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Nutrition in Bone Health Revisited: A Story Beyond Calcium

University of Connecticut, School of Allied Health, Storrs, Connecticut

Address reprint requests to: Jasminka Z. Ilich, PhD, RD, Associate Professor, University of Connecticut, School of Allied Health, 358 Mansfield Road, U-101, Storrs, CT 06269. E-mail: ernst{at}uconnvm.uconn.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
Osteoporosis is a complex, multi-factorial condition characterized by reduced bone mass and impaired micro-architectural structure, leading to an increased susceptibility to fractures. Although most of the bone strength (including bone mass and quality) is genetically determined, many other factors (nutritional, environmental and life-style) also influence bone. Nutrition is important modifiable factor in the development and maintenance of bone mass and the prevention and treatment of osteoporosis. Approximately 80–90% of bone mineral content is comprised of calcium and phosphorus. Other dietary components, such as protein, magnesium, zinc, copper, iron, fluoride, vitamins D, A, C, and K are required for normal bone metabolism, while other ingested compounds not usually categorized as nutrients (e.g. caffeine, alcohol, phytoestrogens) may also impact bone health. Unraveling the interaction between different factors; nutritional, environmental, life style, and heredity help us to understand the complexity of the development of osteoporosis and subsequent fractures. This paper reviews the role of dietary components on bone health throughout different stages of life. Each nutrient is discussed separately, however the fact that many nutrients are co-dependent and simultaneously interact with genetic and environmental factors should not be neglected. The complexity of the interactions is probably the reason why there are controversial or inconsistent findings regarding the contribution of a single or a group of nutrients in bone health.

Key words: osteoporosis, nutrition, osteoporosis prevention, nutrients in bone health

Key teaching points:

• With prolonged life expectancy and the increasing number of elderly, it is predicted that osteoporotic fractures will reach epidemic proportions.

• A substantial effort has been made toward understanding the effect of nutrients, particularly Ca and vitamin D, on bone accretion during youth and bone loss during aging.

• Bone health depends on the whole range of other nutrients and foods as well as the environmental factors.

• The interactions of nutrients among themselves and with other pharmacological, environmental and life-style factors need to be considered when recommendations regarding bone health are given.

• A prolonged deficiency or excess of one or combination of several nutrients, as well as the changes in requirements of some nutrients due to physiological (growth, development, aging, pregnancy) and/or metabolic (disease, reactions to medications) causes might contribute to the osteoporotic problem.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
About sixty years ago, Fuller Albright defined osteoporosis as a disease where there is "too little bone in the bone, but what bone there is, is normal" [1]. By this he meant that, although some bone mass is lost, the chemical composition of the remaining bone is normal. At that time, we knew little about osteoporosis and had no means to treat or prevent it, other than mending the fractures, the ultimate clinical sequelae of the disease. Bone mass (most often expressed as areal bone mineral density) is only one of the components of bone strength. Others include bone quality, structure and turnover. However, it is well established that bone density and bone strength are highly, although imperfectly, correlated [2]. Since it is hard to measure bone quality or structure precisely in vivo, particularly in humans, we depend on the measurement of bone mass in assessing overall bone strength and fragility.

In the past few decades, our understanding of bone metabolism and pathogenesis of fractures has grown tremendously because of the improved technology in measuring bone mineral density (BMD) and in identifying and quantitating the markers of bone turnover. In addition, we now understand the importance of maximizing peak bone mass (PBM) during the first few decades of life. The words of endocrinologist, Charles Dent, given 30 years ago in his key-note address to the International Symposium on Clinical Aspects of Metabolic Bone Disease, that "senile osteoporosis is a paediatric disease," are now fully vindicated [3].

It is worth noting that, like in many other conditions, there is a continuum in bone health for any given age group or segment of population [4], which is genetically determined and possibly environmentally modified. Because bone mass in population conforms to a continuum rather than to a sharp bimodal distribution, it is often hard to distinguish between healthy or osteoporotic bone, based simply on a BMD measurement. The quality of a bone and other risk factors have to be taken into consideration. Table 1 presents the current World Health Organization (WHO) criteria for the diagnosis of osteoporosis [5].

Using the definitions above and the Third National Health and Nutrition Examination Survey (NHANES) III data, conducted between 1988 and 1994, it becomes clear that the prevalence of low femoral BMD is reaching epidemic proportions (Table 2) [7]. The frequently quoted "25 million Americans" affected by this disease have now grown close to 30 million, and even larger numbers of people will be affected by osteoporosis because of increasing life expectancy.

A new system of defining optimal nutrient intakes for healthy populations in the United States and Canada has been developed and is known as the Dietary Reference Intakes (DRIs) [8]. Unlike the previous Recommended Dietary Allowances (RDAs) [9], where only one level of a nutrient was defined, the DRIs delineate different levels of intakes including the Estimated Average Requirement (EAR), the Recommended Dietary Allowances (RDA), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL) (Table 3). The DRIs for the bone-related nutrients (Ca, P, Mg, F and vitamin D) were initially published in 1997 and will be updated as scientific knowledge expands [8].

	BONE CHANGES THROUGHOUT LIFE

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
Fig. 1 shows the changes that occur in bone mass in various stages of women’s lives, along with the principal influences on those changes. During the first two decades of life, bone grows in both length and width. From infancy through young adulthood, bone formation predominates over resorption, resulting in a steady accumulation of bone mass, toward the formation of PBM. Almost half of the adult skeletal mass is gained during the pubescent growth spurt. Ca balance during this time is most positive and ranges from 200 to 300 mg/day [8, 10]. At the completion of puberty, bone continues to increase in thickness and density into young adulthood, when PBM is achieved. It has been assumed that individuals with higher PBM achieved in early adulthood will be at lower risk for developing osteoporosis later in life. Therefore, since rapid skeletal mineral acquisition occurs relatively early in life, the exogenous factors that might optimize peak bone mass to its maximal genetic potential need to be identified.

View larger version (40K): [in this window] [in a new window]   Fig. 1. Changes in bone mass in women (arbitrary units) with age. Principal influences on bone mass are genetics, hormonal status, mechanical loading and Ca intake (throughout life) and structural errors (mostly later in life). Ca = calcium, PBM = peak bone mass.

	CALCIUM

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
The adult human body contains about 1000 to 1500 g of Ca (depending on gender, race, size of the body) of which 99% is found in the bones in the form of hydroxyapatite. For this reason, Ca is probably the most studied nutrient in the area of bone health. Dietary Ca requirement is determined mostly by skeletal needs, and it exerts a threshold behavior. This means that the skeletal response (in this case, skeletal accretion) will occur only when Ca is increased from the deficiency level to a threshold zone. Adding more Ca when the level of dietary intake already exceeds the threshold will not likely improve bone mass. Matkovic and Heaney determined threshold Ca levels for children, adolescents and young adults based on a review of 34 published balance studies [11]. The threshold behavior of Ca in adolescent females was confirmed more recently in a study examining the relationship between Ca intake and urinary Ca excretion [12]. The later study showed that, at Ca intakes of about 1500 mg/day (threshold level for adolescents, as determined by Matkovic and Heaney [11]), urinary Ca starts to rise more rapidly, indicating that skeletal saturation with Ca was reached. Ca threshold for adults is approximately 1100 mg. Therefore, the typical baseline Ca intake of the subjects becomes important when evaluating the literature for efficacy of dietary Ca on bone. For example, if baseline intake was already at the threshold level, additional Ca would not be expected to improve bone.

Growth and Development
There is tremendous interest in Ca intake in American youth, since the skeleton matures at a relatively early age. In young American women, 90% of total bone mineral content was attained at age 17 and 99% was achieved by age 26 [13]. The peak bone density in hip and vertebrae is achieved between ages 17 and 20 [14]. Recent studies by Molgaard et al. [15] suggest that bone accretion is significantly associated with pubertal stages in girls and boys. The peak annual accretion of bone mineral content was reached earlier in girls (12.5 years) than in boys (14.2 years). Assuming that Ca composes 38% of bone mineral, Ilich et al. [10] showed that young girls are able to accumulate approximately 108 g of Ca in one year when progressing from pubertal stage two to pubertal stage three. This amount requires a daily positive Ca balance of about 300 mg, demonstrating the importance of adequate Ca during growth [10] (Fig. 2).

View larger version (39K): [in this window] [in a new window]   Fig. 2. Total body calcium (mean ± SD) measured by dual energy X-ray absorptiometry over a one-year period in 364 teenage girls progressing from pubertal stage 2 to 3. (Adapted from [10].)

Most of the Ca intervention studies performed in children and adolescents also show a positive effect of Ca on bone accretion [26–35]. There have been at least nine longitudinal Ca intervention studies done in girls and boys published to date [26–29, 31, 32, 34–36]. In general, when Ca is supplemented (either as food or a supplement) in girls and boys, bone mineral accretion improves between 1% and 5% at all sites measured. The increment is improved up to 10% when dairy products are used as a source of supplemental Ca [28], and the improvement is more pronounced when baseline Ca intake is low. The length of Ca intervention in most of these studies ranges from 6 to 18 months. The long term effect of the gain in accretion on peak bone mass is not well understood.

Some of the longitudinal clinical trials in children and adolescents showed that the difference in bone mass gained as a result of Ca supplementation disappears when supplementation is terminated [37–40]. A possible explanation for the diminishing difference between placebo and Ca groups could be the "bone remodeling transient" phenomenon. It is speculated that Ca supplementation suppresses bone turnover (due to the suppression of parathyroid hormone), leading to a transient increase in measurable bone mass which then disappears after Ca is withdrawn [41]. In children and adolescents one remodeling cycle might last for about six months. Therefore, this should be the time to begin measurement of the rate of BMD increase, presumably resulting from Ca supplements, and compare it with BMD in the placebo group. If supplementation continues, bone remodeling suppression will continue as well. The above clinical trials lasted from 6 to 18 months, and the final BMD measurements (revealing the diminished difference between groups) were usually performed one year after the study termination. Therefore, some of the studies might not have been long enough to establish a real increase in bone mass caused by Ca supplements. It is likely that, for the difference in bone mass to persist throughout puberty, high Ca intake should be maintained all the time to suppress bone turnover within the expanding periosteal envelope.

The gain in bone density throughout the first several decades translates to lower risk of fracture later in life, and there are two epidemiologic studies that support this contention. They examined bone mass in populations accustomed to different Ca intakes over a lifetime [42, 43]. Both studies were cross-sectional: one in a Croatian and another in a Chinese population. Differences in bone mass in both men and women living in high and low Ca regions were present during young adulthood and continued into old age. These studies indicate that Ca was an important agent for skeletal formation affecting PBM and subsequent rates of bone fractures. Retrospective studies in adults support the above conclusions. Dietary Ca from the distant past (childhood and adolescence) was a significant predictor of current adult bone mass [44–49].

Overall, it is likely that variations in Ca nutrition early in life can account for as much as a 5% to 10% difference in peak adult bone mass. Such a difference, although small, could potentially contribute more than 50% to the hip-fracture rates later in life [42,50].

Young and Middle Adulthood
Because BMD is relatively stable between the ages of 20 and 50, there are relatively few studies evaluating the effect of Ca on bone health during young and middle adulthood. A meta-analysis of the effect of Ca intake on bone mass in women and men (aged 18 to 50 years) was performed by Welten et al. [51]. They analyzed 33 eligible studies: 27 cross-sectional, two longitudinal and four interventional studies and found significant positive correlation between dietary Ca and bone mass. In the two interventional studies, supplementation of 1000 mg Ca in premenopausal women prevented bone loss of about 1% per year in all measured skeletal sites, except the ulna. The overall bone loss for this population is about 0.5% to 1.5% per year.

The conclusions from the above analysis are consistent with those from the meta-analysis conducted by Anderson and Rondano [52]. They summarized the effects of dietary Ca on PBM accrued by premenopausal women during their 20s and 30s and found that both prospective and cross-sectional studies showed a positive effect of Ca intake on bone mineral content. In five interventional studies, the inclusion of Ca-rich foods or Ca supplementation increased or maintained PBM in comparison to control or nonsupplemented groups. Likewise, in 20 cross-sectional studies, there was a beneficial effect of adequate Ca intake on PBM. Presumably, in all these cases the PBM reached was at or close to the maximal PBM within each subject’s genetic potential.

Pregnancy and Lactation
Of particular interest are the changes in Ca and bone metabolism that occur during pregnancy and lactation. There is speculation that increased physiological requirements for Ca in pregnancy and lactation might lead to hazardous and lasting changes on maternal skeletal integrity. An infant is born with about 25 to 30 g of skeletal Ca, which is mostly diverted from maternal stores. Lactational output of milk to meet the infant’s needs in the first four months is about 720 to 750 mL/day, leading to the maternal loss of approximately 250 mg of Ca/day, resulting in a temporary bone loss [53–56]. However, earlier cross-sectional and epidemiological studies (some conducted on women accustomed to low Ca intakes, some on Bantu women with up to six closely spaced pregnancies) did not find an association between pregnancy and bone mass [57, 58]. Pregnancy is associated with hyperestrogenemia and weight gain, both of which have protective effect on bone. In addition, the later part of pregnancy is characterized by increased levels of the active form of vitamin D and increased Ca absorption, all leading toward protection of bone integrity. Some recent studies were more or less in agreement that women do lose bone during lactation, but return to baseline level after weaning [53–56], especially if the lactation is confined to three months or less (a common breast feeding practice in the United States) [59].

The source of Ca during these periods of great physiologic demand of pregnancy and lactation has not been entirely elucidated. Theoretically, the Ca could originate from increased dietary intake, higher intestinal absorption, increased bone resorption, decreased urine Ca excretion or any combination thereof. Two recent, well-conducted studies [54, 60] suggest that dietary Ca is not a major contributor to the changes in bone observed throughout pregnancy and lactation. Ritchie et al. [60] found that fetal demand for Ca was met by an increase in maternal intestinal Ca absorption, and, during lactation, the additional Ca is provided by maternal renal Ca conservation. Five months after menarche resumed in the post-lactating women, trabecular bone density (but not total body bone mineral) was restored to pre-pregnancy values [54]. Both studies agree that the dramatic changes in maternal bone and Ca metabolism occur independently of dietary Ca supply; hence, there is no need for additional Ca intake above current recommendations [8].

While the bone loss in pregnancy and lactation in mature women is self-limiting and a transient phenomenon, the same may not be true in pregnant teenagers, particularly if Ca intake is low. This is the time when skeletal growth and bone consolidation of a pregnant teenage female pose extra demand for Ca beside just mineralization of the fetal skeleton or provision for milk during lactation. Preliminary data of Chan et al. [61] and Scholl et al. [62] point in that direction. Definitive data, particularly with regard to the long-term effect on peak bone mass and adult height, are lacking. Since the number of teenagers, as well as the number of teenage pregnancies, is rising in the US, it would be important to clarify these issues.

Later Adulthood
The gonadal hormones have a tremendous impact on bone health, and this becomes most clear in the postmenopausal woman. The cessation of estrogen secretion in women at the menopause (or testosterone secretion in men) contributes to accelerated bone loss. If untreated, a woman can lose 20% to 30% of cancellous bone (also known as trabecular or spongy bone) and 5% to 10% of cortical bone (also known as compact bone, found primarily in long bones) between age 50 and 60 [63].

When evaluating the effect of dietary Ca on BMD, it is important to distinguish early from late menopause. For the most part, interventional studies done during the early postmenopausal period (within the first five to eight years after menopause) demonstrate that the effects of supplemental Ca are relatively small and appear to be confined to cortical, rather than trabecular bone. A meta-analysis in early postmenopausal women was performed by Cumming [64] and included 49 separate mostly cross-sectional studies. There was a positive correlation between bone mass and Ca intake, such that for each 500 mg increase in dietary Ca, there was a 0.5% to 1% less cortical bone loss, but not trabecular. As expected, the effect was greatest when the baseline Ca intake was low, supporting the threshold hypothesis. Subsequent interventional studies support Cumming’s conclusions [65–68]. Given the large impact of estrogen withdrawal on bone during the early menopausal period, the effect of Ca is small but, nevertheless, an important one.

In general, the effect of dietary Ca on bone loss in the late postmenopausal woman is more pronounced than during the early postmenopausal period. There are at least six studies documenting an increase or maintenance in BMD in mid to late postmenopausal women when additional Ca was given either as a food or supplement [65, 66, 69–72]. Again, not surprisingly the largest improvement is observed when the baseline Ca intakes are the lowest [65]. The combination of estrogen and dietary Ca is more effective than either treatment alone in the late postmenopausal women [73], particularly if Ca intake is low [74]. Conversely, it is quite clear that the bone loss observed in untreated menopausal women is exacerbated by a dietary Ca deficiency [75].

Although the increase in BMD from additional Ca intake is encouraging, the most important outcome variables are bone fractures. An increase in BMD alone would not be all that helpful, if there were no concurrent decrease in fractures. There are at least four studies showing around a 30% reduction in fracture risk in postmenopausal women taking 1000 mg Ca supplement per day [72, 76–78]. In a meta-analysis of 16 observational studies of dietary Ca and hip fractures, there was a small but consistent reduction of fractures [79]. The data suggested that 1 g of dietary Ca/day is associated with a 24% reduction in the risk of a hip fracture. Whether we consider both the BMD and the fracture data, most of these studies are consistent and support the public health policy for increasing Ca intake in older adults. It is worth mentioning that some of the studies were done with simultaneous vitamin D supplementation; as a result, the benefits are probably due to the combined effects.

For more on Ca and bone health and evaluation of published scientific data, readers should refer to the most recent monumental review by Robert Heaney [80].

Calcium Intake
Despite the abundance of evidence supporting the positive effects of dietary Ca on bone, national surveys indicate that Ca intakes in females of all age groups in the US are consistently lower than current recommendations. The 1994 USDA Continuing Survey of Food Intakes by Individuals (CSFII) showed that mean Ca intake in males over the age of nine years is 925 and females over the age of nine years is 657 mg/day. Data from the HANES III survey are consistent with the CSFII. Increasing Ca intake was a primary objective in the Healthy People 2000 and remains a primary objective in the newest version of Healthy People 2010 [81].

Our national Ca deficient diet, particularly for women, places a significant financial burden on our health care system. Bendich et al. [82] estimated the cost-effectiveness of daily Ca supplementation for the prevention of primary osteoporotic hip fractures using the HANES III data. The authors estimate that 2.6 billion dollars in direct medical costs would be avoided if individuals over the age of 50 would consume approximately 1200 mg of supplemental Ca. It is important to note that the effect of dietary Ca on bone is weaker than that of estrogen, bisphosphonates or calcitonin, and Ca alone should not be considered a sole therapy for osteoporosis. However, adequate Ca intake is the basis from which any other therapy or treatment should start [83].

On an opposite note, we need to bear in mind that, on average, about 15% to 40% of people (varying with age, race or gender) are taking mineral and/or vitamin supplements [84]. Due to the growing awareness and attention that osteoporosis has received in recent years, Ca supplement intake has increased. In addition, many foods are now being fortified with Ca (among them, orange juice, breakfast cereals and margarine). Whether it is Ca or any other mineral and/or vitamin, supplements should be taken with caution. While Ca supplementation is justified for most women, there is a possibility that it may cause some adverse effects and imbalance with other cations if taken in excess. In general, the upper tolerable limit of 2,500 mg/day (including diet and supplements) should not be exceeded for a prolonged period of time [8]. Persons at risk for developing milk-alkali syndrome (antacids as Ca supplements are very popular), thiazide users and those with renal failure should be most cautious. The possible interactions of Ca with other minerals are discussed separately in the sections below.

The safety of supplements is not determined just by the amount of intake. Potential contamination of Ca supplements with lead and/or aluminum is a problem that was first recognized in the early sixties when bonemeal, dolomite and fossilized oyster shells and other "natural" supplements became popular [85]. This prompted US Food and Drug Administration warnings and enactment of numerous state and federal measures toward reducing permissible levels of environmental and industrial lead and aluminum exposure [86]. Based on the recent laboratory analysis of lead content in 136 brands of Ca supplements purchased in 1996, it seems that the levels of lead are lower now than some 10 to 20 years ago [87]. That is particularly true for synthesized and refined Ca supplements and infant formulas, while "natural" products still might contain higher amount of lead and more often exceed federal limits [87].

	PHOSPHORUS

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
As an inorganic element, phosphorus (P) is second to Ca in abundance in the human body with 85% of the body’s P bound to the skeleton. P is widely distributed in foods including meat, poultry, fish, eggs, dairy products, nuts, legumes, cereals, grains and cola beverages. It is also added in processing foods. The primary purpose of dietary P is to support growth and to replace losses. Dietary P intakes have risen 10% to 15% over the past 20 years because of the increased use of phosphate salts in food additives and cola beverages [8]. It should be noted that nutrient databases may not reflect these changes and may underestimate actual P intake, particularly when processed foods are a mainstay [88]. Dietary P intakes in US adults range between 1000 and 1500 mg/day, a level well above current recommendations of about 700 mg/day.

Although P is an essential nutrient, there is concern that excessive amounts may be detrimental to bone. For example, a rise in dietary P increases serum P concentration, producing a transient fall in serum ionized Ca resulting in elevated parathyroid hormone (PTH) secretion and potentially bone resorption. The primary function of PTH is to prevent hypocalcemia by increasing bone resorption of calcium. The hypothesis that excess dietary P is harmful to bone was tested in young adults consuming controlled diets containing 1660 mg P and 420 mg Ca. Within 24 hours, the diet resulted in elevated indexes of PTH action [89] that persisted for four weeks [90]. Animal data confirm that the combination of high P and low Ca diets is deleterious to bone mass [91]. However, it is difficult to differentiate the detrimental effects of low Ca from that of high P.

On the other hand, there are data that show the transient decline in serum Ca induced by a P load is caused by an inhibition of PTH-mediated Ca release from bone, thus conferring beneficial effects on bone [92]. Human studies using Ca kinetic methodology showed no effect on bone turnover from doubling P [93], a conclusion supported by a nonisotopic study done in young men and women [94, 95]. The P intake typically consumed in the US diet probably does not adversely affect bone health [8].

A frequently raised issue is the potential adverse effect of consumption of carbonated beverages. Some studies have shown decreased bone mass and elevated fracture rates with the consumption of carbonated beverages [96–98], while others have not shown such a relationship [99]. A possible explanation for the adverse effect of carbonated beverage on bones could be due to the resulting acid load caused by the ingestion of phosphoric acid used as an acidulant. However, other available studies do not differentiate between the beverages made with phosphoric acid or other acidulants, thereby making the proton load effect unclear. The reported adverse effect of carbonated beverages on bones might be due simply to the displacement of milk from the diet and thus to lower Ca intake, rather than to any other plausible mechanism.

	MAGNESIUM

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
There are approximately 25 grams of magnesium (Mg) in the human body, two-thirds of which are in the skeleton and the rest in soft tissue. The Mg in bone is not the integral part of the hydroxyapatite crystal structure (like Ca and P); rather, it is adsorbed on the surface of the crystal. Only a small fraction of Mg in bone is freely exchangeable with extracellular Mg [100]; however, it plays an important role in Ca and bone metabolism. Magnesium deficiency alters calcium metabolism, resulting in hypocalcemia, vitamin D abnormalities and neuromuscular hyperexcitability. The primary reason for the hypocalcemia commonly observed in Mg deficiency is impaired PTH secretion [101].

Animal studies show that Mg deficiency results in decreased bone strength and volume, poor bone development [101, 102] and uncoupling of bone formation and resorption [103,104]. For these reasons, it is thought that Mg deficiency may be a risk factor for osteoporosis. Consistent with the animal studies, numerous populations’ studies demonstrate a positive association between magnesium intake and BMD [105–108]. Most recently, Tucker et al. [109] found that Mg intake was positively associated with hip BMD in both men and women of the original Framingham Heart Study cohort. Several studies found no correlations between Mg intake and bone density [110,111].

The effect of Mg supplementation in humans is poorly understood because of few well-controlled clinical trials. In osteoporotic postmenopausal women, Mg supplementation for one year improved radial bone mass [112]. There were no further increases in BMD at two years on these Mg supplemented women. A second intervention study showed that 600 mg Mg, 500 mg Ca and a multivitamin-mineral supplement improved calcaneous BMD in postmenopausal women in less than a year [113]. The subjects were also taking estrogen, so it is difficult to tease out the potential benefit of the hormones, calcium or multivitamin-mineral preparation.

National surveys consistently show low intakes of Mg among females of all age groups, but particularly among teenagers [114]. The deficiency becomes even more pronounced with the new increased recommendations for Mg [8]. A recent report on Mg balance by Andon et al. [33] showed that teenage girls with low Mg intake (<177 mg/day) were in negative Mg balance. It is noteworthy that the 1997 RDA for teenage girls increased from 280 mg/day (1989 RDAs) to 360 mg/day. Andon et al.’s study [33] did not show any adverse effect of Ca supplementation (total intake approximately 1700 mg Ca/day) on any components of Mg metabolism.

Good sources of Mg in food are whole grains, vegetables (broccoli, squash), nuts and seeds. Dairy products and meats also contribute magnesium to a diet, as well as chocolate and coffee, depending on the amount consumed. "Hard" water contains high concentrations of Mg, and can be considered a dietary source. Although our diets are marginally low in magnesium, we know very little about how Mg affects bone health in humans.

	FLUORIDE

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
Fluoride (F) is an ultratrace element, occurring in minute amounts in food and water supplies. It is completely and readily absorbed in the gastrointestinal tract by passive diffusion. Once absorbed, F readily crosses cell membranes and becomes incorporated into the teeth and bones. There is a strong affinity toward F in bones, particularly during growing period. Because F is not easily released from bone, F toxicity (fluorosis) may be a problem.

An early survey in North Dakota showed the incidence of osteoporosis was lower in an area where F was naturally high in the water [115]. Drinking water fluoridation (at 1 mg/L) is well known to prevent dental caries, but its effect on bone is unknown. Optimal drinking water fluoridation does not appear to alter bone mass in humans (as evidenced from epidemiological studies), nor is the effect on hip fractures clear [116–118].

In the process of bone mineralization, or deposition of minerals into the collagenous matrix of bone to form hydroxyapatite crystals, other species (other than Ca and P) may be incorporated, substituting for Ca in the crystal lattice and usually yielding crystals that are smaller, more soluble and imperfect in size (e.g., with incorporation of Mg or strontium) [119]. This is not a case with F. F incorporation into bone increases the size and, therefore, decreases the solubility of the apatite crystals [120]. This was a rationale for using F supplements for treatment of osteoporosis, as larger crystals are more resistant to osteoclastic attack. However, if the crystals are excessively large, as in the case of skeletal fluorosis, bones may become brittle and more fragile [120].

Do sodium fluoride (NaF) supplements benefit bone and treat osteoporosis? In addition to increasing hydroxyapatite crystals, fluoride seems to be a potent stimulator of osteoblastic bone formation acting primarily on trabecular bone [121] and resulting generally in the 5% to 10% annual increase in spinal bone mass. Although the precise mechanism of F action on bones is not completely clear, it seems that it exerts its effect by sensitizing various skeletal growth factors through inhibition of osteoblastic acid phosphatase [122] or stimulation of osteoblastic replication [123] or both. These properties triggered a great enthusiasm for NaF as a very cheap, relatively safe and effective drug for osteoporosis. However, the results of the pioneering clinical trials conducted in parallel in mid eighties at Mayo Clinic, Rochester, MN, [124] and Henry Ford Hospital, Detroit, MI, [125] were disappointing. Both studies, four-year randomized, double blind, placebo-controlled trials of NaF supplementation in postmenopausal, osteoporotic women showed increase in vertebral bone densities but no decrease in vertebral fracture rates and increase in non-vertebral fractures. Both studies were criticized for a possible high levels of NaF (75 mg/day) used and that better results could have been achieved with lower doses.

Many other similar trials with different NaF dosages were subsequently conducted; however, the data on the effect of F on bone fractures are still inconsistent [126, 127]. Some authors found decreases in fracture rates in the fluoride supplemented subjects [128, 129], while others found negative or inconclusive results [127, 130]. Slow release NaF as a therapy for osteoporosis is used in many European countries; however, its approval in the United States by the Food and Drug Administration is still pending.

	IRON

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
Iron (Fe) may play an important role in bone formation acting as a cofactor for enzymes involved in collagen synthesis [131]. Bone breaking strength was lower in Fe deficient rats, suggesting that Fe deficiency may play a role in bone fragility [132]. We recently examined the relationship between bone mass and ferritin in a four-year clinical trial of Ca supplementation in adolescent girls [133]. There was a trend for a positive association between BMD of forearm and serum ferritin at baseline. A similar trend was noticed between the total body bone mineral density and content and serum ferritin in year 4 of the study, but only in the placebo group [133]. Further studies are necessary to clarify the above trend, particularly in people who are Fe deficient.

Fe absorption may be inhibited by the high intakes of other minerals and trace elements, particularly Ca. Numerous studies have shown the inhibitory effect of Ca on Fe from different supplements (salts) or Ca-containing foods [134–138]. However, when Ca consumption occurs separately from the meal containing Fe, the effect is less clear [139, 140]. Prather and Miller [141] used a rat hemoglobin repletion assay to determine if the inhibitory effect of Ca was due to the Ca, the accompanying anion or a combination of the two. Low, medium and high doses of Ca carbonate, Ca sulfate, Na carbonate or Na sulfate were added to the repletion diet. Ca carbonate reduced iron bioavailability in a dose related manner. Ca sulfate and Na carbonate also decreased iron bioavailability, but only at the highest dose. Based on these observations, it was concluded that both the cation and the anion contribute to the inhibitory effect. Since Ca inhibits both heme and non-heme Fe absorption, Hallberg et al. [142] suggested that the inhibition is occurring in the intestinal mucosal cells where Ca interferes with Fe transport.

However, it is not clear to what extent, if any, higher Ca intake (even when it interferes with Fe absorption) might influence Fe stores in population and what would be the consequences of lower Fe stores on bone mass. There is no effect of Ca on serum ferritin (indicator of Fe stores) in infants [143], adolescent girls, even after a long term supplementation with Ca [133], adults [138] or lactating women [53].

On an opposite note, Fe might act as a toxin to bone cells and contribute to osteoporosis or other bone diseases in people with impaired Fe metabolism and Fe overload. Most typical such cases are in hemochromatosis, African ("Bantu") hemosiderosis, chronic renal diseases (including renal osteodystrophy) and any case of Fe overload with prolonged and repeated Fe therapy or hemotransfusion. It is not always clear whether the insult to bone comes from iron itself, Fe overload-induced hypovitaminosis C or both [144]. Conte et al. [145] compared BMD and bone histomorphometric analyses among patients with primary hemochromatosis, alcoholic cirrhosis and controls. Densitometric and histomorphometric results indicated impairment of trabecular bone in both patient groups compared with controls, while cortical impairments were limited only to hemochromatotic patients. Similar findings resulted from the study of osteoporosis in African hemosiderosis patients [144]. However, in the situations where both Fe overload and alcohol are involved, to what extent the pathological changes are caused by iron alone, by chronic alcoholism or by the associated nutrient disturbances is not known. In chronic kidney diseases, various bone-histomorphometric lesions are attributed to iron and/or other trace mineral overloads, usually as a result of dialysis [146,147].

Although most breakfast cereals and flour are fortified with Fe, its bioavailability from those sources is low. It is also found in dark green vegetables, like spinach (with the lower bioavailability as well). The best Fe sources are red meats, particularly liver and other organ meats.

	ZINC

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
The human body contains one to two grams of zinc (Zn) and about 90% is found in muscle, bone, skin and hair, while blood contains less than 1%. Zn plays an important role in connective tissue metabolism, acting as a cofactor for several enzymes, such as alkaline phosphatase (necessary for bone mineralization), and collagenase (essential for the development of the collagenous structure of bone) [148].

Zn deficiency results in impaired DNA synthesis and protein metabolism, which lead to negative effects on bone formation [148]. The role of Zn in bone formation is well documented in animal models [149], and low serum levels of Zn and excessive urinary excretion are related to osteoporosis in humans [150,151]. Zn concentration in bone is greatly reduced during Zn deficiency [152]. A beneficial effect of Zn supplementation was observed in vertebral and femoral bone mass in rats during strenuous treadmill exercise [153].

Zn is abundant in animal protein foods (red meat, poultry, fish, oysters, eggs), legumes, whole-grain breads and milk. However, the population that may be susceptible to a mild to moderate Zn deficiency are infants and adolescents, due to increased requirements for growth and, in the case of latter, poor eating habits [154,155]. Several dietary constituents may decrease the bioavailability of Zn including phytic acid, dietary fiber, low dietary protein and Ca [156]. Although animal studies show that Ca interferes with the intestinal absorption of Zn [157], human studies are less convincing [158–160]. Long term supplementation of 1000 mg Ca/day (from Ca citrate malate) did not affect any components of Zn metabolism (balance, urinary or fecal excretion) in adolescent girls already consuming low amounts of Zn [161].

	COPPER

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
The body contains about 75 to 100 mg copper (Cu) which is mostly accumulated during growth. Deficiency of Cu is rare as Cu is present in nearly all foods, particularly legumes, nuts, whole grains, beef liver and shellfish. The intake of Cu in the US ranges widely (from 0.7 to 7.5 mg/day) and the safe and adequate intake ranges from 2 to 3 mg/day [9].

Because Cu influences collagen maturation, it could influence bone composition and structure. The enzyme lysyl oxidase is a copper-containing enzyme that catalyses crosslinking of lysine and hydroxyproline in collagen, contributing to the mechanical strength of collagen fibrils [162]. Cu deficiency results in decreased bone strength in rats [132, 163] and chicks [164].

	SODIUM

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
There is a positive relationship between urinary sodium (reflecting Na intake) and urinary Ca excretion. Since the late fifties and early sixties [165, 166], it has been repeatedly shown in animals and humans that dietary sodium, in the form of salt (NaCl) increases urinary Ca excretion [12, 167, 168]. On average, for every 100 mmol (2,300 mg) of Na excreted in urine, there is about 0.6 to 1 mmol (24–40 mg) loss of Ca, in free-living healthy population of various ages [12, 167].

Although it is clear that Na is an important determinant of obligatory Ca loss in urine and causes bone loss in animals (especially at lower Ca intakes) [169, 170], there are only a few studies examining its effect on bone mass in humans. Forearm BMD was significantly and negatively correlated with 24-hour urinary Na excretion in a cross-sectional study of 440 healthy postmenopausal women [171]. Results from cross-sectional studies, one in elderly men and women [172] and another in preadolescent females [12], show strong correlation between urinary Na and Ca. However, there were no direct effects of urinary Na on BMD at spine, hip, forearm or whole body [12,172]. In the only longitudinal study examining bone mass and urinary Na, Devine et al. [173] showed that changes in urinary Na were negatively correlated with changes in BMD of the hip and ankle in postmenopausal women.

Other, indirect evidence of adverse effects of Na on bone comes from short-term interventional studies with Na loading or restriction and markers of bone turnover. Evans et al. [174] showed that postmenopausal, but not premenopausal women, responded to a one-week high Na intake of 300 mmol/day by an increase in deoxypyridinoline (bone resorption marker). In a cross-sectional study of free-living Japanese men and women ranging in age from 20 to 79 years, Itoh et al. showed that the excessive Na intake was associated with higher deoxypyridinoline concentrations, thereby increasing bone resorption [175]. Other studies evaluating the effect of dietary Na on bone markers are inconclusive [176, 177].

The interaction between Ca and Na becomes even more important when considering the trends in intakes of each: Ca intake is lower than recommendations, and Na intake remains consistently high. The estimated minimal requirements for adults are 500 mg/day [9], and the American Heart Association recommendations are at 2,400 mg/day or less [178]. Yet dietary Na intake is generally much higher than recommendations [179]. While the influence of Na on blood pressure is still controversial, its hypercalciuric effect is well established. However, whether habitual salt excess decreases bone mass and presents a risk factor for fracture incidence is still not established. There is a need for prospective, longitudinal studies with repeated bone mass measurements and the assessment of markers of bone turnover after a longer period of intervention with sodium within the range of usual intake (1,500–7,500 mg/day).

	VITAMIN D

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
The vitamin D endocrine system influences Ca and P metabolism by affecting the target organs: intestine, bone and kidney. The active metabolite, 1,25(OH)₂vitamin D₃ (calcitriol) facilitates active Ca absorption in the intestine by stimulating the synthesis of Ca binding protein (calbindin). Vitamin D is also involved in bone turnover, and a deficiency may cause rickets in children and osteomalacia in adults (both characterized by defective mineralization of bone).

We recently demonstrated the important role of calcitriol on bone mass accretion in pubertal girls. Calcitriol concentration was the highest during peak growth (pubertal stages 3 and 4), probably due to the high skeletal demands for Ca. Baseline calcitriol levels also predicted annual change in total body and forearm bone mass of adolescent girls [180].

Vitamin D status declines with age for many reasons: lower exposure to sunlight (particularly in the northern latitudes during winter months), decreased ability to activate precursors in the skin, decreased ability of the kidney and liver to hydroxylate vitamin D, lesser end-organ response to calcitriol itself, reduced dietary intake and diminished absorption from food, as well as the use of anticonvulsant and/or steroid drugs. Consequently, vitamin D deficiency in the aged is not uncommon, particularly in the frail elderly living in northern industrialized cities. Approximately half of the medical inpatients in the Boston-area had low levels serum 25(OH)vitamin D [181]. A similar trend was observed in homebound elderly [182]. However, apparently healthy noninstitutionalized adults in the US have a much lower incidence of hypovitaminosis D [183].

Blood level of 25(OH)vitamin D (an indicator of vitamin D status) varies seasonally. As recently shown, the increase in 25(OH)vitamin D from winter to summer is much lower in black than in white women and inversely related to PTH [184]. Although black women have denser bones despite the lower 25(OH)vitamin D [185], there may be negative consequences that contribute to their higher rate of bone loss at more advanced age. The results from the Study of Osteoporotic Fractures showed no benefits of vitamin D supplements to fracture rates [186]. It was reported earlier that substantial proportion of patients with hip fractures also have osteomalacia, caused by vitamin D deficiency [187]. Vitamin D deficiency may also be associated with reduced muscular function [188], which may increase risk for falling. There are just a few foods that are naturally rich in vitamin D, like butter, margarine, liver and eggs. Therefore, milk in the US (and in Canada) is fortified with vitamin D to the level of 2.5 µg (100 IU) per serving. However, considering the high prevalence of lactose intolerance or maldigestion—25% of the US population and 75% of adults worldwide [189] (although according to some this is an overestimation)—fortifying milk by vitamin D might not be beneficial for that group. When compared to the previous RDAs, the 1997 Requirements [8] for vitamin D were decreased (by half) for adolescents and children, while they were doubled or even tripled for the aged. Ca supplements in the elderly should always be accompanied by vitamin D.

	VITAMIN K

TOP ABSTRACT INTRODUCTION BONE CHANGES THROUGHOUT LIFE CALCIUM PHOSPHORUS MAGNESIUM FLUORIDE IRON ZINC COPPER SODIUM VITAMIN D VITAMIN K ANTIOXIDANT VITAMINS ENERGY PROTEIN FOOD AND FOOD COMPONENTS HERBALS AND BOTANICALS CONCLUSIONS REFERENCES

 
Vitamin K, originally recognized as a factor required for normal blood coagulation, is now receiving more attention for its role in bone metabolism. Vitamin K is a coenzyme for glutamate carboxylase, an enzyme that mediates the conversion of glutamate to gamma carboxyglutamate, (known as a Gla protein). In this conversion, the Gla (dicarboxylic glutamyl) residues attract positive Ca ions and, by that, enhance its incorporation into the hydroxyapatite crystals. There are three Gla proteins associated with bony tissue, of which osteocalcin is the most studied and best known [190]. Osteocalcin is the major non-collagenous protein incorporated in bone matrix during bone formation. However, around 30% of the newly produced osteocalcin stays in circulation, where it serves as an indicator of bone formation. During bone resorption and erosion of bone matrix, osteocalcin is released back into circulation. Therefore, the blood contains osteocalcin that may be a component of bone formation and/or resorption. Although osteocalcin is generally regarded as a bone formation marker, a more appropriate label would be a bone turnover marker. An exact function of osteocalcin is not clear; however, deficiency of vitamin K will result in an increase in undercarboxylated osteocalcin, a protein with low biological activity and detected in osteoporotic patients [191].

There are several population studies showing that low dietary or circulating vitamin K levels are associated with low BMD or increased fractures [192, 193]. Additionally, other studies show that vitamin K supplementation reduces undercarboxylated osteocalcin [194, 195], reduces urinary Ca excretion [195] and improves bone turnover profile [196,197]. There are at least two studies showing that high levels of undercarboxylated osteocalcin (presumably, as the consequence of low vitamin K) are associated with low BMD and increased hip fractures [198, 199]. Warfarin and other anticoagulants (vitamin K antagonists) should, in theory, lower BMD; however, the scientific evidence on this issue is unclear [200, 201].

Recent data from the Framingham Heart Study cohort showed an increased incidence of hip fractures with lower dietary vitamin K (assessed by food frequency) but no association of vitamin K with BMD in elderly men and women [202]. The authors also examined the association with apolipoprotein E genotype. Phylloquinones are transported by lipoproteins and are strongly influenced by apolipoprotein E genotype. In previous research, the highest phylloquinone concentration was noticed in individuals with E2 allele and the lowest with E4 allele; the incidence of fractures was higher [203] and BMD lower [204] in individuals with E4 allele. However, the data from Framingham study did not support the above association.

Vitamin K is supplied to the body from two sources: the diet and intestinal bacterial synthesis. Dietary vitamin K is provided primarily by green vegetables, particularly broccoli, cabbage, spinach, brussel sprouts, turnip greens and lettuce, all of which contain more than 100 µg vitamin K/100 g serving. The 1989 RDA for dietary vitamin K ranges from 55–70 µg per day for the adult or in the range of 1 µg/kg weight/day. The usual diet contains around 300–500 µg vitamin K, so an overt deficiency under normal circumstances would be unusual. Those at risk for a subclinical deficiency would be newborns, those with fat malabsorption or chronic antibiotic use. At this point, there is every reason to recommend high vegetable intakes for bone health, although there is much research t