample boron. FY2005 - Animal studies investigating the effects and mechanisms of action of trace minerals on the IGF-1 proteins and bone status will be conducted in growing and overarioectomized rats. Studies will continue to test the feasibility of use of calcium-41 combined with accelerated mass spectrometry for measurement of bone resorption. Based on animal experiments, a human experiment will be designed that will ascertain whether low silicon intakes are detrimental to maintaining bone density and strength. Complete a human experiment to determine whether magnesium deficiency induces changes in neuropeptide metabolism or causes neurogenic dysfunction such that it results in bone loss leading to osteoporosis. Health is impaired when diets are too low in boron, a fact that implies that specific biomolecules require boron. Capillary electrophoresis experiments will be conducted to determine which candidate biomolecules,
selected on the basis of their chemical structure, bind tightly to boron. Because the concentration of diadenosine oligophosphates are higher in platelets than any other tissue compartment and bind tightly to boron, an experiment will be performed with experimental animals to determine whether blood coagulation factors are affected by dietary boron. To determine how dietary boron affects bone structure, bone and cartilage extracellular matrix microarchitecture, with emphasis on collagen spatial orientation, will be examined in rats fed low or physiological normal amounts of boron. To determine the mechanism(s) by which dietary boron influences immune cell function, Th1 and Th2 cytokines will be measured in a series of experiments with rats fed low or physiological normal amounts of boron. FY 2006 - Controlled feeding studies designed to determine the effects of non-digestible carbohydrates on calcium retention and trace mineral status will be conducted. Controlled feeding studies will
be conducted, using calcium- 41/accelerated mass spectrometry methodology, to test the effects of graded intakes of calcium on bone resorption with the goal of defining calcium requirements in postmenopausal women. The human experiment designed in 2005 to ascertain the practical importance of silicon in bone formation and maintenance will be conducted. An experiment will be performed with experimental animals to determine whether urinary and blood markers of bone turnover are altered by a relationship between nickel content and the fatty acid composition of the diet that could be used to ascertain whether nickel is a practical concern for bone health in humans. To determine the role of dietary boron in hemostasis, selected enzymes in the clotting cascade in rats will be examined for their response to dietary boron. Because boron inhibits the activity of numerous serine protease enzymes, a series of experiments with rats will be conducted to determine whether selected proteases
modulate T-lymphoid and natural killer cell growth. Because boron is important in normal bone development, tissue culture experiments will be conducted to identify the class of molecules in the extracellular matrix most likely to require boron for proper matrix synthesis. 7. What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end- user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? Information about the nutritional of beneficial aspects of ultratrace and trace elements as it became available was routinely transferred to a variety of customers. The customers included nutritional risk assessment groups through direct contact or organized meetings and workshops; the public through web pages of professional organizations, via the popular media; and other scientists through presentations at national and international
meetings and professional publications. 8. List your most important publications in the popular press and presentations to organizations and articles written about your work. (NOTE: This does not replace your peer-reviewed publications listed below). The ARS Daily News Service provided a press release on findings from a recent publication authored by Z.K. Roughead that described the effects of meat protein on calcium metabolism. The release was picked up by various news outlets including the Food Industry Environmental Network. Information was transferred to the public through interviews on two local television stations, and various presentations to regional groups including the North Dakota Stockmen's Association. Information was transferred to the public through the local newspaper (Grand Forks Herald) that was also placed on the Grand Forks Human Nutrition Research Center Home Page.
Impacts
(N/A)
Publications
- Roughead, Z.K., Lukaski, H.C. Inadequate copper intake reduces serum insulin-like growth factor-1 and bone strength in growing rats fed graded amounts of copper and zinc. Journal of Nutrition. 2003. v.133. p.422-448.
- Seaborn, C.D., Nielsen, F.H. Silicon deprivation decreases collagen formation in wounds and bone, and ornithine transaminase enzyme activity in liver. Biological Trace Element Research. 2002. v.89. p.251-261.
- Seaborn, C.D., Nielsen, F.H. Dietary silicon and arginine affect mineral element composition of rat femur and vertebra. Biological Trace Element Research. 2002. v.89. p.239-250.
- Ren, J., Hintz, K.K., Roughead, Z.K., Duan, J., Colligan, P.B., Ren, B.H., Lee, K.J., Zeng, H. Impact of estrogen replacement on ventricular myocyte contractile function and protein kinase B/Akt activation. American Journal of Physiology Heart and Circulatory Physiology. 2003. v.284. p.H1800-H1807.
- Ren, J., Roughead, Z.K., Wold, L.E., Norby, F.L., Rakoczy, S., Mabey, R.L., Brown-Borg, H.M. Increases in insulin-like growth factor-1 level and peroxidative damage after gestational ethanol exposure in rats. Pharmacological Research. 2003. v.47. p.341-347.
- Hunt, C.D. Boron. Caballero, B., Trugo, L., Finglas, P., (eds). Academic Press,London. Encyclopedia of Food Sciences and Nutrition. 2003. p.566-574.
- Combs Jr., G.F., Hassan, N., Hunt, C.D. Risk factors for rickets in Bangladesh. Journal of Trace Elements in Experimental Medicine. 2003. v. 16. Abstract. p.114. Presented by G.F. Combs Jr. at the VIth International Society of Trace Element Research in Humans Conference, Quebec City, Canada. September 2002.
- Roughead, Z.K., Johnson, L.K., Lykken, G.I., Hunt, J.R. Controlled high meat diets do not affect calcium retention or indices of bone status in healthy postmenopausal women. Journal of Nutrition. 2003. v.133. p.1020- 1026.
- Nielsen, F.H. Silicon nutrition affects urinary and plasma indicators of bone and connective tissue metabolism. Anke, M., Muller, R., Schafer, U., Stoeppler, M., (eds.). Schubert-Verlag, Leipzig, Germany. Macro and Trace Elements (Mengen- und Spurenelemente). 2002. p.1231-1237. Presented by F.H. Nielsen at the Workshop on Macro and Trace Elements, Jena, Germany, October 2002.
- Roughead, Z.K. Is the interaction between dietary protein and calcium destructive or constructive for bone?: Summary. Journal of Nutrition. 2003. v.133. p.866S-869S.
- Hunt, C.D., Idso, J.P. Hyperinsulinemia in rats during dietary vitamin D (VITD) and boron deprivation is ameliorated, but not corrected, by improved VITD status. The FASEB Journal. 2003. v.17. Abstract. p.A707. Presented by C.D. Hunt at the Experimental Biology 2003 meeting. San Diego, CA. April 2003.
- Hunt, C.D. Dietary boron alleviates growth cartilage abnormalities induced by vitamin D deficiency in chicks. 11th International Symposium on Trace Elements in Man and Animals. Journal of Nutrition. 2003. v.133(5S-1). p. 230E-231E.
- Nielsen, F.H. Silicon deficiency affects urinary indicators of bone breakdown differently in ovariectomized and ovary-intact rats. The FASEB Journal. 2003. v.17. Abstract p.A706. Presented by F.H. Nielsen at the Experimental Biology 2003 meeting. San Diego, CA. April 2003.
- Roughead, Z.K., Lykken, G.I., Johnson, L.K. Substituting soy protein for meat protein did not affect calcium (Ca) retention or biomarkers of bone and cardiovascular health in a controlled feeding study of healthy postmenopausal women. The FASEB Journal. 2003. v.17. Abstract. p.A705. Presented by Z.K. Roughead at the Experimental Biology 2003 meeting. San Diego, CA. April 2003.
- Durick, K., Lamoureux, J., O'Bryant, D., Griffiths, M.M., Hunt, C.D., Bradley, D.S. Accessible dietary boron prevents the onset and down regulates ongoing collagen-induced arthritis. Book of Abstracts for the 2002 International Symposium on Connective Tissue Research. Autoimmune Arthritis: New Directions.Presented by K. Durick at the Symposium in Memphis, TN. October 2002.
- Durick, K., Lamoureux, J., O'Bryant, D., Griffiths, M.M., Hunt, C.D., Bradley, D.S. Dietary boron supplementation effectively mitigates collagen- induced arthritis in mice. Frank N. Low Research Day. Abstract. p.53. Presentation by K. Durick at the 23rd Annual Frank N. Low Research Day, Grand Forks, ND. April 2003.
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Progress 10/01/01 to 09/30/02
Outputs
1. What major problem or issue is being resolved and how are you resolving it? This project is a consolidation of projects 5450-51000-030-00D, 5450- 51520-012-00D, and 5450-51530-005-00D and has a Project Termination Date of 04/30/2004. Bone and joint diseases are major causes of illness in the US. For example, one out of every two women and one out of eight men over age 50 will have an osteoporosis-related fracture in their life time. However, the causes of osteoporosis and many of the rheumatic diseases (e. g., osteoarthritis and rheumatoid arthritis) are unknown with the notable exception of those determined to have a nutritional (e.g., rickets) or a heritable (e.g., osteogenesis imperfecta) basis. Although it is generally agreed that these diseases (e.g., osteoporosis and arthritis) are of complex etiology with genetic, nutritional and hormonal factors, no effective prevention strategies are known. The treatments available for osteoporosis, osteoarthritis, or
rheumatoid arthritis are characterized by either limited therapeutic value or pharmacologic intervention with significant potential for undesirable side effects. Adequate trace element nutriture is a promising but meagerly examined candidate for helping prevent or ameliorate these bone diseases. For example, several recent findings are consistent with the hypothesis that nutritional copper and zinc deficiencies contribute to the occurrence of bone fractures by reducing bone strength in adults. Physiologic amounts of dietary boron correct manifestations of experimental rheumatoid arthritis in animal models, and improve subjective measures of osteoarthritis in volunteers with the disease. Thus, there is ample reason to determine whether acquired adult trace element deficiencies play a role in the pathogenesis or treatment of osteoarthritis, rheumatoid arthritis, and osteoporosis. Animal and human experiments are and will be conducted to define the biochemical and physiological roles of
various ultratrace (including boron, nickel, and silicon), trace (including copper and zinc), and macro (including magnesium and calcium) elements for optimal bone and joint development and health. The basic approach was to feed experimental animals and human volunteers diets that contained low, adequate, and/or supranutritional amounts of specific trace elements and other selected nutrients and non-nutrients (postulated to affect the metabolism and utilization of specific trace elements). The experimental designs typically simulated specific characteristics of the target population (e. g., ovariectomized rats are used to simulate the postmenopausal state; an injected antigen in rats simulated rheumatoid arthritis). The response of the animals and humans to the dietary manipulations was ascertained by evaluating appropriate biochemical, physiological, and anatomical variables. 2. How serious is the problem? Why does it matter? It has been estimated that the lifetime risk of fracture
exceeds 40% for women and 13% for men. In the elderly, hip fractures are associated with mortality in up to 20% of the cases, with costly long-term nursing home care required for most survivors. Osteoarthritis and osteoporosis alone currently cost more than $50 billion each year in medical costs and lost wages. The annual cost of health care related to osteoporosis is estimated at $14 billion. The lifetime cost of rheumatoid arthritis for an individual patient can be as much as $250,000. As the US population ages, the economic cost of osteoporosis alone is projected to reach $50 billion by the year 2040. In addition to the direct costs, diseases of bones and joints reduce personal independence and quality of life. Dietary modification is a sensible, practical and economically feasible approach to the prevention of osteoporosis and arthritis. As trace minerals are known to be essential for bone health, it is important that we determine their specific role in prevention of these
devastating diseases. 3. How does it relate to the national Program(s) and National Program Component(s) to which it has been assigned? The research program relates to the National Program 107, Human Nutrition, and emphasizes the Program Component Performance Goal 3.1.1- Human Nutrition Requirements. The challenge of this component is to identify essential nutrients, determine their effects on reproduction, development, function and longevity, and to provide information that will be used to develop standards to optimize human health, well-being, and genetic potential throughout the life cycle. All priority objectives, especially mechanism of action, biomarkers, function and performance, and nutrient interactions apply to the research program. Outcomes of the research will be knowledge that will facilitate the detection and prevention of biochemical, structural, physiological and psychological dysfunctions caused by the deficiency or imbalance of specific trace elements, and will
define requirements and safe intakes of specific trace elements for health and well-being throughout the life cycle. 4. What was your most significant accomplishment this past year? A. Single Most Significant Accomplishment during FY 2001: The US Food and Drug Administration has approved a health claim that a daily consumption of 25 g of soy protein is beneficial to heart health. The finding from animal studies that soy protein may also have beneficial effects on bone health needed to be adequately tested in the human population. A controlled feeding trial conducted at the Grand Forks Human Nutrition Research Center (GFHNRC) with postmenopausal women, using sensitive whole body counting methodology, demonstrated that when 25 g of soy protein is substituted for an equal weight of meat protein, on a daily basis for 8 weeks, the amount of calcium that the body retains does not change. Furthermore, urinary and blood biomarkers of bone formation and breakdown did not change. These findings
indicate that the commonly advised practice of substitution of soy protein for meat protein does not provide any additional benefits (associated with phytoestrogens) or risks (associated with phytate) with regards to calcium retention or bone health in postmenopausal women and that the effects of vegetable proteins versus animal proteins on bone health deserve further investigations. B. Other Significant Accomplishment(s): Both boron and long-chain polyunsaturated fatty acids generated from alpha-linolenic acid (omega-3 fatty acids) are needed or beneficial for many of the same life processes, including bone growth and maintenance, apparently through affecting membrane fluidity, membrane-bound enzymes, and signal transduction; thus, it was hypothesized that low or adequate intakes of boron would alter the response of experimental animals to altered dietary intakes of omega-3 fatty acids, or vice versa, in the modification of the physical characteristics of long bones. An experiment
was performed at the GFHNRC with rats that were fed boron-deficient or boron-adequate diets containing either canola oil (high in omega-3 fatty acids) or palm oil (low in omega-3 fatty acids) for 16 weeks before femur bone strength and mineral element composition were determined. Both boron and omega-3 fatty acid intake affected femur bone structure and breaking characteristics, with the effect of one dietary variable influencing the other. The results indicate that the beneficial effects of the omega-3 fatty acids on bone health may be dependent on an adequate intake of boron, an element supplied in goodly amounts by fruits, vegetables, pulses, and nuts. In an animal model study at the GFHNRC, low copper intake during the growth phase of life was determined to adversely affect bone quality (including reduced spinal bone density and long bones density and strength). This is the first study to demonstrate that even marginal intakes of copper reduce blood concentrations of IGF-1, a
small protein important for bone health. These findings indicate that long term exposure to low or marginal intakes of copper can have detrimental effects on bone quality, caused in part, by a reduction in IGF-1 concentrations. Based on these findings, a long term mineral supplementation trial at the GFHNRC has been initiated to examine whether supplemental copper, in conjunction with zinc and calcium, help attenuate bone loss in postmenopausal women. There is evidence that animals and humans require boron in their diets to support several normal biologic processes including immune function and bone development. This suggests that there are unidentified molecules within the cell that bind boron before carrying out their vital functions. The first step in finding these molecules is to test whether boron is concentrated within the cell. The GFHNRC is the first laboratory to demonstrate that the concentration of boron is higher inside of animal cells compared to the surrounding fluid.
This laboratory has initiated a search to find the molecule(s) in animal and human cells that may require boron for normal function. C. Significant Accomplishments/Activities that Support Special Target Populations. None. D. Progress Report. None. 5. Describe your major accomplishments over the life of the project, including their predicted or actual impact? See section 4 above. 6. What do you expect to accomplish, year by year, over the next 3 years? FY 2003 -- Controlled feeding studies will be conducted to test whether healthy individuals adapt their calcium retention in response to calcium supplementation. Because there is no current RDA for calcium, this information will be useful in providing much needed data to help fill in the gaps in the information regarding the requirements for this important nutrient. (ZKR) A previously initiated three-year, double-blind placebo-controlled supplementation study will continue to compare the effects of calcium supplementation with and
without copper and zinc supplementation on bone loss in postmenopausal women. (ZKR) Animal studies will be conducted to examine the mechanisms whereby dietary calcium and trace minerals interact to affect bone growth, and also the effects of soy protein compared to meat protein on bone loss in animal models of postmenopausal osteoporosis. (ZKR) The effect of silicon on bone formation and maintenance will be confirmed and extended through a collaborative study with Jonathan Powell of King's College, London, England, that will determine the nutritional effect of silicon on physical characteristics of bone. Also, a bone cell culture system (SASO-2) will be used to more clearly understand the biochemical mechanisms through which silicon affects bone formation. (FHN) The actions and deficiency signs of nickel and magnesium suggest that these two elements are dependent upon each other to function optimally in some metabolic pathways, including those involved in bone health. Thus, an animal
experiment will be performed to ascertain whether these two mineral elements modify the response to the deficient intakes of each other to affect bone composition and strength, resulting in an indication that these elements are of practical nutritional concerns for bone health when their deficient intakes occur together. (FHN) Boron deprivation is known to affect inflammation in humans and animal models. A study initiated previously will be continued to determine the effects of boron deprivation on manifestations of rheumatoid arthritis in human subjects with an emphasis on measuring variables that will indicate whether low boron nutriture, not uncommon in the United States, is a factor in the prevalence and severity of rheumatoid arthritis. (CDH) Boron deprivation adversely affects bone metabolism and structure but the mechanism of action is unknown. Animal studies will be conducted to examine whether the beneficial effects of dietary boron are attributable to an enhanced rate at
which new bone is formed. (CDH) Severe copper deficiency causes brittle bones. Studies will be conducted to determine whether marginal copper nutritional status greatly impairs bone structure in an animal model of human osteoporosis. (CDH) FY2004 - Based on animal experiments, a human experiment will be designed to be conducted at the Grand Forks Human Nutrition Research Center, or King's College, London, England, to ascertain whether low silicon intakes are detrimental to maintaining bone density and strength. (FHN) The hypothesis that silicon is an essential nutrient involved in the formation or function of bone matrix components including collagen and glycosaminoglycans which, if suboptimal, increases the risk for osteoporosis will be tested by using a SASO-2 cell culture system to ascertain the effect silicon at the molecular level. (FHN) An experiment ascertaining whether a combined marginal intake of copper and deficient intake of zinc is detrimental to bone maintenance and
health will be completed. (FHN) The long-term supplementation trial started in FY2003 will continue. Controlled feeding studies designed to determine the effects of common dietary components (for example: caffeine, sodium and increased calcium intake from supplements and fortified foods) on calcium retention and trace mineral status will be conducted. (ZKR) Animal studies investigating the effects and mechanisms of action of trace minerals on the IGF-1 proteins and bone status will be conducted in growing and overarioectomized rats. (ZKR) Because boron in the diet has many beneficial effects on human and animal physiology, an experiment will be designed and initiated to examine the uptake and retention of boron from a common food source in healthy volunteers. (CDH) Studies will be initiated to elucidate the induction mechanism whereby dietary boron increases the concentration of natural killer cells in the serum of animal models with experimental rheumatoid arthritis. (CDH) Animal
studies will be conducted to determine why a semi-purified diet based on ground corn and supplemented with boron protects better against experimental arthritis than does a commercial rodent chow with ample boron. (CDH) FY2005 - The human experiment designed in FY2004 to ascertain the practical importance of silicon for bone formation and maintenance will be conducted. (FHN) An experiment will be performed with experimental animals to determine whether urinary and blood markers of bone turnover are altered by a relationship between boron and the omega-3 fatty acids that could be used as a basis for a human study to ascertain the influence of these dietary substances on the susceptibility or prevention of osteoporosis. (FHN) Controlled feeding studies designed to determine the effects of functional foods (consuming prebiotics like fermentable dietary fibers) on calcium retention and trace mineral status will be conducted. (ZKR) Animal studies investigating the effects and mechanisms of
action of trace minerals on the IGF-1 proteins and bone status will be conducted in growing and overarioectomized rats. (ZKR) Health is impaired when diets are too low in boron, a fact that implies that specific biomolecules require boron. Capillary electrophoresis experiments will be conducted to determine which candidate biomolecules, selected on the basis of their chemical structure, bind tightly to boron. (CDH) Because the diadenosine oligophosphates bind tightly to boron and are found in platelets in higher concentrations than any other tissue compartment, an experiment will be performed with experimental animals to determine whether blood coagulation factors are affected by dietary boron. (CDH) Because the concentration of diadenosine oligophosphates are higher in platelets than any other tissue compartment and bind tightly to boron, an experiment will be performed with experimental animals to determine whether blood coagulation factors are affected by dietary boron. (CDH) 7.
What technologies have been transferred and to whom? When is the technology likely to become available to the end user (industry, farmer other scientist)? What are the constraints, if known, to the adoption durability of the technology? Information about the nutritional and beneficial aspects of ultratrace and trace elements as it became available was routinely transferred to a variety of customers. The customers included nutritional risk assessment groups through direct contact or organized meetings and workshops; the public through web pages of professional organizations, via the popular media; and other scientists through presentations at national and international meetings and professional publications. 8. List your most important publications and presentations, and articles written about your work (NOTE: this does not replace your review publications which are listed below) Information was transferred to the public through articles in the local newspaper (Grand Forks Herald)
that were also placed on the Grand Forks Human Nutrition Research Center Home Page: "Soy: The latest way to 'bone up' on good nutrition?" (Z.K. Roughead); "A lesson in nutrition from the three little pigs" (Z.K. Roughead). CD Hunt gave presentations on "The beneficial effects of dietary boron on bone structure during nutritional stress" at the MCH Hospital, Malumghat, Bangladesh, and at the US Embassy in Dhaka, Bangladesh, on April 7 and 9, 2002, respectively; "Boron in the Diet: A Possible 'New' Essential Trace Element for Human Health," Annual Carbart Lectures in Natural Sciences, Dakota Wesleyan University, Mitchell, SD, March 26, 2002.
Impacts
(N/A)
Publications
- Hunt, C.D., Vanderpool, R.A. Dietary boron absorption and excretion kinetics in adult male subject during dietary boron supplementation as determined by stable isotope dilution methodology. The FASEB Journal. 2002. v. 16. Abstract. p. A995. Presented by C.D. Hunt at the Experimental Biology 2002 meeting. New Orleans, LA, April 2002.
- Hunt, C.D., Meacham, S.L. Aluminum, boron, calcium, copper, iron, magnesium, manganese, molybdenum, phosphorus, potassium, sodium, and zinc: concentrations in common Western foods and estimated daily intakes by infants, toddlers, and male and female adolescents, adults, and seniors in the United States. Journal of the American Dietetic Association. 2001. v. 101. p. 1058-1060 and, for Table 1, http://www.eatright. com/images/journal/0901/hunt_tables.pdf.
- Seaborn, C.D., Briske-Anderson, M., Nielsen, F.H. An interaction between dietary silicon and arginine affects immune function indicated by Con-A- induced DNA synthesis of rat splenic T-lymphocytes. Biological Trace Element Research. 2002. v. 87. p. 133-142.
- Seaborn, C.D., Nielsen, F.H. Silicon deprivation and arginine and cystine supplementation affect bone collagen and bone and plasma trace mineral concentrations in rats. Journal of Trace Elements in Experimental Medicine. 2002. v. 15. p. 113-122.
- Ralston, N.V.C., Hunt, C.D. Di-adenosine-phosphates and S- adenosylmethionine: Novel boron-binding biomolecules detected by capillary electrophoresis. Biochemica et Biophysia Acta. 2001. v. 1527. p. 20-30.
- Armstrong, T.A., Flowers, W.L., Spears, J.W., Nielsen, F.H. Long-term effects of boron supplementation on reproductive characteristics and bone mechanical properties in gilts. Journal of Animal Science. 2002. v. 80. p. 154-161.
- Nielsen, F.H. The nutritional importance and pharmacologic potential of boron for higher animals and humans. Goldbach, H., Rerkasem, B., Wimmer, M. A., Brown, P.H., Thellier, M., Bell, R.W., editors. Kluwer Academic/Plenum Publishers, New York, NY. Boron in Plant and Animal Nutrition. 2002. p. 37- 49.
- Nielsen, F.H. Boron, manganese, molybdenum and other trace elements. Bowman, B.A., Russell, R.M., editors. ILSI Press, Washington, DC. Present Knowledge in Nutrition, 8th Edition. 2001. p. 384-400.
- Hunt, C.D. Boron-binding biomolecules: a key to understanding the beneficial physiologic effects of dietary boron from prokaryotes to humans. Goldbach, H.E., Rerkasem, B., Wimmer, M.A., Brown, P.H., Thellier, J., Bell, R.W., (editors). Kluwer Academic/Plenum Publishers, New York, NY. Boron in Plant and Animal Nutrition. 2002. p. 21-36.
- Roughead, Z.K. The Body Knows Best? Trends in Endocrinology and Metabolism. 2001. v. 12. p. 329-330.
- Hunt, C. D. Dietary boron alleviates growth cartilage abnormalities induced by vitamin D deficiency in chicks. 11th International Symposium on Trace Elements in Man and Animals. TEMA 11 Conference Schedule and Abstracts. 2002. Abstract p. 62-63.
- Nielsen, F. H. Dietary boron alters the effect of different amounts of dietary omega-3 fatty acids on growth and bone physical characteristics of F1 generation rats. 11th International Symposium on Trace Elements in Man and Animals. TEMA 11 Conference Schedule and Abstracts. 2002. Abstract p. 63-64. Presentation by F.H. Nielsen at the 11th International Symposium on Trace Elements in Man and Animals, Berkeley, CA, June 2002.
- Nielsen, F.H., Milne, D.B., Klevay, L.M., Davis, C.D. Zinc deprivation alters variables of oxidative metabolism and bone turnover, with some alterations modified by dietary copper, in postmenopausal women. Journal of Trace Elements in Experimental Medicine. 2001. v. 14. Abstract. p. 286- 287. Presentation by F.H. Nielsen at the VIth International Society of Trace Element Research in Humans Conference, Quebec City, Canada, September 2002.
- Hunt, C.D. Dietary boron: an overview of the evidence for its role in immune function. Journal of Trace Elements In Experimental Medicine. 2001. v. 14. p. 359-360. Presentation by C.D. Hunt at the VIth International Society of Trace Element Research in Humans Conference, Quebec City, Canada, September 2002.
- Durick, K., Lamoureux, J., O'Bryant, D., Griffiths, M.M., Hunt, C.D., Bradley, D.S. Inflammatory polyarthritis in collagen-induced arthritis is significantly reduced by physiological amounts of dietary boron. Abstract of presentation by K. Durick at the Frank Low Research Day, University of North Dakota, Grand Forks, ND, April 18, 2002.
- Hill, K. Lukaski, H.C, Roughead, Z.K. Low copper intake reduces serum IGF- 1 and bone strength in growing rats. North Dakota Science, Engineering & Mathematics, 9th Annual Poster Session Program Book. 2001. p. 15. Presented by Katie Hill, North Dakota State University, Fargo, ND, July 25, 2001.
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