Nutrition and Risk for Osteoporosis

C H A P T E R

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Nutrition and Risk for Osteoporosis Robert P. Heaney Creighton University, Omaha, NE, USA

INTRODUCTION Nutrition in the Osteoporotic Fracture Context In 1990 osteoporosis was redefined, for the first time in nearly a century, as a condition of skeletal fragility due to decreased bone mass and to microarchitectural deterioration of bone tissue, with consequent increased risk of fracture [1]. This definition was conceptually important because it both acknowledged and encouraged a shift in thinking about osteoporosis from an anatomic to a dynamic condition. Low bone mass became a risk factor for fracture, rather than, as formerly, the defining feature of the disease. This redefinition accompanied a growing recognition that osteoporosis is not a single disorder but a group of more or less discrete fracture syndromes, multifactorial both in etiology and in pathogenesis. The recognition not only of a multiplicity of pathogenetic factors; but of disease heterogeneity adds another dimension of complexity that must be considered when describing and assessing the role of any single factor, whether hormones, exercise, or nutrition (as in this case). Thus, not only is nutrition just one of several interacting factors in any given fracture syndrome, but it may play quite different roles, or none at all, in certain of those syndromes, while being of greater importance in ­others. This was first suggested in the 1979 report by Matkovic and his colleagues from Croatia [2], which showed that high calcium intake was associated with strikingly reduced hip fracture risk, but not with altered risk of distal forearm fracture in the same population. Nutrition affects bone health in two qualitatively distinct ways. Bone tissue deposition, maintenance, and repair are the result of cellular processes, and the cells of bone responsible for these functions are as dependent upon nutrition as are the cells of any other tissue. The production of bone matrix, for example, requires the

Osteoporosis. http://dx.doi.org/10.1016/B978-0-12-415853-5.00028-5

synthesis and post-translational modification of collagen and an array of other proteins (see Chapter 11). Nutrients involved in such synthesis include protein, the vitamins C, D, and K, and the minerals copper, manganese, and zinc. Phosphorus also is indirectly involved in these cellular activities. Additionally the skeleton serves as a very large nutrient reserve for two minerals, calcium and phosphorus, and the size of that reserve (i.e., the massiveness of the skeletal structures) will be dependent in part upon the daily balance between absorbed intake and excretory loss of these two minerals. Bone mass is also dependent upon a variety of non-nutritional factors, such as genetics, mechanical loading, hormonal status, and others. These dependencies complicate the interpretation of low bone mass ­values because, while low bone always means a reduced calcium reserve, simple reduction in bone mass does not necessarily mean that it had a nutritional cause. While several of the chapters in this volume describe in considerable detail the diversity of osteoporosis, it will be helpful here to recapitulate very briefly what is known of the complex domain of osteoporotic fragility. Only against that background will it be possible to situate nutrition adequately amidst the array of other pathogenetic influences. Factors involved in osteoporotic fractures can be organized hierarchically to include the injury itself, the strength of the bone, the mass, density, shape, and architecture of the bone, and the adequacy of nutrition as it affects both bone mass and architecture. Hip fracture is perhaps the most serious of the fragility fractures, inasmuch as it carries an excess mortality, is expensive, and causes significant deterioration in quality of life for most of its survivors. It is, as well, a good example of the many interacting factors that constitute this fracture domain, which will be used in this preliminary overview. Figure 28.1 illustrates, schematically, how the various contributing factors interact for hip fracture.

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Copyright © 2013 Elsevier Inc. All rights reserved.

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Fall (impact at hip)

*

* *

Failure of protective response Insufficient soft tissue energy dissipation

HIP FRACTURE

Low bone mass

*

* *

Excessive remodeling Intrinsic bony fragility

Osteomalacia Long hip axis

Unrepaired fatigue damage

FIGURE 28.1  Schematic representation of the interplay of the principal factors thought to be important in hip fracture. Asterisks denote factors with a recognized nutritional determinant. Source: Copyright Robert P. Heaney, 2006. Used with permission.

It highlights, as well, probable sites in this schema at which nutrition plays a role.

Frailty and Injury Almost all fractures, even those termed “low-trauma”, occur as a result of some injury − the application of more force to the bone than it is able to sustain (see Chapter 22). Usually this is a result of a fall or the application of bad body mechanics (e.g., bending forward to lift a heavy object). Although fracture incidence patterns differ somewhat from site to site, the risk of virtually all fractures rises with age, and all fractures contribute to the burden of illness, disability, and expense that elderly people (and society) bear. The first factor to consider is the fall itself. Normally postural reflexes operate to get the arms into position to break the force of the fall, or to swing the body so that it lands on the buttocks (or both). These reflexes are almost always effective in younger individuals, but they commonly fail in elderly people. As a result, young people rarely strike the lateral portion of the trochanteric region of the hip when they fall, whereas the fragile elderly more commonly do so. The force of the impact, when falling from standing height, may well be sufficient to break even a healthy femur if that force is concentrated in a small enough impact area [3] (see also Chapter 22). Additionally, hip fracture is a particularly serious problem in undernourished elderly individuals who have less muscle and fat mass around the hip, and therefore less soft tissue through which the force of the impact can be distributed to a larger area of the lateral surface of the trochanter. Nutrition enters into this region of the fracture domain both through its effect on propensity to fall [4] and on maintenance of the soft tissue mass. This latter

factor, particularly, is the rationale for the development and successful deployment of hip protectors in elderly people [5]. In some cases nutrition may also influence nerve conduction velocity and central nervous system processing time or contribute to the general feebleness which predisposes to falling. The implication here is that we should attempt to improve general nutrition in elderly people prophylactically, or, failing that, that we should certainly attend to coexisting nutritional problems at the time of fracture repair.

Intrinsic Bony Strength and Fragility Strength in bone, as in most engineering structures, is dependent upon its mass density, upon the three-­ dimensional arrangement of its material in space, and upon the intrinsic strength of its component material (particularly, in bone, as that strength is influenced over long periods of use by the accumulation of unrepaired fatigue damage and by bone remodeling activity). All three factors play some role in most low trauma fractures, and it is not easily possible to say which may be the most important in any given case. Nevertheless, most of the investigative effort in this regard in the past 40 years has been devoted to the measurement of bone mass and density, and hence much of what we know about bone strength in living individuals comes from our observation of this facet of the bone strength triad. There is, in fact, a general consensus that decreased bone mass produces a decrease in bone strength. But there clearly are other fragility factors as well, although there is less of a consensus as to how large a role they play [6]. The data of Ross et al. [7] show that prior spine fracture signifies the presence of fragility independent of, and at least as important, as the fragility due to low bone density. Similarly Hui and Johnston [8] showed that the fracture risk gradient for age, holding density constant, was greater than the risk gradient for density itself. Along the same vein, Chapurlat et al. [9] showed that the antifracture effect of antiresorptives was independent of their effect on bone density. These effects, independent of bone mass, may be partly explained by structural and qualitative defects in bone. One of these is an excess of bone remodeling activity above that needed for repair of fatigue damage. The antiresorptive agents that are the mainstay of therapy today, while they do favorably affect bone mass in most patients, probably produce most of their effect through suppression of that excess remodeling. A commonly observed microstructural defect is excessive loss of horizontal, cross-bracing trabeculae in cancellous bone [10,11]. This may be the basis for the predictive value of prior spine fracture [7]. It appears that women, particularly, are more prone to loss of horizontal trabeculae

V.  EPIDEMIOLOGY OF OSTEOPOROSIS

Introduction

than are men, and this fact is probably also a part of the explanation for the 6:1 to 8:1 female:male sex differential in vertebral osteoporosis. The data of Eventov et al. indicate the probable importance of repair of fatigue damage [12]. Faulkner et al. [13] and Glüer et al. [14] have called attention to a probable role of geometric factors at the hip, specifically to hip axis length and angle, and Gilsanz et al. [15] to the importance of vertebral body size.1 In summary, evidence from several quarters makes it clear that bony fragility has bases other than reduced bone mass or density. Nevertheless, as noted elsewhere in this volume, fracture risk rises by a factor in the range of 1.5- to 2.5-fold for every drop in bone mass/density of one standard deviation. And whatever may be the role of nonmass factors, it is an inescapable fact that most elderly individuals have bone mass values that are more than two standard deviations below the young adult mean; hence they all can be said to be at considerably increased risk for fragility fracture. Why some older people do fracture and others do not appears to be explainable by a combination of random chance, differences in falling patterns, the structural differences just described, and nutritional status. Nutrition enters into this portion of the fracture domain predominantly through its influence on bone mass (or density), on bone remodeling activity, and on propensity to falls. Because many other factors also influence bone strength, nutritional inadequacies can never explain more than a part of the problem, and nutritional interventions can never completely eliminate fragility fractures. It may be, also, that trace nutrients such as certain of the vitamins (e.g., C, D, and K) or minerals such as manganese, copper, and zinc (see section “Other Essential Nutrients”) directly influence the remodeling process and/or the character of the remodeled bone, and hence affect bone strength through their impact on the repair of inevitable fatigue damage. However, little is known about these possibilities in the adult skeleton. Hence, in most of what follows, the emphasis will be on the nutritional factors that influence bone mass and remodeling.

most c­ritical for bone health are calcium, vitamin D, and protein. Calcium intake, specifically, may be inadequate for the straightforward reason that it is low; however, even when statistically “normal”, it may still be inadequate because of subnormal absorption [16] or greater than normal excretory loss [17,18]. Other nutrients are also essential for building a healthy skeleton, but, except for calcium, their effects are usually seen most clearly during growth. (Once built, the skeleton tends to be relatively insulated from many subsequent nutritional deficiencies − see below: section “Problems in the Investigation of the Effects of Nutrition on Bone”). In addition, a number of other factors also influence bone mass, such as smoking, alcohol abuse, and various drugs used to treat a variety of medical illnesses, as well as those ­illnesses themselves. The effects of each of these factors are largely independent. In other words, altering any one of them will not substitute for, or compensate for, adverse effects of the others. Thus, a high calcium intake will not ­prevent the loss of bone that occurs immediately following menopause in women or castration in men. Similarly, physical activity will not compensate for an inadequate calcium intake. Neither will a high calcium intake offset the effects of alcohol abuse or smoking. Much of the apparent confusion in the bone field over the past 25 years could have been avoided if we had better understood that these factors, while interactive, are substantially independent. Finally, although much of the following discussion will focus on calcium, it is necessary to stress what should perhaps go without saying, that calcium is a nutrient, not a drug, and hence its beneficial effects will be confined to individuals whose intake of calcium is insufficient. Also, calcium is not an isolated nutrient; it occurs in foods in combination with other nutrients, and it has been shown that diets low in calcium tend also to be nutritionally poor in other respects as well [19–21]. Thus, while it is necessary to deal with nutrients one at a time in an analysis such as this, the disorders in our patients are likely to be more complex.

Bone Remodeling

Bone Mass/Density Bone mass and density are themselves influenced by many factors. Holding body weight constant, the three most important − or at least the three most commonly found to be limiting in industrialized nations − are physical activity, gonadal hormones, and nutrition. In adults of industrialized nations the nutrients 1Other

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things being equal, a long hip axis increases hip fracture risk, and a small cross-sectional area for vertebral bodies increases spine fracture risk.

Remodeling in bone is the process by which preexisting volumes of bone are removed by osteoclasts and new bone deposited in the resorption cavities by osteoblasts (see Chapters 4 and 36). The entire process at any given bone site lasts several months and is generally considered to be driven by the need to repair local structural defects. Osteocytes in damaged regions are believed to detect excessive mechanical strain and signal the resorptive apparatus to remove the damaged bone, starting from nearby anatomical surfaces. The responsiveness of the osteocytes is, in turn, influenced by circulating

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confusion about the role of nutrition in bone health. Some of these problems are nutrition-specific; others are inherent in bone biology.

Nutrition-Specific Problems

FIGURE 28.2  Diagrammatic depiction of the bowing of vertical trabeculae that occurs in loading. The presence of a resorption bay on the surface of a trabeculae creates local weakness conducive to microfracture. Source: Copyright Robert P. Heaney, 2005. Used with permission.

parathyroid hormone (PTH), as evidenced by the fact that total skeletal remodeling is very high in hyperparathyroid states, and very low when PTH levels are low. Both calcium and vitamin D lower PTH secretion, and as a result, reduce osteocyte responsiveness and the general skeletal level of remodeling activity. Additionally, estrogen, long recognized as a natural, physiologic antagonist of PTH, also alters remodeling activity. Remodeling, while theoretically designed to strengthen bone, nevertheless temporarily creates local weak­ ness because the region from which bone is removed transiently contains less bone. Hence remodeling, when excessive, can be an important fragility factor. Figure 28.2 depicts the reason for this weakness schematically. Fracture risk at most bony sites is increased up to three-fold in patients with mild, asymptomatic hyperparathyroidism [22] (see Chapter 52) and remodeling rate, as measured by biomarkers (see Chapter 67), is at least as good a predictor of fracture as is bone mass or density [23,24]. Remodeling activity in bone doubles across menopause and triples by age 65 years [25]. A change that is preventable by estrogen replacement therapy, and to some extent by high calcium intakes [26].

PROBLEMS IN THE INVESTIGATION OF NUTRITIONAL EFFECTS ON BONE There are significant problems for both observational and experimental approaches to the elucidation of nutrient effects on the skeleton, and failure to recognize or overcome them has led both to seemingly contradictory results among various studies and to substantial

Estimation of Nutrient Intake Two nutrients with clearly established effects on bone are vitamin D and calcium. For both there are substantial difficulties in estimating intake [27,28] (see also Chapter 72). Vitamin D is found naturally in very few foods (mostly oily fish and to a limited extent, egg yolks and, as pre-formed 25(OH)D in the meat of animals exposed to sunshine [29]). For primitive humans, solar exposure would have been the principal source of vitamin D, as is still the case in rural cultures and in the young of even many urbanized societies. Vitamin D is added as a fortificant to fluid and dry milk in the US and Canada (as well as to a few other dairy foods). Serum 25(OH)D concentration is recognized as the best indicator of vitamin D status. Because serum 25(OH)D is affected by season, no single value in any given individual adequately captures his or her year-round average. Measurement of 25(OH) D is also sufficiently costly and invasive so as to be precluded in many epidemiologic studies involving large numbers of subjects. Finally, while vitamins D2 and D3 have to date been considered equivalent in potency (and both measured and used as a fortificant interchangeably), several studies indicate that vitamin D2 exhibits a potency that is from one-half to one-ninth that of vitamin D3 [30–33]. Calcium also presents serious difficulties to the investigator who would attempt to estimate its intake. Food calcium content often varies widely from published food table values − sometimes by a factor of two- to three-fold − reflecting variations in soil mineral content and plant tissue hydration (among other factors). Even commercial milk exhibits 10% to 20% variability from dairy to dairy or state to state. Charles [34] found, in a chemical analysis of foods consumed in a series of metabolic balance studies, that less than 70% of the actual variability in intake among a group of subjects was reflected in the calculated intakes derived from food table values for the foods consumed, despite the fact that the precise quantities of every food eaten were known with high accuracy. Outside of the metabolic ward environment, and particularly in epidemiologic studies, there is the added uncertainty of portion size estimation and food item recall. Large differences in bioavailability create further problems. The calcium of kale or collard greens is highly available [35], while that of spinach is nearly totally unavailable [36]. Thus actual intake and effective intake can differ substantially. Finally, there will be broad daily and seasonal variation in intake patterns. In this regard,

V.  EPIDEMIOLOGY OF OSTEOPOROSIS

Problems in the Investigation of Nutritional Effects on Bone

Heaney et al. [37] showed, in a large series of 7-day consecutive diet records, that any random day picked out of the total record captured only 12.6% of the interday variance, and that the error of an estimate of the 7-day average from any one of its days was ± 178 mg (which means that the 95% confidence interval covers a range of more than 700 mg!). The difficulty of estimating effective calcium intake is compounded by two further problems. First is the use of calcium salts as excipients or “inert” ingredients in many medications, or as non-nutritive additives to various bulk foods. In both cases their calcium content goes unrecognized, and often unacknowledged on the product label. Second is the increased use of explicit calcium supplements since 1982. This should not, of itself, create a problem for estimating calcium intake. However, many tablets in the past exhibited highly variable pharmaceutical formulations [38,39], and hence unpredictable absorbability. Excipient calcium will not often produce major errors in intake estimates unless food source intakes are low (in which case undocumented medication calcium can easily account for one-half the actual calcium intake); nevertheless Heaney et al. [37] reported several cases in which such unrecognized calcium contributed more than 1000 mg/day to the intake. In any event, both causes can lead to serious misclassification of individual intakes in observational or epidemiological studies, and therefore they will bias toward the null any investigation dependent upon intake estimates. An illustration of the effect of this bias is found in a meta-analysis by Heaney [40] of 28 studies in late postmenopausal women published between 1988 and 1992. Twenty-three of the 28 studies reported a positive effect of calcium intake on bone mass, bone loss, or fracture. However, when they were subdivided according to whether the investigators controlled the calcium intake directly, or relied on estimates of intake derived from questionnaires and food records, it turned out that all of the 12 studies in which investigators controlled the intake had demonstrated a significant calcium benefit, while all of the inconclusive studies had been those in which intake had been merely estimated. The difference is explainable by errors in intake estimates in the questionnaire-based studies. Magnitude of Nutrient–Nutrient Interactions It is a commonplace of nutritional science that nutrients interact, thereby altering one another’s requirements.2 Coingested nutrients alter both obligatory renal loss of calcium and intestinal absorption of calcium and phosphorus. While effects on absorption are comparatively 2RDAs

are designed, in theory, to be generous enough to ­accommodate this food-related variability in requirement.

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modest, effects on obligatory loss can alter the minimum daily requirement for calcium substantially. (These effects are covered in more detail later in this chapter.) For our purposes here, it is sufficient only to note that other nutrients, ingested within the normal range of human intakes, so alter ability to maintain calcium equilibrium as to produce a four-fold difference between the lowest and the highest values for the minimum requirement. This is a quite extraordinary range and is virtually without parallel among other nutrients. It is for this reason that it is usually misleading to make comparisons between populations which may differ not only in calcium intake, but in intakes of protein and sodium particularly, as well as in the proportion of animal and vegetable food sources in the customary diet. It is likely that much of the seeming differences in the relationship of calcium to bone status across populations [41] can be attributed to differences in minimum requirement related to nutrient-nutrient interactions, and much of the apparent confusion surrounding this topic, to failure to give adequate consideration to the influence of these interactions.

Bone-Specific Problems The Bone Remodeling Transient The bone remodeling transient is dealt with in greater depth in Chapter 72, as well as elsewhere [42,43]. It is important to mention it briefly in this context because, whenever bone remodeling is altered by an intervention (nutritional in this context), the changes in calcium balance or bone mass which follow will, for a period of 6 to 12 months, reflect, not the effects (if any) of the intervention on steady state bone balance, but shrinkage or expansion of the bone remodeling space caused by asynchrony of the changes produced in bone f­ormation and resorption. This is a particular problem for calcium, since c­ alcium alters endogenous PTH production, and PTH is the principal determinant of the amount of global skeletal remodeling. But any other nutrient (such as vitamin D or phosphorus), which also alters PTH production (whether directly or indirectly), may produce qualitatively similar effects. Thus the classical nutritional stratagem of measuring balance in individuals on differing intake levels for periods of up to a few weeks, then giving them a short rest period, then trying yet another intake for a few more weeks (and so forth), will not work for bone or its measurable surrogates. Unfortunately, there are no easy alternatives. Balance for nutrients that are bulk bone constituents can be assessed only under steady state conditions, and for calcium that means either studying persons on their habitual intakes, or deferring study for 6 to 12 months after altering intake of a given nutrient. Both

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options severely limit what the investigator can do to test various hypotheses involving nutrition and bone status. Isolation of Bulk Bone from Current Nutritional Influences Bone is very much a living tissue, with its cells responding both to systemic influences and to strain patterns within the bony structure. Nevertheless, the mechanical properties of bone reside mainly in the intercellular, nonliving, two-phase composite of fibrous protein and mineral. With the exception of use-related, accumulating fatigue damage, the inherent mechanical properties of this material are substantially determined at the time a unit of bone is formed. The entire skeleton is turned over at a rate of only 8% to 10% per year (and some regions much more slowly). Since it is the currently forming bone that will be most affected by current conditions, nutritional stresses have predictably small effects on total bone strength. The bulk of bone is, in effect, isolated from the systemic and environmental influences that can rapidly produce outspoken effects in soft tissues. This is not to say that there are no effects on bone. Bone cells, damaged by current nutritional problems, may die or otherwise fail in one or another of their monitoring functions. An example is seen with osteocyte death in radiation necrosis, which results in increased fracture risk without apparent change in bone mass or the mechanical properties of the intercellular bone material. But the effects of that failure may become evident only slowly, and they are, accordingly, extremely ­difficult to study. Slow Response Time of Bone A corollary of the slow turnover of bone tissue is that bone mass changes relatively slowly in response to nutritional influences, either positive or negative. A gain or loss of bone amounting to at most 1% to 2% per year is typically all that many interventions can produce in adults. Continued over many years, such a rate of change can have profound effects on skeletal strength, but it is a change that is hard to detect by absorptiometric methods (dual-energy X-ray absorptiometry (DXA)) in short-term investigations, and essentially impossible to detect reliably in individuals. While the gain or loss associated with a nutritional intervention may be real enough, its presence is dwarfed by the relatively huge mass of pre-existing bone, and its detection tends to be swamped by the inevitable noise of measurement. Balance studies can sensitively detect much smaller changes (since the background bone mass is not reflected in the balance value), but they are subject to the problem of the remodeling transient discussed earlier, and sufficient time must be allowed for the system to come into equilibrium if they are to be useful. Serum and urine biomarkers (see ­Chapter 67, Szulc) can sensitively signal

qualitative changes in bone remodeling processes, but they are not sufficiently quantitative for accurate estimation of the size of any change in bone balance which may have been produced by an intervention. Life Phase Specificity of Bony Response As will be developed in more detail below, the ­skeleton is the body’s reserve of the nutrient, calcium. It is the largest reserve of all the nutrients, and one that has acquired an unrelated function in its own right, that is, the mechanical support of our bodies (failure of which is the reason for this volume). While bone strength is clearly a direct function of bone mass (see Chapter 66), and any decrease in bone mass must have mechanical consequences, nevertheless reserves, of their nature, are designed to be called upon, and it should not be surprising to find physiological circumstances in which the reserve will reduce some of its mineral stores, not always because the diet is insufficient to offset excretory and dermal losses, but precisely because the physiological situation demands it, or because the body senses that some of the reserve is no longer needed. Lactation may be one such situation, and menopause another. In any event, nutritional interventions should be expected to produce qualitatively different effects when they are deployed under such differing physiologic circumstances. Comment This discussion of investigative problems is, of necessity, brief. The purpose has been to highlight the inherent difficulty involved in investigating problems at the interface of nutrition and bone status. Failure of bone biologists to recognize nutritional measurement problems and failure of nutritionists to reckon adequately with the complexities of bone biology will lead (and has led) to badly designed, inconclusive, or misleading investigations, as well as to misguided meta-analyses of studies of nutrientbased interventions. This is a problem not only for investigators, but for those who attempt to make sense of what they report. It is not that easy alternatives are being overlooked. Rather, there are no easy alternatives. But, while the problems are difficult, they are not intractable.

THE NOTION OF A NUTRIENT REQUIREMENT Nutritional science was born in the early years of the twentieth century with the then revolutionary recognition that the absence of something could produce disease.3 Once nutritional deficiency was accepted as the 3The

prevailing notion at the time was that all disease was caused by infections or intoxications − that is, by some noxious influence from outside the organism.

V.  EPIDEMIOLOGY OF OSTEOPOROSIS

The Natural Intake of Calcium and Vitamin D

cause of disease, the notion of a requirement centered on the intake needed to avoid the recognizable deficiency disease concerned. While the science of nutrition has advanced notably since its beginnings, particularly in understanding precisely what various nutrients do in the body, prevailing definitions of requirements are still often pegged to early 20th century ability to recognize and characterize disease. There is growing dissatisfaction with this disease-centered approach, but the main problem with the traditional approach to a requirement is not that it is negative (i.e., disease-centered) as that its definition of disease is primitive. It is centered on disorders that develop rapidly and have distinct clinical expression recognizable with the tools of 70+ years ago. However, a deficiency that takes 10 years to develop or to make its presence evident is no less a deficiency than one that develops in 10 days.4 Vitamin K deficiency, for example, produces a bleeding disorder, and this is the defining disease associated with the nutrient. Does absence of bleeding mean that vitamin K nutriture is adequate? We now recognize that vitamin K is necessary for gamma-carboxylation of a large number of proteins in addition to the clotting factors, three of them involved in bone matrix (see below, section “Vitamin K”). We also recognize that gammacarboxylation of these proteins can be very incomplete even when the clotting factors are normally carboxylated, and that physiological vitamin K supplementation completely repairs this deficit. It is not known whether this undercarboxylation expresses itself as disease, but our ignorance in that regard does not guarantee that the absence of clotting disturbance means vitamin K sufficiency. In what follows in this chapter a requirement will be defined as the intake that ensures full expression of known functions of the nutrient concerned, and it will be presumed that any substantial deviation from full physiological expression is harmful until proved safe (see also Chapter 72).

THE NATURAL INTAKE OF CALCIUM AND VITAMIN D It is now recognized that both calcium and vitamin D were present in superabundance in the environment in which the human species evolved. It seems likely that, over the millennia of evolution, human physiology developed mechanisms to protect the organism 4The

first clearly identified deficiency disease, beriberi, t­ ypically develops in from 30−90 days after onset of thiamin deprivation, and it responds to treatment with roughly equal speed. One can speculate whether nutritional science would have developed at all if its disease states had typically had long latency periods.

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from getting too much of these important nutrients. By contrast, contemporary adult humans, living in industrialized nations at higher latitudes, have inputs of these nutrients often only a small fraction of what their primitive ancestors experienced, and human physiology is, therefore, maladapted to what our environment ­currently provides. Vitamin D is produced normally in the skin by a photochemical reaction in which ultraviolet light from the sun changes 7-dehydrocholesterol into previtamin D. As the human species evolved in equatorial East Africa, with ample sunlight year round, two mechanisms coevolved that prevented accumulating an excess of vitamin D. One was skin pigmentation, which slowed the photochemical reaction, and the other was the fact that continued solar radiation degrades previtamin D to inert products before it is taken up into the circulating blood. As a result, vitamin D accumulation in the skin slows or plateaus after a few minutes of sun exposure, with the time varying with skin pigmentation. Circulating levels of 25(OH) vitamin D (25(OH)D) under early conditions can be estimated from values observed in dark skinned, outdoor laborers at tropical latitudes, which have been reported to be in the range of 150 nmol/L [30] or about four- to six-fold what is typically measured in city dwellers at mid-latitudes. A 2012 study of vitamin D status in Masai herders in East Africa revealed a mean of 119 nmol/L, with values ranging up to 171 nmol/L [44]. As humans moved farther and farther north (away from the equator), and needed all the ultraviolet they could get, skin pigmentation became lighter and lighter, not as a Lamarckian sort of inheritance, but because darkskinned individuals were more prone to rickets, which reduced fertility. Still, in latitudes such as that of Boston and farther north, the sun is so low in the sky in winter that effectively none of the responsible ultraviolet wave lengths get through the atmosphere, even on a sunny day [45]. As a result vitamin D tends to be a scarce nutrient at high latitudes, and without careful attention to maintaining adequacy, varying degrees of vitamin D deficiency will be common. Less than a century ago, more than 80% of the children in England showed evidence of rickets [46]. Thanks to nearly universal vitamin D prophylaxis in children, rickets is now a relatively rare disorder. Calcium, too, was present in abundance in the environment in which the human species evolved. The plant foods eaten by hunter-gatherers provided a calcium intake that, adjusted for differences in body size, would have been in the range of 2000 to 4000 mg/day for 60 to 70 kg adults [47,48]. (Contrast that figure with the median value for women aged 20 years and over in the US in the National Health and Nutrition Examination Survey (NHANES)-III study: in the order of 600 mg/day [49].) Sources available to our ancestors included a very large number of greens, tubers, roots, nuts, and berries, many of them with very

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high calcium nutrient densities [48]. Moreover, invertebrate and reptilian sources of animal protein typically have calcium-to-calorie ratios six-fold higher than fish or mammalian meats [50]. By contrast, cultivated cereal plants, legumes, and fruits − the plant foods modern humans mainly consume − exhibit augmented levels of carbohydrate and/or fat without a proportionate increase in minerals and vitamins; thus they almost always have lower calcium densities than do their wild cousins. The agricultural/pastoral revolution, which occurred from roughly 3000 to 10,000 years ago in various parts of the world, made it possible to feed vastly more people than the hunter-gatherer mode permitted. This was partly because of the increased energy content of polyploid cereal mutants (which occur spontaneously, but which, because of their greater seed weight, need human intervention for their efficient propagation). At the same time the agricultural revolution produced striking changes in micronutrient intake, generally for the worse. We see this reflected in modern times in the nutritional deficiencies which result when hunter-gatherers such as the !Kung San people are forced by restriction of their range to take up farming [51]. The effect of the agricultural/pastoral revolution on the calcium density of the diet is depicted in Figure 28.3. Diets of hunter-gatherers would have been in the range of 70 to 90 mg Ca/100 kCal (somewhat higher if invertebrate protein sources featured prominently in the diet). Those who then domesticated animals and lived mainly off their milk (as do all pastoralist societies today) would have had an increase in diet calcium density to perhaps as high as of 200 mg Ca/100 kCal. By contrast, those who settled on the land and subsisted mainly on cereal crops and legumes would, at least from these food sources alone, have had diets with calcium densities under 20 mg/100 kCal. While vegetable greens would have helped when available, calcium intakes based solely on cereals and legumes would probably not have been sufficient to Herding

Diet Ca density (mg/100 kcal)

200

Pastoral/agricultural revolution (c. 8500 B.C.) 150

100

50

High primates Human huntergatherers

5The

Farming 0

sustain bone health. However, there are numerous, wellattested examples of peoples living in stable equilibrium with their environments who have developed nonfood ways of augmenting the meager calcium intake provided by a diet based on seed foods. The addition of lime to corn meal by indigenous peoples in Central America is one well-known example. Less well known is the practice of pregnant Southeast Asian women of drinking a liquid produced by soaking bones in vinegar [52]. Andean Indians have been reported to add both a particular plant ash and a heat-treated rock powder to their cereal gruel [53]. And in most Neolithic communities, cereal grains were ground to flour in limestone mortars and querns, a practice that would have added appreciable quantities of calcium carbonate to the flour5 [54]. All of these practices, whether conscious or otherwise, augmented the calcium intake of a cereal-based diet. By the time of the Iron Age technology had advanced, and millstones were made of harder and harder rock (usually silicon- and aluminum-based rather than ­calcium-based minerals). Without the fortuitous addition of calcium from limestone implements, aggregate calcium intakes would have declined toward the lower line depicted in Figure 28.3. Thus, the low calcium intakes that we take for granted today are relatively late arrivals on the human diet scene. Because hominid and early human diets were very rich in calcium, the human intestine either failed to develop effective absorptive transport mechanisms or actually developed an absorptive barrier to protect against too much calcium. Neither did mechanisms to conserve absorbed calcium develop. (Presumably, there would be little need to conserve in the face of environmental ­surfeit.) Humans typically absorb only about 25% to 35% of the ­calcium in contemporary diets [55] and put about 150 mg/day back into the gut in the digestive secretions [56]. Thus, net absorption of a dietary calcium increment is usually in the range of 10% to 15%, even during much of growth when skeletal need is greatest [57]. Additionally, cutaneous losses are completely unregulated and renal conservation is weak as well. These are precisely the physiologic patterns one would expect with an environmentally abundant nutrient.6

Time

FIGURE 28.3  Changes in calcium concentration of the diet associated with the agricultural/pastoral revolution. Source: Copyright Robert P. Heaney, 1995. Used with permission.

addition of calcium carbonate to bread flour in the UK ­ uring and after World War II, and in Japan in the postwar d years, as well as the fortification of certain breads in the US with ­calcium sulfate, are but modern, conscious instances of what must have been an unwitting ancient practice. 6It is instructive to compare the body’s handling of calcium with that of sodium, which was an environmentally scarce ­nutrient ­during hominid evolution. By contrast with calcium, essentially 100% of dietary sodium is absorbed, and dermal and renal sodium losses can be reduced to near zero.

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Calcium

This is the background to why, despite a high standard of living, and the potential to nourish ourselves at a level never previously achieved in the history of the race, civilized diets tend to be deficient in precisely these two critical nutrients, calcium and vitamin D.

CALCIUM The Skeleton as a Nutrient Reserve Throughout the course of vertebrate evolution, bone developed several times and has served many functions, such as dermal armor and internal stiffening [58]. Evidence from a variety of lines suggests that the most primitive function of the skeleton is actually to buffer the internal milieu for several essential minerals, notably calcium and phosphorus [59]. In some species, phosphorus would have been the critical element; in others, calcium. For both nutrients, the skeleton serves both as a source and as a sink, that is, as a reserve to offset shortages and, to a limited extent, as a place for safely storing surpluses. We see this reserve feature of skeletal function expressed in diverse ways. For example, there is the long established fact that laboratory animals such as cats, rats, and dogs, placed on low calcium diets, will reduce bone mass as needed to maintain near constancy of calcium levels in the extracellular fluid [60–62]. This activity is mediated by PTH and involves actual bone destruction, not leaching of calcium from bone. When calciumdeprived animals are parathyroidectomized, bone is spared, but severe hypocalcemia develops [63]. More physiologically, perhaps, deer temporarily increase bone resorption each year to meet the mineral demands of annual antler formation (which exceed the nutrient ­supply of late winter and spring foliage) [64]. Finally, we see the opposite side of the same function expressed in the now well established fact that augmented calcium intake will slow or reduce age-related bone loss in humans (see below). While retaining this primitive, reserve function, bone in the higher, terrestrial vertebrates acquired a second role, namely internal stiffening and rigidity − what is today the most apparent feature of the skeleton. As such, calcium (or phosphorus) is the only nutrient with a reserve that possesses such a secondary function (with the possible exception of the thermal insulation provided by energy reserves). For typical nutrients, the reserve is first depleted, without detectable impact upon the health or functioning of the organism. Then, after the reserve is exhausted and the metabolic pool begins to be depleted, clinical disease expresses itself. For some nutrients (e.g., vitamin A or energy), the reserve can be quite large, and the latent period may last many months, but for others

653

(e.g., the water-soluble vitamins), the reserve may be very small and detectable dysfunction develops soon after intake drops. With calcium, the reserve is vast relative to the cellular and extracellular metabolic pools of calcium. As a result, dietary insufficiency virtually never impairs biochemical functions that are dependent upon calcium, at least in ways we now recognize. However, since bone strength is a function of bone mass, it follows inexorably that any decrease whatsoever in the size of the calcium reserve − any decrease in bone mass − will produce a corresponding decrease in bone strength. We literally walk about on our calcium reserve. It is this unique relationship which is both the basis for the linkage of calcium nutriture with bone mass and the explanation why reduction in the size of the reserve is a defining characteristic of the major human calcium deficiency syndrome.

Defining the Requirement for Calcium Unlike other nutrients, the requirement for calcium is currently based solely to this secondary function, that is, to the size of the calcium reserve, in other words, to total skeletal and regional bone mass. However, unlike energy, which can be stored as fat without practical limit, the size of the calcium reserve is limited, even in the face of dietary surfeit, by genetic and mechanical factors (see below). As a result, calcium functions as a threshold nutrient, much as does iron. This means that, below some critical value, the effect (bone mass for calcium or hemoglobin mass for iron) will be limited by available supplies, while above that value, that is, the “threshold”, no further benefit will accrue from additional intake. This biphasic relationship is depicted schematically in Figure 28.4, [65] in which the intake–effect relationship is depicted first schematically (A), and then (B) as exemplified by data derived from a growing animal model. In panel B the effect of the nutrient is expressed directly as the amount of bone calcium an animal is able to accumulate from any given intake. However, if “effect” is broadened to mean “any change whatsoever”, then the diagram fits all life stages, even when bone may be undergoing some degree of involution. This generalized form of the threshold diagram is presented in Figure 28.5, which shows schematically what the intake/retention curves look like during growth, maturity, and involution. In brief, the plateau occurs at a positive value during growth, at zero retention in the mature individual, and sometimes at a negative value in elderly people. (Available evidence suggests that there are probably several involutional curves, with the plateau during involution at a negative value in the first 3−5 years after menopause, at zero for the next ∼10 years, and then at increasingly negative values with advancing age.)

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28.  NUTRITION AND RISK FOR OSTEOPOROSIS

140

*

Femur Ca (mg)

120 Bone accumulation

*

100 80 60 40 20 0

Calcium intake

(A)

0

0.2

0.4

0.6

Calcium intake (diet pct.)

(B)

FIGURE 28.4  Threshold behavior of calcium intake. A. Theoretical relationship of bone accumulation to intake. Below a certain value − the threshold − bone accumulation is a linear function of intake (the ascending line); in other words, the amount of bone that can be accumulated is limited by the amount of calcium ingested. Above the threshold (the horizontal line), bone accumulation is limited by other factors, and is no longer related to changes in calcium intake. B. Actual data from two experiments in growing rats, showing how bone accumulation does, in fact, exhibit a threshold pattern. Source: redrawn from data in Forbes RM et al. [65]. Copyright Robert P. Heaney, 1992. Used with permission.

+

Retention

+

* *

Growth

Maturity

*

A Involution B −

−

(A)

Calcium intake

(B)

Calcium intake

FIGURE 28.5  A. Schematic calcium intake and retention curves for three life stages. Retention is greater than zero during growth, zero at ­maturity, and may be negative during involution. Asterisks represent minimum daily requirement. B. The involution curve only. Point B ­designates an intake below the maximal calcium retention threshold, whereas point A designates an intake above the threshold. Source: Copyright Robert P. Heaney, 1998. Used with permission.

In Figure 28.5B, which shows only the involutional curve, there are two points identified: one below (B) and one above (A) the threshold. At A, calcium retention is negative for reasons intrinsic to the skeleton, whereas at B, involutional effects are compounded by inadequate calcium intake, which makes the balance more negative than it needs to be. Point B (or below) is probably where most older adults in the industrialized nations would be situated today. The goal of calcium nutrition in this life stage is to move them to point A or above, thereby ­making certain that insufficient calcium intake is not aggravating any underlying bone loss. The functional indicator of nutritional adequacy for such a threshold nutrient is termed “maximal retention” and can be located in Figures 28.4A and 28.5A at the asterisks above the curves. The intake corresponding to this point represents the minimum daily requirement.

Calcium retention in this sense is “maximal” only in that further intake of calcium will produce no further retention. (This is in contrast to treatment with hormones or drugs, which can sometimes produce further calcium retention.) This approach was used by the Food and Nutrition Board of the Institute of Medicine (IOM) for the first time in its development of recommended intakes for calcium in 1997 [66]. There has been much uncertainty and confusion in recent years about what the threshold intake may be for various ages and physiological states. With the 1994 Consensus Development Conference on Optimal ­Calcium Intake [67] and the report of the Panel on ­Calcium and Related Nutrients [66], the bulk of that confusion has been resolved. The evidence for the intakes recommended by the consensus panel is summarized both in the Conference and Panel reports and in reviews

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Calcium

TABLE 28.1 Various Estimates of the Calcium Requirement in Women 1989 Age (years) RDAa NIHb

1997 DRIc 2011 RDA Balanced

1−5

800

800

–

700

1100

6−10

800

800−1200

960

1000

1100

11−24

1200

1200−1500

1560

1000–1300 1600

Pregnancy/ 1200 lactation

1200−1500

1200–1560 1000–1300 –

24−50/65

800

1000

1200

1000–1200 800−1000

≥ 65

800

1500

1440

1200

1500−1700

DRI: daily reference intake; NIH: National Institutes of Health; RDA: ­recommended daily allowance. a Chevalley et al. (1994) [74]. b  Recommendations for women as proposed by the Consensus Development Conference on Optimal Calcium Intake [67]. c  The so-called “adequate intakes” of the new DRI values, multiplied by a factor of 1.2× to convert them into RDA format [66]. d  Estimates derived from published balance studies [57].

of the relationship of nutrition and osteoporosis [40,68], and will be summarized only briefly in ensuing sections of this chapter. It is worth noting, however, that the recommendations of the Consensus Conference, while expressed in quantitative terms, were basically qualitative: contemporary calcium intakes in North America and Northern Europe, by both men and women, are too low for optimal bone health in Caucasian individuals. The most persuasive of the evidence leading to this conclusion came in the form of several randomized controlled trials showing both reduction in age-related bone loss and reduction in fractures following augmentation of prevailing calcium intakes [69–78]. But randomized controlled trials, at least as performed to date, are not well suited to dose ranging (largely because of the problem of the remodeling transient − see above). Hence, while the panel was convinced that prevailing intakes were too low, their recommended levels in several cases involved ranges, and were clearly prudential judgments, centered of necessity on intakes employed in the trials concerned. Table 28.1 sets forth the recommendations e­ merging from these various consensus processes. As can be seen, while the 1994 National Institutes of Health (NIH) ­recommendations are, for most ages, substantially higher than the 1989 recommended daily allowances (RDAs) [79], they are actually quite close both to values derivable both from available balance studies and to the 1997 recommendations of the IOM. An important qualifier of the concept of maximal calcium retention (and therefore of the threshold diagrams that employ it as the dependent variable) is the fact that it is limited to what can be measured by metabolic ­balance or absorptiometric methods, that is, bone

655

mass or change therein. Bone strength, as noted earlier, depends not only on bone mass but upon remodeling activity as well. The threshold concept works as well for remodeling as it does for mass, at least in theory. Unfortunately, no data currently exist which would permit construction of threshold diagrams using remodeling as the outcome variable. All that is known for certain is that an intake reducing remodeling to optimal levels would be higher than that required to produce maximal retention. As shown by McKane et al. [26], an intake of 2400 mg Ca/day was sufficient to reduce remodeling in postmenopausal women to premenopausal levels, but virtually no other studies bear on this important point. Thus, current calcium intake recommendations have to be understood as reflecting the average minimum daily requirement to ensure maximal calcium retention, not optimal bone strength.

The Requirement at Various Life Stages There have been in excess of 250 studies published relating calcium intake to bone status, summarized and reviewed elsewhere [68]. In those studies in which the investigators controlled calcium intake, essentially all showed that calcium intakes above the then prevailing RDAs conferred a bone benefit. Even among the observational studies, in which calcium intake was not investigator controlled and could only be estimated, about 80% were positive. There is, thus, an overwhelming mass of evidence establishing the importance both of calcium for bone and of ensuring intakes higher than prevailing levels or former recommendations. What cannot easily be determined from controlled trials (as has already been noted) is the precise location of the intake threshold, that is, the point where bony retention is maximal and bone remodeling reduced to the level needed solely for repair. The following sections focus on estimating the requirement for maximal calcium retention by age and ­physiological state. Growth The human skeleton at birth contains approximately 25 to 30 g of calcium and, in adult women, 1000 to 1200 g. All of this difference must come in by way of the diet. Further, unlike other structural nutrients such as protein, the amount of calcium retained is always substantially less than the amount ingested. This is because, as already noted, absorption efficiency is relatively low even during growth, and because calcium is lost daily through shed skin, nails, hair, and sweat, as well as in urine and nonreabsorbed digestive secretions. The gap between calcium intake and calcium retention is larger than is generally appreciated. In the adult with a modest but repairable skeletal deficiency, only about 4% to 8% of ingested calcium is retained. While retention efficiency is generally

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28.  NUTRITION AND RISK FOR OSTEOPOROSIS

higher during growth, even when bone accumulation is most rapid, less than half of the intake is actually retained − ranging from a high of 40% in term infants to 20% in young adults [57]. Even premature infants, with a permeable gut membrane and a relatively huge mineralization demand, exhibit net absorption of less than 60% [80], and cutaneous and urinary losses mean that they retain even less than that figure. This inefficient retention is not so much because ability to build bone is limited but because, as noted elsewhere, human physiology is optimized to prevent calcium intoxication, not to cope with chronic shortage. Aside from the obvious fact that one cannot store what one does not ingest, how does suboptimal calcium intake limit bone mass accumulation? Except in unusual circumstances, it is not through limiting bone deposition. In most animal experiments as well as human observations, low calcium intake probably does not limit the growth in bone length or breadth. This is because boneforming sites do not “see” the diet. They are exposed only to circulating levels of calcium, phosphorus, and the calciotrophic hormones, and even in the face of frank dietary calcium restriction, blood calcium levels change very little. An inadequate calcium intake does, however, result in a bone with a thinner cortex and fewer, thinner trabeculae. This comes about through modulation of the balance between the normal, ongoing processes of bone formation and bone resorption. To understand how dietary intake interacts with the modeling process, it is necessary to recall that bone reshapes itself continuously during growth. In growing long bones new bone is deposited at the periosteal surface of the mid shaft, at the endosteal surface of the submetaphyseal shaft, and at the growth plate. At the same time, bone is resorbed at the endosteal-trabecular surface and on the outer surface of the metaphyseal funnel. This process, termed “modeling” produces concentric expansion of both external shaft diameter and medullary cavity diameter. Modeling reshapes bones so that they conform to growth in body size. The difference between the amount deposited and the amount resorbed is equal to the net bone gain (or loss). When ingested calcium is less than optimal, the endosteal-trabecular resorptive process increases, and ­ the balance between formation and resorption, normally positive during growth, falls towards zero. This occurs because PTH augments bone resorption at the endostealtrabecular surface in order to sustain the level of ionized calcium in the extracellular fluid. When the demands of mineralization at the periosteum and growth plates exceed the amount of calcium absorbed from the diet and released from growth-related bone modeling, more PTH is secreted and resorption increases still further, until balance becomes zero or even negative. If calcium is the only limiting nutrient, it is usually considered that

growth in size continues normally, but that a limited quantity of mineral now has to be redistributed over an ever larger volume. This reciprocal relationship between calcium intake and bone resorption is beautifully illustrated in a study in adolescent girls, the data of which are depicted in Figure 28.6 [81]. It is especially noteworthy in this study that it was bone resorption and not mineral deposition that was affected by calcium intake. Usually children’s diets in western nations are not so calcium-deprived as to preclude entirely any increase in bone mass, but occasional instances of severe restriction have been reported. Then, high levels of PTH drive phosphorus levels in the extracellular fluid so low that mineralization is inhibited and a rachitic type of lesion develops [82,83], even though vitamin D status may be normal. In such circumstances, bone growth does slow.7 Short of such extreme situations, the principal perceptible effect of inadequate calcium intake during growth in developed countries is a skeleton of low mass − ­normally shaped and sized, but containing a smaller than normal amount of bone tissue. Having said that, it must be noted that there are at least two studies suggesting that augmented calcium intake may influence bone size as well as bone mass [84,85]. The first [84] is difficult to interpret because the supplementation included extra protein, phosphorus, 1800 Absorption Resorption

1600 Ca input to ECF (mg/day)

656

1400 1200 1000 800 600 400 200 0

850 mg

1900 mg Ca intake

FIGURE 28.6  Calcium input from intestinal absorption and bone resorption in adolescent girls studied at two calcium intakes. The rise in absorbed calcium at the higher intake produced a nearly identical fall in the amount of calcium released from bone. ECF: extracellular fluid. Source: Drawn from published data of Wastney et al. [81]. Copyright Robert P. Heaney, 2006. Used with permission. 7This issue is complicated by the fact that diets so severely d ­ eficient

in calcium are commonly inadequate on other grounds as well, for example, protein and calories. Consequently, the growth-stunting undoubtedly has multiple causes.

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Calcium

were assembled by Matkovic [87]. More recently Jackman et al. [88] studied a series of adolescent girls (each at two intakes, varying from subject to subject), and reported an intake threshold at very nearly the same level as found by Matkovic and Heaney in their metaanalysis [51]. Both approaches clearly show the plateau type of behavior that both animal studies and theoretical considerations predict. They also confirm that, at intakes less than the plateau threshold, daily storage is less than optimal, that is, accumulation of bone is being limited by intake. Any such limiting intake must be considered inadequate. Table 28.2 and Figure 28.8 summarize some of the relevant calculations flowing from the type of analysis of aggregated balance data exemplified in Figure 28.7 for various stages of growth [57]. First are the threshold intake values, as judged from the assembled balance studies. In some instances these values are slightly higher than both the NIH figures and current RDAs (Table 28.1), but in general the various estimates are 1000 800 Balance (mg/day)

and other key nutrients as well as calcium, but the second [84], with better matching of other nutrient intakes, also showed a small effect of extra calcium on both bone mass and stature. Most of the periosteal expansion and growth in length, and much of the endosteal expansion during growth, are genetically and mechanically determined. Studies in twins have shown that a large fraction of the variability in peak bone mass is accounted for by the genetic program [86] (see also Chapter 42). However, as already noted, endosteal expansion can be increased in the face of insufficient calcium intake beyond what would be dictated by the genetic program. Thus, while an abundant diet will not produce more bone than the genetic program calls for, a deficient diet must restrict what a growing individual is able to accumulate (see Fig. 28.4B). Optimal peak bone mass for any given individual can be defined as a skeleton in which the balance between the concentric expansions of growth is solely determined by the individual’s genetic program and is not reduced by an exogenous shortage of calcium. Correspondingly, optimal calcium intake can be operationally defined as the intake which permits this full expression of the genetic program. As just noted, net bone accumulation will be greater as calcium intake increases, but only to the point where endosteal-trabecular resorption is due solely to the genetic program governing growth, and is not being driven by body needs for calcium. Above that level, as seen in Figures 28.4 and 28.5, further increases in calcium intake will produce no further bony accumulation. The intake required to achieve the full genetic program, and thus to assure peak bone mass, is the intake that corresponds to the beginning of the plateau region in Figures 28.4 and 28.5. This value will be different for different stages of growth, in part because growth rates are not constant and also because, as body size increases, obligatory calcium losses through skin and excreta increase as well. The best approach to determine this value in humans lies, as with the laboratory animal, in testing various intakes for their influence on calcium retention, that is, finding the plateau and locating its threshold. (In healthy individuals calcium retention amounts to the same thing as bone tissue accumulation, since calcium is normally stored in the body only in the form of bone.) Over the past 75 years many such studies have been performed. When these reports are combined, it is possible to make out the pattern of plateau behavior found in laboratory animals and, from the aggregated data, to estimate the intake values that correspond to the threshold [57]. Figure 28.7 represents one example of the relationship between intake and retention, combining the results of many published studies of calcium balance. It is derived from a subset of the adolescents whose balances

600 400 200 0 −200 −400 0

500

1000 1500 2000 Intake (mg/day)

2500

3000

FIGURE 28.7  The relationship of calcium intake, on the horizontal axis, to calcium retention (balance), on the vertical axis, for a subset of the adolescents described by Matkovic and Heaney [57]. Note that, despite the “noisiness” that is inevitable in measurements of balance in humans, there is clear evidence of an intake plateau, as observed in the animal experiments of Fig, 28.4. Note also that, for this age, the threshold of the plateau occurs at about 1500 mg Ca/day. Source: Copyright Robert P. Heaney, 1992. Used with permission.

TABLE 28.2  Critical Values for Calcium Intake and Retention Efficiency, by Agea Age (years)

Intake threshold Subthreshold x-Axis intercept (mg/day) retention efficiencyb (mg/day)

0−1

1090

+0.407

13

2−8

1390

+0.238

183

9−17

1480

+0.356

320

18−30

957

+0.200

732

a  b 

Derived from analyses of published balance studies during growth [57]. Slope of the relationship of retention on intake.

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28.  NUTRITION AND RISK FOR OSTEOPOROSIS

600

Balance (mg/day)

Infants Adolescents 400

200

Children Young adults

0 0

500 1000 Calcium intake (mg/day)

1500

FIGURE 28.8  Regression lines for the subthreshold regions of the intake–balance relationships in infants, children, adolescents, and young adults, from the data of Matkovic and Heaney [57]. Source: Copyright Robert P. Heaney, 1992. Used with permission.

quite close to one another. Aside from the usefulness of these threshold values themselves, an especially notable feature of the data in Table 28.2 is that even after linear growth has ceased (i.e., in young adults), calcium retention still occurs if the intake is high enough to support it. In other words, bony consolidation can continue after growth in stature has ceased. For this reason, calcium intake in young adults needs to be sufficient not only to maintain skeletal equilibrium but to support this continuing augmentation of bone mass. Figure 28.8 shows, for the four age groups delineated in Table 28.2, the best-fit regression lines for the intake regions below the age-specific thresholds. This analysis of the data reveals a number of interesting features. First, although the slopes are qualitatively similar, there are nevertheless some important quantitative differences among the age groups. The ability to make use of an increment in calcium intake is greater in infancy and adolescence (i.e., the slope is larger) when skeletal growth is most rapid, and lower in childhood and the young adult years, when growth is slower, as would be expected. Perhaps of even greater interest is the rightward displacement of the regression lines in Figure 28.8 with advancing age. This phenomenon, reflected in the values in Table 28.2 for X-axis intercept, reflects the effect of age on obligatory loss. While zero balance (the X-axis intercept) is obviously not healthy for a growing organism, these zero-balance intake values are useful in that they reflect how much calcium an individual must ingest just to stay even (i.e., not to lose bone) at the ages concerned. As Figure 28.8 shows, infants can reduce calcium loss to nearly zero on zero calcium intake. For older children and young adults, it takes larger and larger calcium intakes to sustain even zero balance. Most of this effect is accounted for by a rise in urine calcium with age. It is probably body size that is forcing the higher obligatory requirement since, in a multiple regression model

of these data, body size continues to have an effect even after controlling for age [57]. At least 28 randomized controlled trials of calcium supplementation in children and adolescents have been published through 2005 (e.g., [72,73,85,88–90]), together with several longitudinal observational studies in young adults (e.g., [91]). All of the controlled trials were positive, as were three-quarters of the observational studies. As mentioned above, the bone remodeling transient contributes to the measured difference in these controlled trials. The relative size of its contribution remains uncertain; nevertheless, simulation of the remodeling transient indicates that the gain reported in these studies is greater than can be explained by that mechanism alone. In all studies, supplemental calcium elevated the children’s intakes above the 1989 RDA. The finding of greater bone gain in the supplemented children than in the control group underscores the inadequacy of the earlier RDA values. In other words, they indicate that the RDAs for 1989 and earlier lie on the ascending portion of the threshold curves of Figures 28.4 and 28.5, rather than on the plateau. Hence, these studies reinforce the higher requirement values shown in Table 28.2. Where post-trial follow-up data were obtained, most of these studies showed that some or all of the bone gained during supplementation was lost following cessation of the supplement. While some of this reversal is due to a negative remodeling transient, loss of benefit is to be expected for any nutrient on reversion from a state of adequacy to a state of deficiency. In one trial [87], a group of pubescent girls received approximately the 1989 RDA while the other group was held to a calcium intake of 450 mg/day (far less than the RDA but unfortunately not uncommon for girls of that age). As predicted, growth in stature was the same in both groups, but bone mass failed to increase in the low-intake group, while it did in the high-intake group. ­Matkovic et al. [92] had previously shown that intakes as low as 450 mg/day in adolescent girls did not support positive calcium balance, mainly because, despite intense skeletal demand at that life-stage, urinary conservation of calcium remained inefficient. While this third study does not specifically address the issue of what the intake requirement ought to be during adolescence, it does clearly document the deleterious effects of intakes well below the RDA. All of these intervention studies, as already noted, produce a remodeling transient. None was designed to evaluate steady-state changes, and hence their positive findings cannot be translated directly into a specific intake recommendation. However, the 4-year longitudinal study of young adults by Recker and his colleagues [91] involved no alteration of calcium intake and hence avoided the problem of the transient. This

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Calcium

study showed prospectively that bone augmentation continues well into the third decade. Bone mass gains in their subjects ranged from 0.5% per year for the forearm to 1.25% per year for total body bone mineral. The rate of accumulation was inversely proportional to age, with the best estimate of the age at which the rate reached zero being approximately 29 to 30 years. This suggests that the window of opportunity to achieve the full genetic program appears to remain at least partly open until about age 30 years. A follow-up, randomized controlled trial of calcium supplementation in young women of the same age showed continued bone accumulation in the third decade, but found no greater retention in the calcium supplemented group (at 2092 mg/day) than in the control group (at 824 mg/ day) [93]. Given the relatively high calcium intake in the control group, this trial had limited power to find an effect of additional calcium, particularly as many of the subjects would already have been at or above their ­personal thresholds. The importance of ensuring full realization of the genetic potential for skeletal development lies in the fact that bone mass seems to track throughout life. NewtonJohn and Morgan first noted this phenomenon in 1970 in cross-sectional data [94], and Matkovic et al. showed very clearly in their study of two Croatian populations [2] that those who had higher mass at age 30 year remained higher than the others out to age 75 years, even though both groups were apparently losing bone with age. The same phenomenon has been seen in shorter term, longitudinal studies [95–97], both across puberty and in the postmenopausal years. Dertina et al. [95] have gone so far as to suggest that those most at risk for late life osteoporosis can be detected before puberty. Maturity Once peak bone mass has been achieved, the principal force acting on the skeleton is no longer the impetus of growth, but the mechanical loads imposed in ordinary, everyday usage (see also Chapter 21). Skeletal structures, like all engineering structures, deform slightly under load (see Fig. 28.2). The skeleton senses that degree of deformation, and attempts to adjust its mass (by controlling the balance between bone resorption and bone formation) so that this deformation remains in the order of 0.1% to 0.15% in any given dimension (see also Chapters 21 and 22). If a bone is loaded so heavily that it consistently bends more than that amount, then the balance between local formation and resorption is adjusted to favor formation, thus making that region stiffer. And conversely if a bony segment is little used, and its bending is less than that critical amount, the s­ keleton senses that it has an excess of bone in the region concerned, and adjusts remodeling balance to remove some of the apparent surplus.

659

This reference level of bending is one of the fascinating physiological constants of nature. Across the vertebrates, for all species and all bones studied to date, bone mass is regulated such that any given bone deforms by about that critical 0.1% to 0.15% in ordinary use. This reference level of bending is termed a set-point, and the bone remodeling apparatus operates to minimize local deviations from this critical value. The cellular basis for the set-point and the precise nature of the apparatus which detects departures from it remain unknown;8 however, there is suggestive evidence that localizes this sensing apparatus to the network of osteocytes embedded in bone. For several years it has seemed likely that one of the principal determinants of the set-point of this mass-regulating system is the level of gonadal hormones. Circumstantial evidence in support of this connection includes the facts that estrogen receptors in bone are concentrated in osteocytes [98], and that true bone density rises sharply at puberty [99] and declines by about the same amount at menopause (whether natural or artificial) [100]. These life-phase changes are what one would expect if estrogen influences the set-point.9 While adjustments in mass around the set-point presume an adequate calcium intake, it turns out that prevailing intakes tend to be closer to adequate during the ages 25 to 50 years in women, since estrogen improves the efficiency of intestinal calcium absorption [55,100] and of renal calcium conservation [101,102]. Thus estrogen not only increases the reference level of bone density but it helps the body access and retain the mineral necessary to augment bone to that higher level. For this reason, except for the special circumstances of pregnancy and lactation (discussed below), the years from 25 to 50 are a time in life when a woman’s skeletal calcium need is at its lowest. She is no longer storing calcium, and her absorption and retention are operating at their adult peak efficiency. Welten et al. [103] in a meta-analysis of 33 studies performed on adults between 18 and 50 years of age, found a positive association between calcium intake and bone mass in this age group, and noted that it seemed prudent to maintain an intake of 1500 mg/day during this life period. This is a higher figure than either the NIH recommendations or the 1997 RDAs of Table 28.1. Heaney et al. [101], using balance methods in estrogenreplete women ingesting their habitual calcium intakes, found a mean intake for zero balance of slightly under 8Bone

is not unique in this regard: the molecular basis for the setpoint in most biological feedback systems is not known. 9The same level of bending sensed as tolerable in an ­estrogen-deprived state lies above the reference level when ­estrogen is present (and the setpoint is lower). The bone ­remodeling apparatus responds by adding bone to reduce the size of the difference from the reference level of bending.

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1000 mg/day, and Nordin et al. [104], also using balance methods, arrived at a figure slightly above 800 mg/day. Recker et al. [105], in a small prospective study of bone mass in premenopausal women, found no detectable bone loss over a 2-year period on an estimated mean calcium intake of 651 mg. Baran et al. [106], studying women in their fifth decade, found bone loss in a control group receiving 892 mg Ca/day. Loss occurred only from year 2 to year 3, and not during the first 2 years of observation, and it is not clear from that paper whether the apparent loss in year 3 was related to the loss of sampling units which occurred between years 2 and 3, or whether there was actual loss in those who remained in study. Requirement estimates based on balance studies make no provision for sweat loss of calcium since, by design, balance methods usually eliminate vigorous exercise. The importance of sweat loss has been highlighted by a study in male college athletes showing sweat calcium losses of over 200 mg in a single vigorous workout ­session [107]. Moreover, there was a perceptible loss of BMD across a playing season that was preventable by adding calcium supplements to the athletes’ already good diets. It is likely that the lost bone would have been regained after the playing season was over (so long as the diet was adequate), that is, that the skeleton was acting in its capacity as a calcium reserve during the playing season. Nevertheless, the study makes clear how large and important sweat losses can be. Undoubtedly such losses contribute to the low bone mass described in women athletes who often have less than generous calcium intakes. In conclusion, the bulk of the available evidence suggests that it is important to maintain an intake of 1000−1500 mg/day during the mature years. Moreover, there are other health reasons for maintaining a high calcium intake during this period [108], even if bone health can be supported adequately by an intake in the range of 800 to 1000 mg/day. Pregnancy and Lactation Pregnancy and lactation are circumstances in which the mother must provide for maintenance of her own skeleton as well as for construction of her child’s. Specifically, during the 9 months of pregnancy, she provides the fetus with 25 to 30 g of calcium, and in her milk during the ensuing 9 months of lactation, another 50 to 75 g. This aggregate is in the range of 7% to 10% of her own total body calcium and would, presumably, produce a corresponding decrease in bone mass if she were not able to obtain some or all of the required quantities from ingested calcium. It has always seemed intuitively attractive, therefore, to recommend an increased calcium intake during these physiologically demanding life stages [79] (see also Table 28.1). Moreover, given the

relatively low calcium intakes of modern industrialized societies, it might be expected that a history of multiparity and extended lactation would be associated with lower bone mass and increased risk of osteoporosis. In general, however, epidemiological studies have found, if anything, the contrary. Most studies report a positive association between parity and bone mass/density [109–114], although occasional reports of negative associations can be found [115]. Much of the positive association is due to increased ponderosity, and after correcting for weight, the positive correlations tend to become statistically nonsignificant. Nevertheless, most are still on the positive side, and there is little or no hint in the available evidence that the calcium drain of pregnancy and lactation adversely affects the maternal skeleton. Bone remodeling accelerates in pregnancy [116–121], and maternal intestinal calcium absorption efficiency increases to the highest level since early infancy. Both changes begin well before significant fetal skeletal accumulation of calcium [116,122]. Both humans and rats show anticipatory storage of skeletal minerals prior to onset of fetal skeletal mineralization [114,116], and Heaney and Skillman [116] estimated, from balance studies in pregnant women studied on their habitual calcium intakes, that cumulative calcium balance at term exceeded fetal needs, and that the mother, therefore, went into lactation with a skeletal surplus. Brommage and Baxter [117] reported data consistent with a skeletal surplus in rats at delivery, and ultrasound methods suggest that the same occurs in pregnant mares [118]. However, this will not be possible if calcium intake is very low. Barger-Lux et al. [123] reported bone loss across pregnancy in young women with dietary calcium to protein ratios averaging 6.6 mg/g. During lactation the majority of reports indicate that some degree of bone loss regularly occurs [108,109, 112–115,119,120,124–127], particularly in presumably reactive bony sites such as the centers of the vertebral bodies and the ultra-distal radius [124,125]. In contrast, this loss appears to reverse after weaning, and may, therefore, represent to some extent a negative remodeling transient like what occurs in deer at the time of antler formation [64]. Immediately following delivery, absorption efficiency falls to or toward nonpregnant, nonlactating levels and remains at this relatively low level throughout lactation, despite the continuing drain of lactational calcium loss [116,120,128]; however, urinary calcium falls at the same time and remains low throughout lactation and for several months postweaning [119], while bone remodeling remains elevated [119,120]. This is a physiological situation conducive to replacement of lost bone.10 10The importance of urinary loss for balance is discussed below: “Nutritional Factors that Influence the Requirement.”

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Calcium

Lactating rats lose nearly one-third of their skeleton during milk production [126]. This loss doubles if the animals are placed on low calcium diets, but it does not diminish when the normally high calcium diet of a rat is increased as much as three-fold [126]. It is likely that this bone loss represents an anticipatory phenomenon, that is, rather than the calcium being drawn out of bone by the drain of lactation, the bone pumps calcium into the circulation for milk production. This is suggested by the reduced PTH levels during lactation [129], by the usually reported failure of increased calcium intake to reduce the loss, and by the high serum phosphorus levels during lactation.11 How this outpouring of skeletal mineral for the benefit of lactation occurs is less clear, although it is certainly plausible that the hypoestrin state of lactation would, like menopause or athletic amenorrhea, shift the bone set-point, and result in some downward reduction in bone density (thereby, effectively, releasing stored calcium and phosphorus). High maternal concentrations of parathyroid hormone-related protein (PTHrP) during lactation may also contribute to rapid bone turnover and mobilization of calcium from the maternal skeleton [130] (see also Chapter 30). While Kalkwarf et al. [131] found no effect of calcium supplementation, a few reports suggest that even the modest reductions in bone mass normally found during human lactation can be reduced or eliminated by extra calcium [124,125]. The relatively slow growth of human infants (e.g., in comparison with rats) imposes a lower lactational burden on a human mother, and some of the differences between species may be attributable to quite significant differences in lactational demands for mineral. Given the concordance of the balance data and the epidemiological evidence, it seems likely either that adaptive mechanisms are usually sufficient to accommodate the calcium demands of pregnancy and lactation or that postweaning adjustments compensate for whatever bone may have been lost. As it turns out, there is ­physiological evidence to indicate that both occur. Compensatory physiologic adjustments surrounding pregnancy and lactation are more vigorous than at other life stages, and the current consensus is that a high calcium intake makes less long-term difference to a woman’s skeleton at this life stage than at most other times in her life. In summarizing the available literature, the panel responsible for the 1997 RDAs noted that there was no evidence on which to base a recommendation 11In

this latter respect, phosphate is as necessary for milk ­ roduction as is calcium, and high serum phosphate levels serve p that important purpose. The contrary causal flow, that is, lactation pulling calcium out of bone, would work against the lactational need for phosphorus, since PTH, mediating the response to all calcium needs, lowers serum phosphorus.

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for a higher calcium intake during pregnancy and lactation than that considered optimal for other women of the same age. They did add, however, that the situation with adolescent pregnancy was problematic and inadequately studied, and that perhaps some increment above the adolescent recommendation in such individuals might be prudent. Menopause It has been noted already that estrogen seems to adjust the bending set-point of bone. Accordingly, whenever women lose ovarian hormones, either naturally at menopause or earlier as a result of anorexia nervosa or athletic amenorrhea, the skeleton seems to sense that it has more bone than it needs, and hence allows resorption to carry away more bone than formation replaces. (Precisely the same change occurs when men lose testosterone for any reason.) This is equivalent to raising the bone bending set-point, as described above. While varying somewhat from site-to-site across the skeleton, the downward adjustment in bone mass due to gonadal hormone lack amounts to approximately 10% to 15% of the bone a woman had in the lumbar spine and ∼6% at the total hip prior to menopause [100]. The importance of this phenomenon in a discussion of nutrient effects is to help distinguish menopausal bone loss from nutrient deficiency loss and to stress that menopausal loss, which is due to absence of gonadal hormones, not to nutrient deficiency, cannot be readily influenced by diet. Almost all of the published studies of calcium supplementation within 5 years following menopause failed to prevent bone loss [69,132,133]. Even Elders et al., who employed a calcium intake in excess of 3000 mg/day, succeeded only in slowing menopausal loss, not in preventing it [133]. However, Dutch women tend to be calcium-replete, because of high national dairy product consumption, and other studies have shown effects of calcium supplementation in the early menopausal years that are intermediate between placebo and estrogen [78,132,133]. It is likely that, in any group of early menopausal women, there are some whose calcium intake is so inadequate that they are losing bone for two reasons (estrogen lack plus calcium insufficiency). Important as menopausal bone loss is, it is only a one-time, downward adjustment, and, if nutrition is adequate, the loss continues for only a few years, after which the skeleton comes into a new steady state (although at a 5−15% lower bone mass). It is in this context that the importance of a high peak skeletal mass becomes apparent. One standard deviation for lumbar spine bone mineral content in normal women is about 10% to 15% of the young adult mean, and for total body bone mineral, about 12%. Hence a woman at or above one standard deviation above the mean can sustain the 15% menopausal loss and still end up with as much

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bone as the average woman has before menopause. By contrast, a woman at or under one standard deviation below the young adult mean premenopausally drops to two standard deviations below the mean as she crosses menopause and is therefore, by the World Health Organization (WHO) criteria [134], already osteopenic and verging on frankly osteoporotic. As noted, the menopausal bone mass adjustment amounts to a loss at the spine of 10% to 15%, and at the hip, ∼6% [135]. Hip bone change, both immediately before and after this menopausal downward adjustment, averages about −0.5% a year, while, except for the menopausal loss, the spine curve is flat. But this is so only so long as calcium intake is adequate. In this regard, it is important to recall the nonskeletal effects of estrogen, described above, that is, improvement of intestinal absorption and renal conservation [55,101,102]. Because of these effects, an estrogen-deficient woman has a higher calcium requirement, and unless she raises her calcium intake after menopause, she will continue to lose bone after the estrogen-dependent quantum has been lost, even if the same diet would have been adequate to maintain her skeleton before menopause. In other words, early in the menopausal period, her bone loss is mainly (or entirely) because of estrogen withdrawal, while later it is because of inadequate calcium intake. Figure 28.9 assembles, schematically, the set of factors contributing to bone loss in the postmenopausal period. The figure shows both the self-limiting character of the loss due to estrogen deficiency and the usually slower, but continuing loss due to nutritional deficiency, when present. Unlike the estrogen-related loss which mostly plays itself out in 3 to 6 years, an ongoing calcium deficiency loss will continue to deplete the skeleton

Lumbar spine calcium (g)

1100 1000 900

Estrogen deficiency 15%

800

Disuse/entropy 6% Ca and vitamin D deficiency 16%

700 600

indefinitely for the remainder of a woman’s life, that is, unless calcium intake is raised to a level sufficient to stop it. Furthermore, since both absorption efficiency [55] and calcium intake [48] decline with age, the degree of calcium shortfall typically worsens with age. Thus it is important for a woman to increase her calcium intake after menopause, even though, for the first few years, doing so will not prevent estrogen-withdrawal bone loss. Both the 1984 NIH consensus conference on osteoporosis [136], and the 1994 Consensus Conference on Optimal Calcium Intake [67] recommended intakes of 1500 mg/day for estrogen-deprived postmenopausal women. It may be that the optimal intake is somewhat higher still (see below), but median intakes in the US for women of this age are in the range of 500 to 600 mg/day [49], and if the bulk of them could be raised even to 1500 mg/day, the impact on skeletal health would be considerable. Senescence There is general agreement that bone is lost with aging. Early cross-sectional data had suggested that spine loss began as early as age 30 to 35 years, but, except for the hip, longitudinal studies have not borne that out for most skeletal regions (e.g., spine, forearm) [105]. Significant loss at these sites probably does not begin until sometime in the sixth or seventh decade.12 This age-related bone loss occurs in both sexes, regardless of gonadal hormone levels. However, it is obscured at the commonly measured spine site in the years immediately following menopause in women by the substantially larger effect of estrogen withdrawal (see Fig. 28.9). It probably occurs, however, even in estrogen-treated women, at about the same rate as in men. This rate varies by skeletal region and is generally reported to be in the order of 0.5% to 1.0% per year by the seventh decade, and accelerates with advancing age. Age-related loss involves both cortical and trabecular bone and can be due to several causes. These include disuse atrophy consequent upon reduced physical activity, an entropic kind of loss due to accumulation of random remodeling errors which, of their nature tend to be irreversible,13 reduction in androgenic steroid levels, and finally nutritional deficiency loss. These types of bone loss are summarized in Figure 28.9.

12For

0

5

10

15

20

Time menopausal (years)

FIGURE 28.9  Partition of age-related bone loss in a typical postmenopausal woman with an inadequate calcium intake. Based upon a model described in detail elsewhere [100]. Source: Copyright Robert P. Heaney, 1990. Used with permission.

certain bony regions density (BMD) may begin to decline earlier [137], but in most such instances there is a countervailing periosteal expansion, such that total regional bone mass remains constant and bone strength is, if anything, greater. 13Examples include over-large Haversian cavities, fenestrated ­trabecular plates, and severed trabecular spicules which, once disconnected, become unloaded and hence are subject to rapid resorption [138].

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Calcium

While nutrient deficiency is clearly only a part of the problem, nevertheless it is common. Intestinal calcium absorption efficiency declines with age [55], at the same time as nutrient intake itself generally declines [49]; the result is that the diet of aging individuals becomes doubly inadequate. This inadequacy is clearly expressed, for example, in the rate of bone loss reported by Chapuy et al. [70] in the untreated control group of their large randomized trial of calcium and vitamin D supplementation. These women, with an average age of 84 years and with calcium intakes that averaged 514 mg/day, were losing bone from the femur at rates of slightly more than 3% per year. That there was a causal connection between intake and bone loss is demonstrated by the fact that the loss was completely obliterated with calcium (and vitamin D) supplementation. It is in this age group that the most dramatic and persuasive evidence for the importance of a high calcium intake has been produced in recent years. This is primarily because most fragility fractures rise in frequency with age, and hence the opportunity to see a fracture benefit (if one exists) is greater then.14 Chapuy et al. [70] showed a reduction in hip fracture risk of 43% by 18 months after starting supplementation with calcium and v ­ itamin D, and a 32% reduction in other extremity fractures. ­Dawson-Hughes et al. [69], in another controlled trial, showed a 55% reduction in nonvertebral fractures, using 500 mg Ca and 700 international units (IU) vitamin D in a mixed group of older men and women. In another study in elderly women, Chevalley et al. [74], resolved the question left unanswered in the study of Chapuy et al. (whether it was the calcium or the vitamin D which was responsible for the effect) by giving vitamin D to both controls and treated subjects, but calcium only to the treated group. They, too, found a reduction in femoral bone loss and in fracture incidence (vertebral in this case) in the calcium supplemented women. Recker et al. [75] in a 4-year, randomized controlled trial in elderly women (mean age 73 years), showed that a calcium supplement reduced both age-related bone loss and ­incident vertebral fractures. Their subjects had all received a multivitamin supplement containing 400 IU of vitamin D; hence most or all of the effect in the ­calcium-supplemented group can be attributed to the calcium alone. The studies of Chevalley et al. [74] and Recker et al. [75] should not be interpreted to mean that vitamin D is unimportant in this age group. It is now virtually certain that intakes of both calcium and vitamin D are inadequate in many elderly individuals (see below), and the 14Reduction in bone loss is only presumptively beneficial. Until it can be shown that fracture incidence is reduced, bone mass effects are less persuasive, and despite the abundant theo­retical ­underpinnings of why bone mass should be important, only fracture reduction is ultimately convincing.

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high prevalence of combined deficiency has complicated study of the actual requirements of either nutrient in this age group. The importance of these studies lies in the fact that, even after insuring vitamin D repletion, there was still a calcium benefit, and hence presumptively calcium deficiency in this age group. Heikinheimo et al. [139] had earlier shown the converse in an elderly Finnish population. Vitamin D supplementation in this population (which tends to be calcium replete) significantly reduced all fractures, both in institutionalized and in free-living individuals. The calcium intake achieved in the Chapuy study was about 1700 mg/day, in the Chevalley study was 1400 mg/day, and in the Recker study was about 1600 mg/day. These values are in the range of the intake found by Heaney et al. [101,140] to be the mean requirement for healthy estrogen-deprived older women (1500−1700 mg/day). All these studies are, therefore, fully c­ onsistent with a recommendation in the range of 1500 mg/day (Table 28.1). An important feature of these controlled trials in already elderly individuals was that bone mass was low in both treated and control groups at the start of the study, and while a significant difference in fracture rate was produced by calcium supplementation, even the supplemented groups would have to be considered as having an unacceptably high fracture rate. What these studies do not establish is how much lower the fracture rate might have been if a high calcium intake had been provided for the preceding 20 to 30 years of these w ­ omen’s lives. The studies of Matkovic et al. [4] and Holbrook et al. [141], although not randomized trials, strongly suggest that the effect may be larger than has been found with treatment started in the eighth and ninth decades of life. Both of these observational studies reported a hip fracture rate that was roughly 60% lower in elderly people whose habitual calcium intakes had been high. While findings from observational studies such as these had not been considered persuasive in the absence of proof from controlled trials, the trials with fracture endpoints have now met that need. This is another instance of the point made in Chapter 75 that, when applied appropriately, the data of observational studies and of controlled trials can complement one another in useful ways. Additional reinforcement comes from McKane et al. [26], who studied the effect of a large calcium supplement on PTH secretory dynamics in elderly women. In brief, a mean calcium intake of 2413 mg/day lowered PTH levels 40%, to the young normal range, and normalized the abnormal PTH secretory dynamics typical of the elderly female. They concluded that the combination of declining oral calcium intake, deteriorating ­vitamin D status, reduced calcium absorption, and impaired renal conservation of calcium in elderly people leads

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to parathyroid gland hyperactivity and increased bone resorption. Together the aggregate of available studies underscores the importance of achieving at least the 1400 to 1500 mg target figure for elderly people. At the same time it must be stressed, once again, that osteoporosis is a multifactorial condition, and that removing one of these factors (i.e., insuring an adequate calcium intake) cannot be expected to eradicate all osteoporotic fractures.

Nutritional Factors that Influence the Requirement There are several nutritional factors that influence, or have been proposed to influence, calcium requirement. The principal interacting nutrients are sodium, protein, caffeine, and fiber. Fiber and caffeine influence calcium absorption [142–144] and typically exert relatively minor effects, while sodium and protein influence ­ urinary excretion of calcium [142,143], and can be of much greater significance for the calcium economy. Protein, in addition, is important for sustaining the bone formation phase of bone remodeling. Phosphorus and fat are sometimes mentioned in connection with calcium absorption, but their effect in humans seems minor to nonexistent. The basis for the importance of nutrients acting on absorption and excretion is illustrated in Figure 28.10, which partitions the variance in calcium balance observed in 560 balances in healthy middle-aged women studied in the author’s laboratory. As Figure 28.10 shows, only 11% of the variance in balance among these women is explained by differences in their calcium intakes, and absorption efficiency explains only another 15%. By contrast, urinary losses explain slightly more than 50% [15].15 The dominance in Figure 28.10 of renal Urine 51%

Intake 11% EFCa 23%

Absorption 15%

FIGURE 28.10  Partition of variance in calcium balance in normal women among the input–output processes involved in calculation of balance. EFCa: endogenous fecal calcium. Source: Copyright Robert P. Heaney, 1994. Used with ­permission. 15I

have already remarked upon the importance of urinary ­calcium loss in the context of the declining retention efficiency with age in growing children, and have noted that the drop in urine calcium during lactation and postweaning helps to ­compensate for lactational demands.

excretion would be trivial in primary bone-losing syndromes, but it is particularly noteworthy that it appears to be operative in conditions of health, for it means that obligatory losses through the kidney pull calcium out of the ­skeleton [145,146]. Influences on Intestinal Absorption of Calcium FIBER

The effect of fiber is variable, and generally small. In acute, single-meal absorption tests, many kinds of fiber have no influence at all on absorption, such as the fiber in green, leafy vegetables [36,40]. Moreover, fibers of the class termed nondigestible oligosaccharides such as lactulose and dextrins, rather than interfering with absorption, have been shown in rats to increase both mucosal mass and calcium absorption [147], and there are reports in humans suggesting a similar effect, at least on absorption [148–150]. The current theory is that volatile fatty acids produced in fermentation of the NDOs by colonic flora evoke gut hormone responses that regulate mucosal mass (thereby serving to match the metabolic cost of replacing the mucosa every 5 days to the level of food intake). The fiber in wheat bran, by contrast, reduces absorption of coingested calcium in single-meal tests, although except for extremes of fiber intake [151], the antiabsorptive effect is generally relatively small. Often considered together with fiber are associated food constituents such as phytate and oxalate, both of which can reduce the availability of any calcium contained in the same food. For example, for equal ingested loads, the calcium of beans is only about half as available as the calcium of milk [152], while the calcium of spinach and rhubarb is nearly totally unavailable [36,153]. For spinach and rhubarb, the inhibition is mostly due to oxalate. For common beans, phytate is responsible for about half the interference, and oxalate, the other half. The effects of phytate and oxalate are highly variable. There is a sufficient quantity of both antiabsorbers in beans to complex all the calcium also present, and yet their combined absorptive interference is only half what might have been predicted. With the exception of bran, these interferences generally operate only on calcium contained in the same food. This is because the antiabsorber is usually already fully complexed with calcium in the ingested food. Thus, spinach does not typically interfere with absorption of coingested milk calcium. CAFFEINE

Often considered to have a deleterious effect on the calcium economy, caffeine actually has the smallest effect of the known interacting nutrients. A single cup of brewed coffee causes deterioration in calcium balance of ∼3 mg [143,144,154], mainly by reducing absorption of

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Calcium

calcium [143]. The effect is probably on active transport, although this is not known for certain. This effect is so small as to be more than adequately offset by a tablespoon or two (about 17–34 mL) of milk [143,154]; and café au lait or caffe latte produce a substantial net calcium gain, despite their caffeine content. FAT

Fat also has sometimes been presumed to reduce calcium absorption by a similar mechanism, that is, formation of calcium soaps with unesterified fatty acids released in the chyme by intestinal lipases. However, in healthy adult humans no appreciable effect of fat intake on calcium absorption has been found. This is at least partly explained, as with phosphorus (see below), by the fact that the normal small intestine absorbs fat much more avidly than it does calcium. At intakes in the range of recommended levels, the feces contain a considerable stoichiometric excess of calcium relative to fatty acids. Influences on Renal Conservation of Calcium PROTEIN AND SODIUM

As noted, the effects of protein and of sodium can be substantial [17,18,144,155]. Both nutrients have been reported to increase urinary calcium loss across the full range of their own intakes, from very low to very high − so it is not a question of harmful effects of an excess of these nutrients (but see below, section “Protein”). Sodium and calcium share the same transport system in the proximal tubule, and every 2300 mg sodium excreted by the k ­ idney pulls 20 to 60 mg of calcium out with it. Every gram of protein metabolized in adults may cause an increment in urine calcium loss of about 1 mg [16].16 This latter effect is believed to be due to excretion of the sulfate load produced in the metabolism of ­ sulfur-containing amino acids (and is thus a kind of endogenous analog of the acid-rain problem). At low sodium and protein intakes, the minimum calcium requirement for skeletal m ­ aintenance for an adult female may be as little as 450 mg/day [145], whereas if her intake of both nutrients is high, she may require as much as 2000 mg/day to maintain calcium balance. A forceful illustration of the importance of sodium intake is provided by the report of Matkovic et al. [92] that urine calcium remains high in adolescent girls on calcium intakes too low to permit bone gain. The principal determinant of urinary calcium in such young women is sodium intake [156], not ­calcium intake. 16This protein effect would be predicted to be less during growth, and particularly when growth is rapid, as in infancy. Then, much of the ingested protein is incorporated into tissue, while in adults, with no net tissue gain, protein catabolism matches protein intake.

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Differences in protein and sodium intake from one national group to another may be part of the explanation of why studies in different countries have shown sometimes strikingly different calcium requirements [41]. At the same time, one usually finds a positive correlation between calcium intake and bone mass within the national range of intakes [157]. Hence, while sodium (and protein) intake differences across cultures may obscure the calcium effect, they do not obliterate it. The acid/alkaline ash characteristic of the diet is also important, although the quantitative relationship of this diet feature to the calcium requirement is less completely developed. Nevertheless, it has clearly been shown that substitution of metabolizable anions (e.g., bicarbonate or acetate) for fixed anions (e.g., chloride) in various test diets will lower obligatory urinary calcium loss substantially [158,159]. This suggests that primarily vegetarian diets create a lower calcium requirement, and provides a further explanation for the seemingly lower requirement in many nonindustrialized populations. However, it is not yet clear whether, within a population, vegetarians have higher bone mass values than omnivores [160], and such limited data as are available suggest, in fact, the contrary [161–163]. PHOSPHORUS

Phosphorus is commonly believed to reduce calcium absorption, but the evidence for that effect is scant to nonexistent, and there is much contrary evidence. Spencer showed no effect of even large increments in phosphate intake on overall calcium balance at low, normal, and high intakes of calcium [164]. In adults, Ca:P ratios ranging from 0.2 to above 2.0 are without effect on calcium balance when studied under metabolic balance conditions and adjustments are made for calcium intake [144]. Still phosphorus intake is not without effect on the calcium economy. It depresses urinary calcium loss and elevates digestive juice secretion of calcium, by approximately equal amounts (which is why there is no net effect on balance [56,155]). While it is true that stoichiometric excesses of phosphate will tend to form complexes with calcium in the chyme, various calcium phosphate salts have been shown to exhibit absorbability similar to other calcium salts [165], and phosphate is, of course, a principal anion of the major food source of calcium (dairy products). In any case, phosphate itself is more readily absorbed than calcium (by a factor of at least two- to three-fold), and at intakes of both nutrients in the range of their respective DRIs, absorption will leave a stoichiometric excess of calcium in the ileum, not the other way about. This explains the seeming paradox that high calcium intakes can block phosphate absorption (as in management of end-stage renal disease), while achievably high phosphate intakes have little or no effect on calcium absorption.

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ALUMINUM

Although not in any sense a nutrient, aluminum, in the form of aluminum-containing antacids, also exerts significant effects on obligatory calcium loss in the urine [166]. By binding phosphate in the gut, these substances reduce phosphate absorption, lower integrated 24-hour serum phosphate levels, and thereby elevate urinary calcium loss. This is the opposite of the more familiar hypocalciuric effect of oral phosphate supplements. Therapeutic doses of aluminum-containing antacids can elevate urine calcium by 50 mg/day or more. Enhancers of Calcium Absorption Relatively little work has been done on enhancers of calcium absorption. Lactose is said to improve absorption, but the effect may be confined to the rat. As already noted, certain nondigestible oligosaccharides (such as inulin) have been reported to increase calcium absorption [150]. Human studies using various simple carbohydrates have generally shown some enhancement [167], but the effect may be confined to intestines damaged by disease or surgery, since it has been hard to find in healthy subjects [168]. Also, the effect of various carbohydrates may be nonspecific, due instead to alteration of the gastric emptying pattern associated with coingestion of other food constituents − what has been characterized as the “meal effect” [169]. Nevertheless, given the generally low absorbability of calcium, the prospect of finding substances that might improve calcium bioavailability has enticed many food processors. Various food fractions, such as casein phosphopeptide, derived from milk, have been found to improve calcium absorbability in certain experimental systems [170], although its effect in humans is probably small [171]. Likewise, certain amino acids, notably lysine, have been thought to enhance calcium absorption [172], but human evidence in their regard is sparse and inconsistent. Protein, in short-term feeding studies has been shown to increase calcium absorption appreciably [173], but the effect appears to wane over time [174] (see also section “Protein”). Even fat might theoretically be viewed as an enhancer, since it is known to slow gastric emptying. However, we have been unable to find, using multiple regression methods, any effect of even large variations in fat intake on absorption fraction in our observational study of middle-aged women. Intake versus Interference For diets high in calcium, as would have been the case for our hunter-gatherer ancestors, high protein and possibly high sodium intakes could have been handled by the body without adverse effects. These nutrients create problems for the calcium economy of contemporary adult humans mainly because we typically have calcium intakes that are low relative to those

of preagricultural humans. This is because at prevailing low intakes, compensatory adjustment mechanisms are already operating and for many individuals, capacity for further adaptation (e.g., increased absorption efficiency) is very limited. An increased demand for only 40 mg Ca/day would require a nearly 40% increase in intestinal absorption at intakes at the bottom quartile for North American and European women today, while the same demand can be met by an increase of only 1% to 2% in absorption efficiency at intakes such as prevailed during hominid evolution. The former is not possible, while the latter is easily accomplished. Thus, while there is some emphasis today among nutritionists on regulating intake of interfering nutrients, the real problem is not so much that the intakes of these other nutrients are high, as that calcium intake is too low to allow us to adjust to the inevitable nutrient– nutrient interactions that occur with any diet.

VITAMIN D Vitamin D is discussed extensively in Chapter 13. Here the focus will be mainly on certain bone-related nutritional features of this multifunctional nutrient. It has long been recognized that vitamin D is important for absorption of calcium from the diet. Its role in that regard lies in facilitating active transport, mainly by inducing the formation of a calcium-binding transport protein in intestinal mucosal cells and of membrane calcium transporters. This function is particularly important for adaptation to low calcium intakes. There is also, apparently, a second vitamin D-related absorption mechanism, transcaltachia [175], which is nongenomic but nevertheless requires occupancy of the classical v ­ itamin D receptor by 1,25(OH)2D. Finally absorption also occurs passively, probably mainly by paracellular diffusion. This route is probably not dependent upon vitamin D, and is not as well studied. 25-hydroxyvitamin D (25(OH)D), in addition to being an indicator of vitamin D status, is an important storage form of the vitamin. Although usually considered to be about three orders of magnitude less potent than calcitriol in promoting active transport in animal receptor assays, there is growing evidence that it may possess physiological functions in its own right [176–182], and in the only human dose–response studies performed to date, 25(OH)D was found to have a molar potency in the range of 1/125 to 1/400 that of 1,25(OH)2D3 [181–183], not the 1/2000 figure derived from its relative affinity for the vitamin D receptor. Gross absorption fraction correlates positively with serum 25(OH)D concentration in adults (but not with 1,25(OH)2D concentration) [178,184], and in controlled dosing experiments exhibits threshold behavior (Fig. 28.11) [185–187]. Below serum

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Vitamin D

1200

48

1000

40

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32 Needed to offset 200 mg/day obligatory loss

600 400

24 16 8

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Active absorption (%)

Net absorption (mg/day)

1400

0 0 −200

Zero balance across the gut 0

500

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Calcium intake (mg/day)

FIGURE 28.11  Calcium absorption fraction as a function of serum 25(OH)D from three published studies [185–187]. Source: Copyright Robert P. Heaney, 2003. Used with permission. 0.5 0.4 Absorption fraction

25(OH)D levels of about 80 nmol/L, vitamin D status limits absorption, while above ∼80 nmol/L, other physiological controls take over. The proportion of absorption by active transport and passive diffusion varies with intake and is not well characterized in humans; at high calcium intakes (above 2000 mg/day) gross absorption fraction approaches that observed in anephric individuals (about 10−15% of intake). Under these circumstances it is likely that active transport contributes relatively little to the total absorbed load. Nevertheless, it is clear, at prevailing calcium intakes, that vitamin D status influences absorptive performance, and that it thereby influences the minimum calcium requirement. Simple calculation suffices to establish the magnitude of this influence. Assume an intake of 1000 mg Ca/day. To that is added about 150 mg in the form of the calcium of digestive secretions and sloughed off mucosa, for a total daily gut input of ∼1150 mg. If passive absorption is at a level of 12.5% of intake, net absorption would amount to 144 mg, leaving the individual in negative balance across the gut of ∼6 mg/day (and, of course, producing no calcium gain for the body to offset renal and cutaneous losses). If, however, vitamin D-mediated, active transport is operating, so that, for example, total absorption was 27.5%, net absorption becomes +109 mg. The relationship of active transport to net absorption is shown graphically, for various intakes, in Figure 28.12, which makes clear that meeting physiological demands for calcium would require very high calcium intakes in the absence of vitamin D. (That situation is depicted by the bottom line in the figure, which is the contour for

0.3 0.2 0.1 0

0

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40

60

80

100

120

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Serum 25(OH)D (nmol/L)

FIGURE 28.12  Relationship of calcium intake, net calcium gain across the gut, and vitamin D-mediated, active calcium absorption. Each of the contours represents a different level of active a­ bsorption above a baseline passive absorption of 12.5%. (The values along each contour represent the sum total of passive and variable active ­absorption.) The horizontal, dashed lines indicate zero and 200 mg/ day net absorption, respectively. The former is the value at which the gut switches from a net excretory to a net absorptive mode, and the ­latter is the value needed to offset typical urinary and cutaneous losses in mature adults. Source: Copyright Robert P. Heaney, 1999. Used with ­permission.

net calcium absorption when active absorption is zero. The other lines depict various levels of active transport, reflecting, in turn, varying degrees of vitamin D sufficiency.) Vitamin D status commonly deteriorates in elderly people, whose plasma 25(OH)D levels are generally

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lower than in young adults [188,189]. These elderly people, without histological or biochemical evidence of osteomalacia, nevertheless exhibit high PTH levels, high serum alkaline phosphatase levels, and low absorptive performance, all of which move to or toward optimal with supplemental vitamin D [188–191]. The rate of agerelated loss of bone has been found to be inversely correlated to dietary vitamin D [192]. Low-dosage ­vitamin D supplementation of ostensibly healthy postmenopausal women significantly slows wintertime bone loss and reduces the annual parathyroid-mediated activation of the bone remodeling system that occurs in winter through late spring [189]. These changes all suggest relative vitamin D inadequacy in most adults. Low 25(OH)D levels in elderly people are partly due to decreased solar exposure, partly to decreased efficiency of skin vitamin D synthesis, and partly to decreased intake of milk, a major dietary source of the vitamin in North America. Moreover, elderly people exhibit other abnormalities of the vitamin D endocrine system which may further impair their ability to adapt to reduced calcium intake. These include decreased responsiveness of the renal 1-α-hydroxylase to PTH [193] and possibly, also, decreased mucosal responsiveness to calcitriol [194] (although available data do not permit distinguishing a decrease in mucosal responsiveness from a simple decrease in mucosal mass). For all these reasons there is a consensus that the requirement for oral vitamin D intake rises with age [30,190,195–198], and a body of data which strongly suggests that relative vitamin D deficiency plays a role in several components of the osteoporosis syndrome. The first direct evidence was the randomized, controlled trial by Heikinheimo et al. [139] showing substantial reduction in all fractures in an elderly Finnish population given a single injection of 150,000 to 300,000 IU vitamin D each fall [17].17 More recently, Trivedi et al. [199] reported a 33% decrease in fractures in a healthy older British cohort given 100,000 IU vitamin D3 every 4 months. Other trials showing no significant fracture reduction either used lower vitamin D doses or had poor compliance with supplementation (or both) [200–203]. A meta-analysis of all vitamin D trials published through 2004 [204] showed a significant reduction in hip fracture risk, but only in trials using mean daily doses of 700 IU or greater, and only if the achieved serum 25(OH)D concentration reached ∼75 nmol/L or higher. In its 2011 report on DRI [205], the IOM specified 400 IU/day as the estimated mean requirement for every person over the age of 1 year, with an RDA of 600 IU/day out to age 70 years, after which the RDA rose to 800 IU/day. The IOM judged a serum level of 50 nmol/L to be adequate 17This dose amounts to a daily average exposure of 410−820 IU, and can hence be considered a physiological intake.

to ensure vitamin D benefits for the population. This conclusion was not shared by most working vitamin D researchers, and The Endocrine Society released treatment guidelines [206] a few months later which specified substantially higher values – an RDA ranging from 1500 to 2000 IU/day, and a minimum serum 25(OH)D value of 75 nmol/L. If a serum 25(OH)D concentration of 75 to 80 nmol/L is taken as the lower limit of normal, several studies have shown, by that criterion, that from 65% to nearly 100% of older adults are vitamin D deficient [207–210]. This fact, plus the benefit of vitamin D supplementation in the foregoing studies, lead inexorably to the conclusion that vitamin D inadequacy is prevalent in the ­middle-aged and elderly people of Northern Europe and North America. Moreover, in virtually none of the studies showing a benefit of supplemental vitamin D was frank osteomalacia a significant feature of the problem. Hence, as discussed above, this criterion for true vitamin D deficiency is much too restrictive to be nutritionally useful today. However, 2010 data show that histological evidence of osteomalacia persists out to serum 25(OH)D concentrations of 75–80 nmol/L [211], a finding that underscores the likely correctness of The Endocrine Society guidelines [206] and the inadequacy of the IOM ­recommendations for vitamin D. The vitamin D oral requirement depends upon solar exposure, and can be operationally defined as the amount needed to raise prevailing levels of serum 25(OH)D to 80 nmol/L or higher. (Some studies suggest achieving values of 100 nmol/L or above.) While intakes of ∼600 IU/ day will usually sustain serum 25(OH)D levels [198,212] at initial values, doses of 1000 to 2000 IU/day will commonly be needed in patients with osteoporosis [212] to achieve a level of 80 nmol/L. What is not clear from the above is how much of the effect of vitamin D is due to facilitating gut adaptation to marginal calcium intakes, and how much may represent an extraintestinal effect of the vitamin in its own right, for example on muscle tone or coordination. Lower extremity function in elderly people is an inverse function of serum 25(OH)D [213], and randomized controlled trials of vitamin D supplementation show significant reduction in falls [187,214]. Calcitriol receptors are widely distributed in many tissues, and calcitriol enhances PTH-mediated bone resorption and functions in gene expression involved in cell differentiation and in the immune response. Furthermore, calcitriol elicits a prompt and sizable increase in osteoblast synthesis of osteocalcin [215]. Additionally, elevating serum 25(OH) D levels in elderly people improves the often incomplete gamma carboxylation of osteocalcin (see below, section “Vitamin K”). Nevertheless, patients with vitamin D-dependent rickets type II, who lack functional calcitriol receptors, show essentially complete remission of

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Vitamin K

most of their skeletal pathophysiology with intravenous calcium infusions alone [216].

PROTEIN Two seemingly contradictory facts seem reasonably well established with respect to protein intake and the calcium economy: (1) protein often increases urinary calcium loss [144,217,218] and (2) protein aids recovery from hip fracture [219,220] and slows age-related bone loss [220,221]. For the most part, the studies establishing these diverse and to some extent contradictory effects have been performed by varying only the nutrient concerned. For example, the calciuric effects of protein have been demonstrated most clearly in studies in which purified protein or protein hydrolysates were used, with each gram of protein resulting in an approximate rise in urinary calcium excretion of 1 mg. However, in longterm studies, in which the protein was fed as meat or dairy and in which subjects were adapted to particular protein intakes, urinary calcium does not rise with protein intake [222,223]. The difference in response is due, presumably, to the fact that high protein foods contain substantial quantities of other nutrients such as phosphorus (which is hypocalciuric in effect) [222], and to delayed adaptation that cannot be captured in shortterm experiments. Kerstetter et al. [173] have reported that high protein intakes enhance calcium absorption, an effect which would counter a calciuric effect (were there to be one). Not every investigator has been able to reproduce this finding in chronic feeding studies [222,223] and it may be, to the extent that the phenomenon is operative, that, like the urinary calcium effect, it applies only acutely. The very reproducible calciuric effect of pure protein or amino acids had led, several years ago, to the tentative conclusion that high protein intakes might be deleterious for the skeleton. However, not only do the studies involving food sources of protein, such as those just cited, not support that conclusion, but epidemiological studies, such as those from the Framingham osteoporosis cohort [221] indicate instead that age-related bone loss in postmenopausal women is inversely related to protein intake, not directly, as might have been predicted from the calciuric effect. In this connection it is of interest to examine the interaction of protein and calcium intakes in the study of Dawson-Hughes and colleagues [224]. In their randomized controlled trial of calcium supplementation, the bone gain associated with calcium supplementation was confined to individuals in the highest tertile of protein intake, while in the placebo group there was a nonsignificant trend toward worsening bone status as protein intake rose. This latter effect is what would be

predicted if there were some degree of protein-induced calciuria without an offsetting increase in absorbed calcium. ­Protein intake in this study spanned only a relatively narrow range, and was not randomly assigned to the subjects, and so these results cannot be considered final. However, corroborative data from one long-­ running study [225], show exactly the same relationship. The slope of calcium balance on calcium intake in these women was positive only in those with protein intakes above the median for the group (∼62 g/day). These studies exhibit two interesting features: (1) high protein intake facilitated the positive effect of calcium; and (2) most of the protein was from animal sources (as was true for the Framingham osteoporosis cohort, as well). This latter point provides no support for the hypothesis that ­animal foods (as contrasted with vegetable protein sources), by increasing urinary calcium loss, artificially elevate the calcium requirement. The importance of achieving an adequate protein intake is at least two-fold. First, protein is a bulk constituent of bone. Because of extensive post-translational modification of amino acids in the collagen molecule (e.g., cross-linking, hydroxylation, etc.) many of the amino acids released in bone resorption cannot be recycled into new protein. Hence, bone turnover requires a continuing supply of fresh dietary protein. Second, protein elevates serum insulin-like growth factor (IGF)-1 [226,227], which is trophic for bone [227]. For both reasons a diet inadequate in protein would be expected to reduce the bony response to calcium. Moreover, several studies of increased protein intake have shown rises in serum IGF-1 [226,227]. Thus, it may be tentatively concluded that protein intakes in the individuals concerned were suboptimal. To the extent that this is true, and that both of the bulk constituents of bone (calcium and protein) are ingested at suboptimal intakes, then it follows that the true effect of neither nutrient can be discerned in studies that do not ensure full repletion of the other.

VITAMIN K The chemistry and physiology of vitamin K have been extensively reviewed elsewhere [222,228–232]. In brief, vitamin K is a fat-soluble vitamin that exists in several forms (“vitamers”) and is found in the diet mainly in green leafy vegetables. The principal vitamers are K1 (phylloquinone) and K4 (menaquinone). Biochemically, vitamin K is necessary for the gammacarboxylation of glutamic acid residues in a large number of proteins. Most familiar are those related to coagulation, in which seven vitamin K-dependent proteins are involved in one way or another. The gammacarboxyglutamic acid residues in the peptide chain

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bind calcium, either free or on the surface layers of crystals, and have been thought to function in varying ways including catalysis of the coagulation cascade, inhibiting mineralization (as in urine) [233], and serving as osteoclast chemotactic signals [234]. Vitamin K deficiency classically produces bleeding disorders, but the liver, where the clotting factors are produced, is highly efficient in extracting vitamin K from the circulation, and gamma-carboxylation declines substantially in other tissues before the deficiency is severe enough to result in bleeding disorders. It may thus be that the bleeding tendencies which have been the hallmark of vitamin K deficiency are, in fact, the last manifestation of deficiency. If so, what the other clinical expressions of deficiency may be remains uncertain. Four vitamin K-dependent proteins are found in bone matrix: osteocalcin (bone gla protein (BGP)), matrix gla-protein, protein S, and periostin [235]. Osteocalcin and possibly periostin are unique to bone. There is also a kidney gla protein (nephrocalcin) [236], which may be involved in renal conservation of calcium. Osteocalcin binds avidly to hydroxyapatite (but not to amorphous calcium phosphate) and is chemotactic for bone-resorbing cells. Originally thought to be synthesized and gamma-carboxylated by osteoblasts as they deposit bone matrix, it now seems that osteocalcin is synthesized by osteocytes [237], particularly those newly embedded in forming bone matrix (see also Chapters 10 and 11). Roughly 30% of the synthesized osteocalcin is not incorporated into matrix, but is released instead into the circulation, where, like alkaline phosphatase, it can be measured and used as a rough indicator of new bone formation (see Chapter 67). In vitamin K deficiency, such as would occur with coumarin anticoagulants, serum osteocalcin levels decline, and the degree of carboxylation of the circulating osteocalcin falls dramatically. Further, binding to hydroxyapatite of the osteocalcin produced under these conditions falls precipitously soon after starting anticoagulant therapy. It would seem, therefore, that vitamin K deficiency would have detectable skeletal effects. The problem is that they have been very hard to find. Rats reared and sustained to adult life under near total suppression of osteocalcin ­ gamma-carboxylation show only minor skeletal defects, mostly related to abnormalities in the growth apparatus [215]. Warfarin anticoagulation therapy in humans has generally not been found to be associated with decreased BMD or increased fractures [238,239]. However, an osteocalcin knockout mouse exhibits a skeleton significantly more dense than normal [240], a finding compatible with osteocalcin’s p ­ utative role in facilitating resorption. In aging humans, the problem of detecting skeletal abnormalities is c­ ompounded by the relative isolation of bone from current ­ nutritional stresses, discussed earlier in

this chapter (see section “Isolation of Bulk Bone from ­Current ­Nutritional Influence”). Various vitamin K-related abnormalities have been described in association with osteoporosis, but their pathogenetic significance remains unclear. Circulating vitamin K and menaquinone levels are low in hip fracture patients [241], but since these levels reflect only recent dietary intake [242,243], it is uncertain to what extent they reflect prefracture vitamin K status. Osteocalcin is undercarboxylated in patients with osteoporosis, and this defect responds to physiological doses of vitamin K [244,245]. Finally, urine calcium has been reported to be high in some patients with osteoporosis and to fall in response to physiological doses of vitamin K [246,247]. In the same subjects, urine hydroxyproline was also found to be high and to fall on vitamin K treatment. The effect was confined to subjects with pretreatment hypercalciuria, and could plausibly be explained as a defect first in a calcium transport protein, with a consequent renal leak of calcium, and a corresponding PTH-mediated increase in bone resorption (reflected in the increased hydroxyproline excretion). In observational studies low vitamin K intake and/or low serum levels of vitamin K have been variously associated with low BMD at hip and spine [248,249] in older men and in older women not taking estrogen replacement. In two prospective study cohorts, low vitamin K intake was associated with increased risk of hip fracture [250,251]. Trials of menaquinone have yielded mixed results, with some showing improvement in BMD and ­geometry, and others not [245,252,253]. Several Japanese studies have reported that a vitamin K homolog (menatetrenone, MK-4), used in supraphysiologic doses (45 and 90 mg/day, as contrasted to nutritional intakes ≤1 mg/ day), protects BMD and reduces osteoporotic fractures [254–257]. Whether or not variation in vitamin K intake is ultimately judged to be important for bone health, serum vitamin K levels are indicators of general nutritional status, and the observation of low vitamin K levels in patients with osteoporosis, especially in those with hip fracture, may be a reflection mainly of the often poor general nutrition of these individuals [241–243]. If minimizing uncarboxylated osteocalcium turns out to be important, it is worth noting that the amount of vitamin K needed to do that rises with age [258]. One possible reason why studies of vitamin K and bone are often null lies in the fact that clinical populations are often deficient in calcium, vitamin D, and protein as well. Under such circumstances, testing vitamin K alone would be predicted to be uninformative. As was stressed for protein, above, nutrients act in concert, not alone. Manifestly, much about vitamin K and bone health remains unclear and more work must be done. Until such questions are resolved, it would seem prudent to ensure in

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Other Essential Nutrients

elderly people a sufficient vitamin K intake to achieve full expression of the gamma-carboxylation of all vitamin K-dependent proteins.

OTHER ESSENTIAL NUTRIENTS Magnesium Magnesium is an essential intracellular cation, a cofactor of many basic cellular processes, particularly those involving energy metabolism. Principal food sources include legumes, nuts, fish, certain fruits such as bananas and avocados, dairy, and certain leafy greens such as spinach. The RDA for magnesium for individuals over age 50 years is 420 mg for men and 320 mg for women. Intake data from NHANES indicate that about two-thirds of adults fail to meet the respective RDA. The consequences of this shortfall are uncertain. In the face of true magnesium deficiency, there is widespread cellular dysfunction, including the cells and tissues that control the calcium economy and bone remodeling, among others. While slightly more than half the body magnesium is contained in the mineral of bone, it is less certain whether it plays any role there or, like zinc (see below), is present accidentally (insofar as it was present in the extracellular fluid (ECF) bathing the mineralizing site). In contrast, magnesium alters the surface properties of calcium phosphate crystals, and its concentration in bone is sufficiently high to exert such an effect there. However, the physical–chemical equilibrium between bone crystals and the dissolved minerals in the ECF is itself poorly understood; hence any role of magnesium therein is correspondingly uncertain. The skeletal effects of magnesium deficiency have been reviewed in detail by Rude et al. [259]. Clinical magnesium deficiency clearly occurs in humans of all ages, most often resulting from severe alcoholism or intestinal magnesium leaks, as from sprue or from ileostomy losses. One well-studied manifestation is hypocalcemia, now recognized to be due to refractoriness of the parathyroid glands to the hypocalcemic stimulus itself, coupled with refractoriness of the bone resorption apparatus to PTH. Low bone mass is also a common feature in these situations, and moderately low magnesium intake in growing rats results in reduced bone mass, despite continuing normal serum magnesium concentration [260]. Clinically, humans with magnesium deficiency commonly have calcium deficiency as well, and for the same reasons – a varying combination of low intake, renal wastage, and intestinal leakage. It would be expected, therefore, that osteoporosis is very common in such individuals, as is the case. How much of this bony deficit is due to the magnesium deficiency and how much

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to the calcium deficiency is unclear. (In a clinical sense the question is moot: both deficiencies need repairing.) Treating the underlying condition and replacing lost calcium increases bone density in these patients, but Rude et al. [261] have shown that even when the underlying condition is controlled and serum magnesium seemingly normal, additional magnesium supplementation will produce a further increase in BMD. This latter observation highlights one of the difficulties besetting this field − the assessment of magnesium status. Serum magnesium is recognized not to be a reliable indicator of tissue magnesium repletion. Many investigators favor the magnesium tolerance test [262], that is, measuring % retention of an intravenous infusion of magnesium. This is, unfortunately, not practicable in clinical practice. Nevertheless the observations of Rude et al. highlight the fact that serum magnesium values within the “normal” reference range may mask a capacity to respond to further magnesium supplementation. This is precisely the point at which magnesium intersects the arena of the pathogenesis and treatment of common postmenopausal osteoporosis. Unfortunately there is probably no segment of the osteoporosis field more beset with poorly designed, poorly executed, and inadequately powered studies than this one. For example, two small trials, one not randomized, the other with high loss of subjects during the trial, reported bone gain in postmenopausal women given a supplement containing magnesium [263,264]. Neither study constitutes persuasive evidence of a magnesium effect. The upshot of these and many other even weaker studies is that it is simply not possible to say with any certainty what may be the role that magnesium plays in pathogenesis or treatment of osteoporosis. One well-designed study [265] in 23 preadolescent girls who, by history, had low magnesium intakes, showed that magnesium oxide supplementation resulted in significantly greater BMC accumulation at the total hip site. The study was small, but is consistent with findings in growing animals [260]. One fact seems certain: in any unselected group of individuals with low bone mass, calcium and/or ­vitamin D supplementation results in clear skeletal benefits (see above), without using extra magnesium. And despite the fact that magnesium may be necessary for the functioning of such cells as those responsible for synthesizing 1,25(OH)2D [266], there is clear proof that supplemental magnesium does not enhance calcium absorption in typical older adults. Spencer et al. [267] more than ­doubled daily magnesium intake in a group of volunteers and could find no effect on calcium absorption, whether from low or normal calcium intakes. Similarly, the many randomized controlled trials demonstrating efficacy of calcium supplementation in reducing age-related bone loss and fractures all achieved their effect without supplementing with magnesium.

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However, absence of proof is not the same as absence of effect. One cannot say, in the routine management of osteoporosis, that the results would not have been even better had extra magnesium been provided as well. Since sprue syndromes can be silent [268], subtle magnesium deficiency could well exist in some individuals with otherwise typical osteoporosis (to mention only one potential cause of magnesium deficiency). Hence, lacking the ability easily to identify individuals with unrecognized magnesium deficiency, it is hard to argue against prudent attention to magnesium supplementation in individuals who have osteoporosis or are at high risk for fragility fractures. Support for this approach comes from investigation of PTH response to low vitamin D status. It is widely reported that mean serum PTH rises as serum 25(OH)D falls [208,269,270], but what is noteworthy in all these reports is the observation that a substantial fraction of individuals with low vitamin D status do not exhibit the expected PTH elevation. Sahota et al. [271] evaluated magnesium status in individuals who did not respond to vitamin D deficiency by elevating PTH, using the magnesium tolerance test, and found that they had pathologically high values for magnesium retention – suggesting a silent magnesium deficiency. This was confirmed by the fact that magnesium supplementation, without other interventions, resulted in elevation of serum PTH to values within the range expected for vitamin D deficiency. As noted above, parathyroid response has been known to be blunted in clinically evident magnesium deficiency, but it had not been understood that milder degrees of deficiency could produce a similar effect. As most adults have magnesium intakes below the RDA, these findings suggest that there could still be considerable potential for exploration of the role of this possibly underappreciated nutrient.

Trace Minerals Several trace minerals, notably copper, zinc, and manganese, are essential metallic cofactors for enzymes involved in synthesis of various bone matrix constituents. Ascorbic acid (along with zinc) is needed for collagen cross-links. In growing animals, diets deficient in these nutrients produce reasonably well defined skeletal abnormalities [272,273]. Additionally, zinc deficiency is well known to produce growth retardation and other abnormalities in humans. But it is not known with certainty whether significant deficiencies of these elements develop in previously healthy adults, or at least, if they do, whether such deficiencies contribute detectably to the osteoporosis problem. Copper Copper is of particular interest. The principal sources of copper in the diet are shellfish, nuts, legumes, whole grain cereals, and organ meats. True dietary copper

deficiency is considered to be rare and to be confined to special circumstances, such as with total parenteral nutrition or infants recovering from malnutrition. ­Recognized manifestations in humans have usually centered on disorders of hemopoiesis, mainly as an iron-refractory, hypochromic anemia and leukopenia. Osteoporosis or fragility fractures have not been generally considered to be a part of the syndrome. However, copper-deficient premature infants have underdeveloped, weak bones that fracture easily and respond to copper supplementation [274], and in one human with copper deficiency due to a copper transport defect, the patient’s morbidity included osteoporosis [275]. Copper is a necessary cofactor for lysyl oxidase, one of the principal enzymes involved in collagen crosslinking. These cross-links are important for connective tissue strength, both in tension and in compression, as they prevent the fibrils from sliding along one another’s length. Bone formed under conditions of lysyl oxidase inhibition is mechanically weak, independent of mass. Copper deficiency is reported to be associated with osteoporotic lesions in sheep, cattle, and rats [272–276]. Mice deficient in superoxide dismutase – for which copper and zinc are metallic cofactors – exhibit bone loss, decreased bone turnover, and reduced cross-links [277]. Copper has not been much studied in connection with human osteoporosis, but in one study in which serum copper was measured, levels were negatively correlated with lumbar spine BMD, even after adjusting for body weight and dietary calcium intake [278]. In another [279] postmortem specimens of bone from osteoporotic individuals were reported to contain fewer cross-links than bone from age-matched controls. Zinc Zinc is a known constituent of about 300 enzymes, including alkaline phosphatase, and it plays a role with other proteins, such as the estrogen receptor molecule. Its principal sources in the human diet are red meat, whole grain cereals, shellfish, and legumes. A 70 kg adult body contains 2−3 g zinc, about half in bone. Most of this bony zinc is located on the surfaces of the calcium phosphate crystals and probably has no metabolic significance there. (Many cations present in the mineralizing environment adsorb to the oxygen-rich phosphate groups on crystal surfaces and get stuck there as free water is displaced by new mineral deposition.) A fortuitous consequence of this situation is that urine zinc reflects bone resorption. Thus Herzberg et al. [280] have shown that urine zinc rises with age, is higher in patients with osteoporosis, and is reduced when postmenopausal women are given estrogen [281]. While some etiologic connection between zinc and osteoporosis cannot be ruled out, these observations are most easily explained as reflections of the enhanced bone resorption found in many patients with osteoporosis, the elevated resorption

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Conclusion

of the estrogen-deprived, postmenopausal state, and the well-known antiresorptive effect of estrogen. Urinary zinc excretion probably functions as a marker for bone resorption, rather than as a reflection of the underlying disease mechanisms. In contrast, of known nutrients, zinc is the one most strongly related to serum IGF-I [282], a growth factor known to be osteotrophic even in adults. In this connection, Schürch et al. [283] have shown the importance of IGF-I in recovery from hip fracture. In an observational study from Sweden, fracture risk was higher in individuals with low zinc intakes [284], and, after adjusting for other nutrients, the risk gradient showed the expected dose–response relationship. New et al. [285] in a dietary survey of nearly 1000 British premenopausal women found high zinc intakes to be associated with higher bone density values at both spine and hip. Suggestive paleolithic evidence connecting zinc intake with bone status is provided by ancient skeletons discovered in Canary Island cave burials (where contamination by, or leeching of minerals into, ground water is considered not to have occurred). Bones with normal zinc content per unit ash, concentrated in one region of the Islands, tended to be robust, while those with low zinc contents, on another island, were found to be osteoporotic [286]. Zinc content of bone, as suggested above, is determined by the circulating zinc levels when bone is mineralizing, and thus low bone zinc probably reflects low zinc intake throughout life. Whether this exposure played an etiologic role in the low bone mass of these skeletal remains is conjectural. Manganese While manganese is also recognized as an essential nutrient, its precise role in nutrition is much less well characterized than that of copper and zinc. Although manganese deficiency is well recognized in both laboratory and farm animals, there is no generally recognized manganese deficiency syndrome in humans. Manganese is widely distributed in foods and is especially rich in tea. Bone manganese content is, like that of copper and zinc, a reflection mainly of serum levels prevailing at the time bone is formed, and thus a reflection of dietary manganese. Bone manganese probably has no other metabolic significance, per se. Manganese is capable of activating many enzymes, but for most the effect is nonspecific. Manganese is, however, believed to be the preferred metal ion for certain glycosylation reactions involved in mucopolysaccharide synthesis. In this connection, manganese deficiency could interfere with both cartilage and bone matrix formation. Animals reared on manganese-deficient diets exhibit general growth retardation, but careful measurements indicate that long-bone growth is disproportionately affected [287], possibly reflecting a specific problem with

endochondral bone formation. There is also indication of delayed skeletal maturation, suggesting a role of manganese in chondrogenesis. Strause et al. [288] showed this quite nicely in a rat model in which demineralized bone powder is implanted subcutaneously. In control animals, cartilage forms around the powder implant, then osteogenesis occurs. In manganese-deficient animals neither development took place. In further work, Strause et al. [289] showed that manganese-deficient rats had both disordered regulation of calcium homeostasis and decreased bone mineral density. Because histology was not performed, it is not possible to say whether this represented impaired mineralization or osteoporosis. Finally, Reginster et al. [290] found low serum manganese in a group of 10 women with osteoporosis. What significance any of these findings may have for the bulk of human osteoporosis is uncertain. In one four-way, randomized intervention trial, a trace mineral cocktail including copper, zinc, and manganese slowed bone mineral loss in postmenopausal women, when given either with or without supplemental calcium [291]. There appeared to be a small additional benefit from the extra trace minerals; however, the only statistically significant effect in this study was associated with the calcium supplement. This could mean that trace mineral deficiency plays no role in osteoporosis, but it could also mean that not all of the women treated suffered from such deficiency. In fact, since both osteoporotic and age-related bone loss are multifactorial, it could be presumed that only some of the subjects in such a study would be deficient, since there is no known way to select subjects for inclusion on the basis of presumed trace mineral need. Thus the suggestive findings of this study have to be considered grounds for further exploration of this issue.

CONCLUSION With the exception of the few outspoken effects on discrete systems and diseases by which nutrition defined itself a century ago (e.g., scurvy, rickets, beri-beri), nutrient effects tend to be subtle and pervasive. Most nutrients alter the functioning of most body systems and tissues, not just one or two. Unlike drugs, for which effects are designedly discrete and can be contrasted with a drugfree state, nutrients exert multiple, often small effects, and almost always work in concert with other nutrients. It is not possible, either for ethical or practical reasons, to contrast a nutrient-free state with a nutrient-added state, as one would do to establish a drug effect. As a result the full effects of nutrients are hard to study. The focus of this chapter has, of necessity, been bone. But it must be understood that the nutrients affecting bone and reviewed briefly in the foregoing have important effects on total body functioning, not just

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bone. By the same token, nutrients not covered in this chapter, such as folate, riboflavin, and B12 undoubtedly have bony effects as well. They are just not yet as well characterized. Nutrition can be said to be “good” when the supply of energy, structural building blocks, and bioactive trace nutrients does not limit the self-regulation of body systems. Although the term “minimum daily allowance” is no longer used in nutritional policies, in point of fact, that is the approach still used to define nutritional requirements, that is, the requirement is the lowest intake a person one can get by on without manifesting certain untoward effects. For many n ­ utrients – perhaps most – these recommendations will not ensure good nutrition, as just defined. Nevertheless, the burden of proof has been placed on those who contend that more would be better. Perhaps a more rational approach would be to start from the intakes to which human physiology is adapted, and to place the b ­ urden of proof on those who contend that a lesser intake would be safe.

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Conclusion

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V.  EPIDEMIOLOGY OF OSTEOPOROSIS

Conclusion

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V.  EPIDEMIOLOGY OF OSTEOPOROSIS