journal of Internal Medicine 1992: 231: 169-180

Calcium in the prevention and treatment of osteoporosis R. P. H E A N E Y From the Department o j Internal Medicine. Creighton University. Omaha. Nebraska. USA

Abstract. Heaney RP (Department of Internal Medicine, Creighton University, Omaha, Nebraska. USA). Calcium in the prevention and treatment of osteoporosis. journal of Internal Medicine 1992: 231: 169-180. Osteoporotic fractures have many sources. Low bone mass is one such, and inadequate calcium intake, in turn, is one of the causes of low bone mass. Calcium intake may be inadequate because it is low in its own right or, even if ‘normal’, it may not be sufficient to compensate for exaggerated obligatory losses. Inadequate calcium intake may cause bone mass to be low either because calcium intake during growth limits achievement of genetically programmed skeletal mass, or because low intake later in life aggravates involutional loss, or both. Ensuring a generous calcium intake throughout life will prevent both of these consequences. However, it is important to stress that even a calcium surfeit will not prevent or reverse bone loss due to inactivity, gonadal hormone deficiency, alcohol abuse or, indeed, any other factor. Calcium is a nutrient, not a drug. The only disorder it can be expected to alleviate is calcium deficiency. However, the evidence suggests that calcium deficiency is prevalent among Western populations, particularly in North America, and that it thereby contributes substantially to their osteoporotic fracture burden. This component of that burden is therefore entirely preventable.

Keywords; ageing, bone loss, bone fragility, calcium deficiency, calcium intake, osteoporosis.

The osteoporotic fracture context Bone health in the later years of life primarily involves the ability to sustain routine, everyday activities (and the injuries commonly associated with them) without suffering low-trauma fractures. Fracture is thus the ultimate focus of our concern about bone health. It is the manifestation of osteoporosis which we seek to prevent, or are asked to treat. To appreciate what prevention of osteoporosis means, and what may be realistically achievable by different stratagems, it is necessary to understand how and why low-trauma fractures occur. The cluster of factors involved constitutes the osteoporotic fracture context, depicted schematically in Fig. 1. The focus of this review is nutrition, and specifically calcium, but as is clear from Fig. 1, calcium is not the only factor involved, and adjustment of calcium intake certainly cannot be the only preventive stratagem we employ. The major factors operative in the fracture context, listed in Fig. 1, are arranged hierarchically, from left

to right, in accordance with their logical proximity to the fracture event. The most proximate are factors such as force and fragility. The more fragile the bone, the less force will be required to produce a fracture. However, the actual fracture-producing force is usually the result of a fall or some other injury, or the application of bad body mechanics. Only 2-6% of falls in the elderly result in fracture, but the risk of fracturing as a result of a fall is greater with a fragile skeleton than with a strong one. Hence causes of falls, such as environmental hazards, poor vision, postural instability, central nervous system dysfunction, syncopal attacks, as well as various medications that may lead to such problems, must all be considered as part of a comprehensive fracture context. The force which a bone actually experiences in a fall is also influenced by such factors as softtissue mass, which absorbs energy in falls and hence lessens the force directly applied to bone (this last point is undoubtedly part of the reason why overweight women have only about one-third the expected risk of developing a n osteoporotic fracture). 169

X

IMB 231

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R. P. HEANEY

Injuryffall Poor architecture

Oestrogen deficiency

Force

Fragility

Propensity to fall

Reduced bone mass

Inadequate Ca intake

Excessive obligatory Ca loss

Low Ca intake

Inactivity Poor Ca absorption

Fatigue damage

Environmental hazards

Other

Fig. I . A comprehensive overview of the osteoporotic fracture context, listing some of the factors that contribute first to fracture. then to skeletal fragility, then to low bone mass, and finally to calcium deficiency (proceeding from left to right). Only the central element at each level is expanded. Off-centre elcments should be understood as having their own contributory factors, just as does the central one (copyright. Robert P. Heaney. 1989: used with permission).

Some investigators consider these factors to be more important than low bone mass for fractures such as those of the hip [l].In any case, for a given degree of osseous fragility, it is likely that substantial differences in fracture rate will result from differences in these non-osseous factors. Also included in Fig. 1 are the three factors currently considered to be likely contributors to intra-osseous fragility, i.e. low bone mass, fatigue damage, and ineffective bony architecture [ 2 ] . Low bone mass is the factor that has given its name (' osteoporosis ') to the entire clinical syndrome, and is a self-evident problem. However, with the availability of modern methods for measuring bone mass, it has become clear that many individuals with otherwise typical osteoporotic fractures have only mild or moderate bone loss, and often no more bone loss than is found in apparently healthy age-matched peers. Bone is generally considered to have a reasonable reserve of strength and it is likely, therefore, that the fragility in such cases is due to more than bone loss alone. Fatigue damage is a newer concept to biological scientists, but is a well-recognized cause of structural failure in engineering materials, and is now known to occur in bone at physiological levels of loading. It must therefore be considered a plausible contributor to fragility, even though its precise role in the osteoporotic problem is not yet clearly established.

This is partly because fatigue damage is essentially undetectable in vivo, and is thus very difficult to study. The presumption, however, is that one of the functions of bone remodelling is the removal and repair of volumes of bone that have sustained fatigue damage. Hence one would expect to find increased numbers of fractures in regions of loaded, but inadequately remodelled, bone. This is almost certainly the basis of the fractures that characteristically occur in radiation-damaged bone, and current thinking inclines toward the view that fatigue damage is an important factor in the common hip fracture. A recent study from Israel [3] reported the absence of remodelling in the bone at the site of femoral neck fracture in 90 out of 102 consecutive cases. Decreased trabecular connectivity would also be expected to produce a major decrease in the strength of cancellous bone [4]. Loss of lateral bracing trabeculae has been shown to occur to a greater extent in ageing women than in men [S, 61 and has for that reason been proposed as the basis for the difference in frequency of vertebral compression fractures between women and men. Thus low bone mass can no longer be viewed as the sole factor responsible for skeletal fragility. However, it remains an important feature of the problem. As Johnston has pointed out, a difference of as little as 5% in bone mass may mean as much as a 40% difference in fracture risk 171.

CALCIUM A N D OSTEOPOROSIS

Some of the factors that influence bone mass itself are listed in the third column of Fig. 1. It is here that calcium nutrition first enters the scene, but it shares the stage with gonadal hormones, exercise, and a host of life-style factors, medications, and other hormones. Heredity, not listed because it is an uncontrollable factor, is nonetheless also of great importance [%lo], accounting perhaps for as much as 80%of the variance in bone mass among members of a population [7]. Nutrition shares the remaining 20% with the other factors that influence bone mass. It is essential to see the role of calcium in this broader perspective, both to interpret published studies, and to form realistic expectations about what is feasible for nutritional prophylaxis of this disorder. Even calcium nutrition, which is my concern in this review, cannot be adequately addressed if we focus solely on calcium intake. As the last column of Fig. 1 indicates, an intake may be inadequate not simply because it is low, but because of high obligatory calcium loss or poor intestinal calcium absorption efficiency as well. Obligatory loss has been shown to be at least as strongly correlated with bone mass as intake itself [ll].Calcium absorptive efficiency also plays a crucial and fairly obvious role. However, the degree of variation in absorption efficiency found among normal women [12] is less well recognized. The reasons for this variation are not understood, but their consequence is that a given intake may be more than adequate for one woman with high absorption and low obligatory loss, but quite inadequate for another, whose absorption efficiency is lower, or obligatory loss higher, or both. It follows that an estimate of calcium intake can only be an indirect index of the true status of calcium nutrition. Hence, the various epidemiological studies that relate crude calcium intake to bone mass or bone loss will inevitably show' only a weak correlation. While, as we have seen, low bone mass is neither the sole determinant of fragility nor sufficient in its own right to explain most osteoporotic fractures, it appears to be a necessary condition for fracture. Hence, optimization of bone mass remains an important stratagem for reducing the risk of incurring low-trauma fractures late in life. It is for this reason that calcium nutrition merits attention.

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The calcium economy An adequate intake of calcium is necessary both for skeletal growth and for skeletal maintenance. Gonadal hormones, adequate mechanical loading, and sufficient calcium intake all contribute to achievement of the genetic potential for bone mass. Failure on any of these grounds will limit peak mass. Unfortunately, supplying these factors later, when growth forces are less active, does not appear to permit late achievement of the once possible, genetically programmed mass. The most these factors appear to be able to achieve after the age of 35 years is to slow or eliminate remodelling-related losses, i.e. to protect the bone an individual possesses at that time. This is clearly worth doing, but its limitations must be understood. While the need for calcium during growth is generally accepted, the need for a maintenance intake to offset excretory and other losses has been less universally acknowledged [13]. Daily losses are of three sorts : dermal, urinary and intestinal. Whatever the route, all such losses must be offset by absorption of ingested calcium if an individual is to maintain skeletal integrity. Whenever losses exceed absorbed intake, the bone mass will be reduced in order to maintain extracellular fluid calcium ion levels. This phenomenon has been demonstrated repeatedly in many laboratory animal models, dating back at least to 1928. This temporary 'borrowing' ofbone calcium is a normal adaptive mechanism, and may even serve a secondarily useful purpose, in that the burst of remodelling induced by a temporary calcium deficiency may serve to activate removal of an accumulated burden of fatigue damage. From the animal data it appears that most or all of the 'borrowed' bone can be replaced, at least if an adequate diet again becomes available. However, if the deficit is chronic, and more and more bone has to be borrowed in this way, elements of bony scaffolding are lost, and it is then no longer possible to restore lost bone, no matter what the intake. Obligatory loss, discussed in more detail elsewhere [14, 151, is particularly important in this context. It consists of calcium secretion and excretion that is either not controlled by any known component of the calcium regulatory apparatus, or can be shown to continue even under conditions of calcium deficiency. Dermal losses are a particularly important component of obligatory loss, because they are so often ignored in calculations concerning the calcium 8-2

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economy. Dermal losses in the form of sweat and desquamated epithelium amount to at least 0.40.6 mmol d-' under sedentary conditions, and are known to be higher during exercise. This figure must be augmented by hair, nail and various nonexcretory, secretory losses, and the total may be as high as 1.5 mmol d-' [14]. The relationship between intake, excretory loss, and retention of calcium is complicated, inasmuch as both absorption and excretion are themselves related to intake in a non-linear manner. Briefly, as intake rises, both urinary and endogenous faecal losses increase as well, while the absorption fraction falls. Wilkinson gathered published data on net absorption from 212 balances in normal individuals [16] and found, for intakes of > 500 mg d-', a slope of net absorption on intake close to +0.110. In over 500 studies of our own in healthy perimenopausal women, my colleagues and I found a slope of +0.096. These very similar values mean that net absorption rises by only about 10%of an increment in intake. While a fraction this low may seem an inefficient arrangement, it can help to put this relationship in perspective if we note that current estimates of the natural calcium intake in man are well in excess of 1500 mg d-' [17]. Thus the calcium regulatory system may well have been designed (or have evolved) to deal with relative abundance rather than with relative scarcity. Under such circumstances, highly efficient calcium absorption would, in fact, be maladaptive. Because some of the absorbed calcium will be excreted in the urine, the relationship between intake and retention is even less efficient. Both in the extensive studies of Nordin [8] and in our own work [18, 191, the slope of urinary calcium on calcium intake in mature women, studied while consuming diets matched to their habitual intakes, is approximately +0.06. Thus, with about 10%of an intake increment absorbed, and 6 % excreted in the urine, only about 4 % will be retained (exclusive of dermal losses). In fact, this is almost exactly the value for the 'lope Of measured On intake we have found in Our Own studies [ l 8 V 19i. The implications of this are illustrated by the fact that at prevailing adult levels of absorption efficiency, dermal loss demands an intake Of as much as 10.5-13.5 mmol d-'. Quantitatively somewhat larger than the dermal losses are the frank excretory losses, and particularly that component which may properly be regarded as

obligatory. While some women can reduce fasting urinary loss to extremely low levels, not all can do so. Sodium and protein intakes are major determinants of obligatory calcium loss through the kidney [20, 211. Caffeine, once considered a cause of increased urinary loss, has recently been shown to be without detrimental effect, at least when consumed in moderation by women with above-average calcium intake [22]. Many other factors probably influence the ability to conserve calcium as well. It is likely that inter-population differences in apparent requirement reflect differences in the intake of these other nutrients, with their associated effect on obligatory loss in the urine. Also obligatory is the loss of calcium contained in the digestive juices and in desquamated intestinal epithelium, neither of which is related to plasma [Ca"] or to circulating PTH. Together they may be regarded as the calcium cost of digestion. This digestive-juice calcium averages about 3.53.75 mmol d-' in adult women [23]. While some of this amount is reabsorbed together with food calcium, given the generally low absorptive efficiency for calcium, most will be lost in the faeces. For this reason digestive-juice calcium can be a substantial route of loss, particularly when the absorption efficiency is below average. This is also the reason why net absorption can actually be negative at low intakes or low absorption efficiencies. Table 1 . Intakes required for calcium equilibrium Extraintestinal obligatory loss (mmol Ca d-I)

2.5

Absorption fraction

0.20 0.25 0.30 0.35 0.40

27.1 21.1 17.1 14.3 12.1

3.75 33.4 26.1 21.3 17.8 15.2

5.0 39.6 31.1 25.4 21.4 18.4

6.25 45.9 36.1 29.6 25.0 21.5

Table 1 summarizes these relationships and expresses them as the ingested calcium intake required to produce equilibrium for four arbitrarily selected (but typical) levels of obligatory loss, and for various levels of absorption efficiency. The equation used in these calculations, derived from the studies cited previously, is as follows: Required intake =

TIC +Net Abs - Absfx (Prox) Absfx

CALCIUM A N D OSTEOPOROSIS

where TIC = total intestinal calcium secretion (expressed as mmol d-'), Net Abs = the difference between ingested intake and faecal output (expressed as mmol d-I), Absfx = fractional absorption, and Prox = that portion of the TIC-generally 80-85 %-secreted sufficiently orad to be absorbed at the efficiency of food calcium [27]. In this calculation, typical adult levels of digestive-juice calcium secretion are assumed (TIC = 3.5 mmol d-' : Prox = 2.875 mmol d-l). The values in Table 1 clearly demonstrate the importance not only of absorption efficiency, but also of obligatory loss. What the data in Table 1 cannot directly show, however, is the adjustments that must be made when excretory loss changes following an increase in intake. Thus, at an absorption efficiency of 0.25. the table shows that the intake required to offset an increase in loss of 1.25 mmol (from 3.75 to 5.0 mmol) would increase by 5 mmol (i.e. c. 26 to 31 mmol). However, this is true only if the absorption fraction remains constant which, unfortunately, is not the case. Instead, as intake rises, absorption efficiency falls, and while more total calcium is absorbed, the absorption fraction is lower. If, for the sake of illustration, we assume that fractional absorption drops by only 10% (i.e. to 0.225), then the foregoing equation yields a value for the required intake that is no longer 31.1 mmol d-l, but 34.9 mmol d-', or a n overall increase in required intake of 3.775 mmol, just to offset a n increase in obligatory loss of 1.25 mmol d-'. These calculations are intended to be merely illustrative. As the empirical data already reviewed show, the actual net absorption from an intake increase is even less than this illustration suggests.

Calcium in prevention of osteoporosis The role of calcium intake in prevention of osteoporosis can be reduced to two basic components : building the largest bone mass possible within the limits of the genetic programme, and protecting what bone mass one has managed to accumulate. The studies described above have contributed significantly to our understanding of the maintenance requirement, and have also shown that this requirement changes at different life stages. Still, in a sense, they may be regarded as theoretical calculations. To be compelling they need to be buttressed by observations which demonstrate that calcium intake makes a difference to bone health. Such data do in fact exist, and will be reviewed below. For

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example, epidemiological data show that high, lifelong calcium intake reduces the risk of hip fracture by about 6 0 % [24, 251. Such studies highlight the practical importance of ensuring a n adequate calcium intake throughout life, and put to r e s t - o n e would hope-the dangerous notion that, practically speaking, there is no calcium deficiency state in man ~131. There follows a review of current evidence regarding the actual level of calcium intake required to build and protect bone mass during the periods of skeletal accumulation, maturity and involution. My focus is exclusively on women, because they have been studied far more extensively than men, because they carry a much greater osteoporosis burden than do men, and because, in the US at least, their calcium intake is on average 40% lower than that of men [261.

Life-stage requirements for calcium Childhood. From birth to the age of 10-12 years, bone mass increases from an average of about 0.6 mol of calcium to about 10 mol. Through most of this period the increase is approximately linear, and thus daily retention must average about 2.5 mmol. Recent isotope-based studies in children indicate that the average absorption efficiency is 3 5 4 5 % [2 71. Taking a conservative estimate for aggregate excretory and dermal losses of 2 . 5 4 mmol d-l, it follows that an intake of 14-16 mmol d-' should be sufficient to meet the needs of bone growth during childhood. Allowing for interindividual variation leads to a n estimated RDA value close to 20 mmol for children up to 11-12 years of age. Adolescence. During adolescence, skeletal growth accelerates, and at the peak of the adolescent growth spurt, skeletal growth requires daily retention of 9-10mmol calcium [28]. Even averaged over the age range 12-18 years, daily retention must be about 6 mmol, or more than twice the rate during childhood. Newly available, isotope-based studies of the absorption fraction in adolescents in their midteens yield values in the 3 0 4 0 % range [29], and no estimates in contemporary adolescents from any source exceed 4 0 4 5 % [27, 301. Further obligatory losses, principally through the urine, are relatively high (4.5-5.5 mmol d-' [30]). It seems paradoxical that the utilization efficiency for calcium should fall at the time of greatest need, and it may be that the

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explanation for this phenomenon in adolescent women needs to be sought in concomitant changes in other dietary or life-style factors. Whatever the reason, the phenomenon has obvious implications for calcium requirement. To absorb sufficient calcium both to mineralize the growing skeleton and to offset known excretory losses requires, at prevailing absorption efficiencies, a mean intake close to 30 mmol d-' throughout adolescence. Allowing for population variation, the adolescent RDA should be higher still, perhaps 3 5 4 0 mmol. This conclusion is supported by the balance studies of Matkovic et al. [30]. in which increasing dietary calcium from 6.25 to 4 0 mmol d-' in adolescent females produced no significant increase in urinary calcium. This finding strongly suggests that, even at an intake of 4 0 mmol d-l, the capacity of the growing skeleton to utilize dietary calcium has not been saturated. Since the average daily calcium retention rate during adolescence is at least twice that during childhood, it makes good sense to suggest that the adolescent RDA should also be at least twice the childhood recommendation. Young adulthood. Skeletal accumulation continues from 20 years to about 3 0 years of age, although at a slower rate. It has been suggested in recent years that bone mass, rather than continuing to increase, actually starts to decline as early as 20 years of age. This suggestion was based primarily on crosssectional studies of spine bone mass at that age, which appeared to show a decline after age 20 years [31], but a recent longitudinal study by Davies et al. has shown a clear increase in bone mass, even at the spine, between the ages of 20 and 30 years [32]. In this study, spine BMC increased at a rate of about 7% per decade, and if this value is extrapolated to the whole skeleton, it is found to be equivalent to a retention of about 0.5 mmol d-'. Garn's data for cortical bone [33] would suggest a slightly higher daily retention rate. Thus a figure of 0.5 mmol is a conservative one. At the same time it should be noted that the mean calcium intake of the young women in the Davies study was 19 mmol d-l, which is less than optimal as indicated by the foregoing calculations, and hence it is possible that an even higher accumulation rate might have been found had the intakes been higher. Absorption efficiency has been extensively studied in this age group, and is known to average about 32%. Obligatory losses average 5 mmol d-' and

hence, taking a conservative estimate for skeletal retention of 0.5 mmol d-', a mean intake of 22.525 mmol should be sufficient. Again, making allowance for population variation in absorption and excretion, the RDA should probably be 30 mmol up to the age of 30 years. The most recent edition of the RDAs in the US did, in fact, extend the adolescent figure of 30 mmol from the age of 1 8 years, up to 24 years [34], an important step in the right direction.

Maturity. In the absence of pregnancy and lactation, a woman's requirement from the age of 3 0 years until the menopause is probably the lowest since childhood. Absorption averages 30-3 5 "/o and extraintestinal excretory losses average 4-5 mmol d-', values that translate to a mean requirement to maintain equilibrium of 15-1 7.5 mmol d-'. Nordin's balance data [11], which did not take into account dermal losses, point to a figure that is only slightly lower, 12.5-15 mmol d-l. Hence the two estimates are essentially congruent. Both lead to a calculated RDA for this age category of 20-25 mmol.

Involution. Involutional bone loss in women has two major components. The first is related to oestrogen withdrawal (either at the time of menopause, or after termination of oestrogen replacement therapy), and is self-limited [35]. The same kind of rapid bone loss occurs in young women who become oestrogen deficient for any reason, and has also been reported for castrated males. It is as if the skeleton has different mass set-points for the hormone-replete and hormone-deprived states, and the bone loss that occurs immediately following gonadal hormone withdrawal represents a transition from one steady state to another. This transition can be approximated by an exponential function, with very rapid loss occurring during the first 1-3 years [36]. This oestrogen-withdrawal bone loss appears to be intrinsic, and thus to have essentially no extrinsic (i.e. nutritional) cause. As a result, it is at best only partially offset by such measures as high calcium intake and exercise. Dawson-Hughes et al. showed no benefit from increased calcium intake in women from 1-5 years after the menopause, but substantial protection thereafter [3 71. The second component of involutional loss is a slower, but continuing, process that is probably due in part to factors such as decreased mechanical loading, decreased muscle mass, accumulation of structural errors and, in some women, nutritional

CALCIUM AND OSTEOPOROSIS

deficiency. Probably by 5-6 years after the menopause, when bone is approaching its new equilibrium mass, the calcium economy is once again dependent on external factors. At this life-stage an oestrogendeprived woman is placed at two additional disadvantages. Lack of oestrogen results in a fall in calcium absorption efficiency, amounting to about a 7 % reduction from immediate premenopausal levels r121. At the same time, urinary calcium loss increases [ l l , 181. Since calcium requirement is a function of the balance between absorbed intake and obligatory losses, it follows inexorably that a simultaneous deterioration in both absorption and excretion will lead to an increased calcium requirement. In a very large group of studies from my laboratory [18, 191, in which both calcium balances and double-isotope absorption methods were employed, the oestrogendeprivation effect appears to increase the calcium requirement by about 12.5 mmol d-' [18, 191. This observation partly accounts for the increase in recommended intake from 25 mmol d-' to 37.5 mmol d-' adopted by the NIH Consensus Development Conference on Osteoporosis [381.

Evidence relating calcium intake to bone health It must be stressed once again that both fracture and bone fragility are multifactorial. and that meeting the foregoing calcium intake requirements will not prevent bony deterioration or weakness due to nonnutritional causes. Even so, populations with higher average intakes would be expected to have stronger bones and fewer fractures. The literature dealing with this topic is extensive, and most of it supports this expectation. Cumming, in a recently published meta-analysis of this literature [39], found the evidence for a positive correlation between calcium intake and bone strength/bone health to be conclusive. Since the time of his meta-analysis, even stronger evidence has been published, including a randomized controlled trial extending for 2 years and involving over 300 postmenopausal women [3 71. Dawson-Hughes et al. found that raising the calcium intake from a mean of about 10 mmol d-' to about 22.5 mmol d-l effectively abolished age-related loss in women six or more years past the menopause. A skeletal benefit of higher calcium intakes is also indicated by a longitudinal study of hip fracture in a retirement community [25], in which calcium intake of > 1 9 mmol d-' was associated with 6 0 % fewer

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hip fractures in both men and women, than in individuals with intake of < 10-11 mmol d-'. A Hong Kong study published in Chinese [40] found the same protective effect, although at substantially lower intakes, and a British study found a positive effect of calcium intake on hip fracture in men, but not in women [41]. Also indicative of the importance of adequate calcium intake are two recent reports of a protective effect of thiazide diuretics on hip fracture [42, 431, in both of which the use of thiazides was associated with significantly fewer hip fractures. In one of these studies [43], the effect was demonstrably dosedependent, and was not related to the use of other antihypertensive medication. 'I'hiazides are known both to decrease urinary calcium losses and to protect bone mass, and it is plausible that their fracture benefit is related to this effect on calcium metabolism, i.e. they improve the 'adequacy' of any given intake. Negative studies, of which there have been several (e.g. [13, 19, 44]), need to be interpreted in the context of the issues and methods involved, the most important of which is timing. Studies in the immediate postmenopause (e.g. [45, 461) have almost all been negative. The reasons have already been discussed: bone loss at that time represents a downward adjustment of bone mass caused by a fall in oestrogen production. Such studies have no bearing on the protective effect of an adequate calcium intake at other stages in a woman's life. The most important of the methodological issues is our inability to estimate accurately even current calcium intake [47], as well as the known poor correlation between present and past intake [48]. For other nutrients there are usually independent measures which can buttress intake estimates (e.g. serum albumin for protein, haemoglobin levels for iron, serum levels for various vitamins, hair or nail analysis for various trace elements, etc.). No independent measure exists for assessment of the adequacy of calcium nutrition, and we are thus restricted to working with what we can learn from dietary intake assessments.

Optimal intake The study of Dawson-Hughes et a/. [37] might be interpreted as indicating that full benefit had been realized in postmenopausal women at intakes of < 2 5 mmol d-', and the negative studies of van Berensteijn from the Netherlands [49], where almost

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Table 2. Estimated calcium requirements in US women Life-stage (years)

Mean requirements (mmol d-')

Estimated RDA (mmol d-')

Skeletal accumulation : 1-1 2 12-1 8 18-30

12.5-1 5 30 20-2 5

20 37.5 30

Maturity:* 30-menopause

15-20

20-25

Involution : Menopause Senescence

25-30

+ 5 years

?

7

37.5f

mature adults can ensure is that calcium deficiency will neither be causing skeletal weakness in its own right nor aggravating the weakness produced by other causal factors. Furthermore, an adequate calcium intake cannot be expected to prevent or reverse the bone loss and fragility due to other factors. Calcium is a nutrient, not a drug. The only disorder it can be expected to alleviate is calcium deficiency. However, the evidence strongly indicates that calcium deficiency is prevalent in many Western populations, and that it thereby contributes to their osteoporotic fracture burden.

* Non-pregnant, non-lactating women.

Calcium in treatment of osteoporosis all women have a calcium intake of about 25 mmol d-', would appear to point to the same conclusion. The reasons why a real effect may be hard to find when only individuals at the upper end of an intake range are studied have been discussed by Beaton in his 1986 McCollum lecture [SO]. Nevertheless, Hansen et al. recently reported that Danish women with intakes of > 37.5 mmol d-I had substantially greater bone mass at menopause than women with intakes below that level, and they maintained that advantage 12 years later, after both groups had sustained the expected bone loss of the menopause [5 11. Thus uncertainty about optimal calcium intake in mature adults persists. However, that uncertainty should not obscure the fact that the evidence from both clinical and metabolic studies is overwhelming : higher calcium intakes confer a bone-protective effect. Some of this protection is due to the development of greater peak bone mass, and some is due to protection against age-related loss. Probably the best available approach for estimation of optimal intake is the metabolic one, already described in detail. This is simply because it is the only method that can adequately quantify and control the independent variable (i.e. calcium intake). Table 2 summarizes the requirement estimates developed above for the various life-stages; it thus establishes the target intakes for calcium which are best calculated to prevent osteoporosis. In concluding this section on prevention, it is important to stress once again both that osteoporosis is a multifactorial disorder and that inadequate calcium intake is only one of several interacting factors that determine whether low-trauma fractures will occur. All that a n adequate calcium intake in

In patients who have already demonstrated bony fragility by sustaining one or more low-trauma fractures, treatment must be directed first at pain control, then at fracture healing and rehabilitation. Good nutrition plays an important role in this process, as with recovery from any other injury, but calcium itself occupies no unique position with regard to these therapeutic objectives. However, there are two other therapeutic goals in which calcium does play a n important role. The first of these is protection against further deterioration of the skeleton caused by an inadequate calcium intake. The second is the support of more specific therapies, the end result of which is an increase in bone mass. Whatever may have been the specific pathogenesis of bony fragility in any given patient with osteoporosis, it is important to ensure that homeostatically mediated bone breakdown, due to inadequate calcium intake, is not contributing to a worsening of the situation. Just as low calcium intake can lead to bone loss in the pre-fracture years, the same is true after fracture. All other therapeutic efforts will be in vain if we fail to stop a diet-related, continuing weakening of the skeleton. At least four recent controlled trials have used calcium supplements for their placebo groups [52-551. In all of them bone loss was completely arrested, generally with supplemented intakes in the range of 37.5 mmol calcium d-' or higher. Whether supplemental calcium by itself will reduce the fracture rate is uncertain. Riggs et al. [56], in a series of uncontrolled studies, reported an apparent 50 % reduction in fracture rate in subjects given calcium and vitamin D alone, compared to untreated patients. However, there are no formal data from controlled trials with regard to this issue.

CALCIUM A N D OSTEOPOROSIS

The second goal is the support of the bone-forming effect of other therapies, such as fluoride, which is able to increase the spinal bone mass at a rate of c. 10%per year. If dietary intake is inadequate, net bone mass accumulation cannot take place, since the mineral must come from somewhere. If bone mass is to increase, sufficient mineral has to be supplied from the diet (or supplements) both to support the increase in bone mass and to offset obligatory losses. This is a near truism that has not, unfortunately, always been adequately appreciated. The best that the body can do when intake is limiting is to transfer mineral from one region to another, increasing bone resorption to match the increase in bone formation produced by the therapy. On the basis of the available data, calcium intake in patients treated for osteoporosis should be at least 37.5 mmol d-'. Some trials are currently investigating intakes of > 60 mmol d-'.

Calcium sources The best source of calcium is food. Calcium supplements have a role, but their name defines what that role should be - a ' supplement' to what is obtained from food sources. It is not just a matter of one source being more bioavailable than another (in fact, the differences in absorbability between foods and supplements are small). Rather it is because bone health is not a single nutrient issue. Diets low in calcium are commonly low in other nutrients as well [57]. Zinc, manganese, copper, ascorbic acid, protein and vitamin D are all known to be essential for normal bone development, although the precise role of each in the maintenance of the adult skeleton has not yet been established. Also, as has already been stressed, fractures are not due simply to low bone mass, but to a cluster of factors, many of which have nutritional correlates. In a very important study, Delmi et al. [58] demonstrated both that hip fracture patients exhibited multiple evidences of malnutrition on admission, and that a protein-based, multinutrient supplement produced a dramatic improvement in recovery from the injury, compared to unsupplemented patients. Also, as is well recognized by physicians, it is extremely difficult to persuade patients to adhere faithfully to a pill-taking regimen, even when the medication is essential for the treatment of an acute illness. It is very much more difficuIt to achieve good compliance over periods of years when no immediate

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benefits can be perceived by the patient. Thus any strategy that attempts to maintain good nutrition on a regimen of voluntary pill-taking appears to be doomed to failure, at least for the average member of the population. These are some reasons why food must be considered the preferred source of calcium. When supplements are indicated, certain practical questions arise. Which supplement is best ? When should supplements be taken? Should they be taken with meals, between meals, or at bedtime? Should they be taken once a day or in divided doses? Calcium supplements are available in a bewildering variety of preparations, both liquid and solid. The accompanying anions include carbonate, phosphate, sulphate, acetate, lactate, gluconate, glubionate, glycerophosphate, citrate and citrate-malate (CCM), as well as various chelated complexes. The calcium density of these salts ranges from a minimum of 6.3% by weight (calcium glubionate) to a maximum of almost 40% (calcium carbonate, oyster shell, hydroxyapatite). Some (e.g. calcium carbonate) are formulated separately both as antacids and as calcium supplements. So far as is known, the antacid formulations function perfectly well as supplements. Some sources are currently used only as food additives/fortifiers (e.g. calcium sulphate, CCM). Market-dominant products vary from one country to another. In the US, calcium carbonate is the principal chemical form in supplements. Coingestion of calcium supplements with foods results in a 20-2 5 % improvement in absorption compared to the values obtained when a sourcecis ingested on an empty stomach [59]. In addition to this meal effect, applicable to both food and supplement calcium sources, some individuals will substantially malabsorb calcium carbonate from a n empty stomach [59], even though they absorb the carbonate salt normally when it is taken with a meal. We do not know how to detect such individuals in advance, and the reason for this failure is quite unknown. Gastric acid production probably aids absorption of the less soluble preparations when they are ingested on an empty stomach, but acid production is not required for absorption if the calcium source is ingested as a part of a meal [60]. The absorbability of calcium from several salts for which reliable tracer-based data are available [61] is listed in ascending order in Table 3. Various food sources are also included for comparison. The comparability of most sources is apparent. The calcium salts not listed have not been subjected to absorption

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Table 3. Table 3. Absorbability of calcium from certain supplement and food sources* Source

Fractional absorption

Salt/preparationf Hydroxyapatite Tricalcium phosphate Calcium carbonate Calcium citrate Bone meal/bone powder Calcium-citrate-malate Bisglycinocalcium

0.203f0.110 0.252f0.130 0.296 0.054 0.296 k 0.060 0.333k0.113 0.363k0.076 0.440f0.104

Food Spinach Low phytate soybeans Milk Kale

0.01 2 f0.007 0.306 k 0.054 0.339k0.095 0.405 k 0.101

* Values adjusted to an intake load of 7.5 mmol.

t

See Ref. [62] for details. Mean values +SD are shown, measured under standard meal conditions

testing by any acceptable method. As the data in Table 3 suggest, existing differences in absorbability between most sources, where these are known, are generally sufficiently small to be easily compensated for by slight differences in dosage. Much more important than intrinsic absorbability of the component salt is the quality of the tablet formulation [62, 631. Poorly formulated products do not disintegrate under simulated gastric conditions in vitro, even when the salt contained would otherwise be highly soluble in gastric juice. It is likely that such preparations are very poorly absorbed in vivo. Thus generic calcium supplements, such as are commonly used in the US, are not reliable. One must either prescribe or use a brand-name product with proven reliability, or resort to a chewable or effervescent preparation (for neither of which is disintegration a factor). Calcium absorption efficiency varies inversely as the logarithm of the size of the load. This means that 2 5 mmol of calcium taken as two doses of 12.5 mmol each from a low calcium diet results in 30% more calcium actually being absorbed than when it is taken in a single dose, and four divided doses of 6.25 mmol each result in 60% more calcium absorption. For this reason, a divided dose regimen is generally preferable (for example, four times a day - with meals and at bedtime). However, with this issue, as with all therapeutic decisions, there will be trade-offs. Compliance is apt to be less good with a four-times-a-day regimen than with only one dose

per day, and the physician will have to match the prescription to the patient. There are other trade-offs that must be considered with regard to the timing of doses as well. As already noted, calcium absorption is better with meals than on an empty stomach. However, it is also known that large calcium loads will interfere with iron absorption [ 5 2 ] ,and this is as true for food calcium sources as it is for medicinal ones. This general type of nutrientnutrient interference is not specific for calcium, and would not be a problem in a well-nourished individual. It is simply one of many examples of how most nutrients interact with one another in the process of digestion and absorption. However, in a woman with a borderline iron deficiency, this interference should be borne in mind when prescribing a calcium supplement regimen. The only calcium preparation studied to date that does not interfere with iron absorption is calcium-citrate-malate (CCM), now available only as a fortifier in fruit juices [64]: iron absorption in that situation is protected both by the ascorbic acid of the fruit juice and by the citrate anion of the calcium source. It is likely that calcium citrate would also interfere less with iron absorption than, for example, calcium carbonate, but the question has not been directly tested. Although a supplement will be absorbed somewhat less well at bedtime (unless taken with a snack), taking calcium at that time has much to recommend it, since most PTH-mediated bone breakdown occurs during the fasting state, and some of this bone loss can be prevented by taking a calcium supplement at bedtime [65]. Thus there are advantages and disadvantages to all of the possible regimens. This is probably no less true for the dosing of many clearly medicinal agents as well. We simply know more about calcium absorptive physiology than we do about the absorption and interaction of many drugs. On balance, a four-times-a-day regimen appears to be optimal for most patients. Finally, in situations where supplements are recommended, it is important to perform a total nutritional assessment in order to recognize and address the presence of other limiting nutrient intakes.

References 1 Cummings SR. Nevitt MC. A hypothesis: the causes of hip fractures. J Cerontol Med Sci 1989: 44: M107-Ill.

CALCIUM A N D OSTEOPOROSIS

2 Heaney RP. Osteoporotic fracture space: an hypothesis. Bone Miner 1 9 8 9 : 6 : 1-13. 3 Eventov I. Frisch B. Cohen 2. Hammel I. Osteopenia. hematopoiesis and osseous remodelling in iliac crest and femoral neck biopsies: a prospective study of 102 cases of femoral neck fractures. Bone 1 9 9 1 : 12: 1-6. 4 Mosekilde L. Age-related changes in vertebral trabecular bone architecture-assessed by a new method. Bone 1 9 8 8 : 9 : 247-50. 5 Kleerekoper M. Feldkamp LA, Goldstein SA. Flynn MJ. Pafitt AM. Cancellous bone architecture and bone strength. In: Christiansen C. Johansen JS, Riis BJ. eds. Osteoporosis 1 9 8 7 : 294-300. 6 Aaron JE, Makins NB. Sagreiya K. The microanatomy of trabecular bone loss in normal aging men and women. Clin Orthop Re1 Res 1987: 215: 260-71. 7 Johnston CC Jr. The relative importance of nutrition compared to the genetic factors in the development of bone mass. In: Burckhardt P, Heaney RP, eds. Nutritional Aspects o/ Osteoporosis. Proceedings of International Symposium, Lausanne. Switzerland. May 1991. New York: Raven Press, 1991. 8 Slemenda C. Christian J. Williams C. Johnston CC. Jr. The changing relative importance of genetics and environment in adult women. / Bone Miner Res 1 9 8 9 : 4 : S413. 9 Evans RA. Marel GM. Lancaster EK, Kos S. Evans M. Wong SYP. Bone mass is low in relatives of osteoporotic patients. Ann Intem Med 1988: 109: 870-73. 10 Seeman E. Hopper JL, Bach LA et al. Reduced bone mass in daughters of women with osteoporosis. N Engl [ Med 1989; 320: 554-8. 1I Nordin BEC. Polley KJ. Need AG. Morris HA, Marshall D. The problem of calcium requirement. Am [ Clin Nutr 1 9 8 7 : 4 5 : 1295-304. 12 Heaney RP. Recker RR. Stegman MR. Moy AJ. Calcium absorption in women : relationships to calcium intake, estrogen status, and age. J Bone Miner Res 1989 : 4 : 469-75. 13 Kanis JA. Passmore M. Calcium supplementation of the diet, I and 11. BM/ 1989: 298: 137-40, 205-8. 14 Jensen FT. Charles P. Mosekilde L, Hansen HH. Calcium metabolism evaluated by '"calcium-kinetics: a physiological model with correction for faecal lag time and estimation of dermal calcium loss. Clin Physiol 1983; 3: 187-204. 15 Charles P. Nutrition and the obligatory calcium losses. In: Burckhardt P. Heaney RP. eds. Nutritional Aspects of Osteoporosis. Proceedings of International Symposium, Lausanne. Switzerland. May 1991. New York. Raven Press: 1991. 16 Wilkinson R. Absorption of calcium, phosphorus and magnesium. In: Nordin BEC. ed. Calcium. Phosphate and Magnesium Metabolism. London: Churchill Livingstone. 1 9 7 6 : 36-1 12. 17 Eaton SB. Konner M. Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med 1985 : 312: 283-9. 18 Heaney RP. Recker RR, Saville PD. Menopausal changes in calcium balance performance. / Lab Clin Med 1978: 9 2 : 9 5 3-63. 19 Heaney RP. The calcium controversy: a middle ground between the extremes. Public Health Rep 1989: S104: 36-46. 2 0 Heaney RP. Recker RR. Effects of nitrogen, phosphorus, and caffeineon calcium balance in women. J Lab Clin Med 1 9 8 2 : 99: 46-55. 21 Goulding A. Effects of varying dietary salt intake on the fasting urinary excretion of sodium, calcium and hydroxyproline in young women. NZ Med J 1 9 8 3 : 9 6 : 953-4.

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2 2 Barger-Lux MJ, Heaney RP. Stegman MR. Effects of moderate caffeine intake on the calcium economy of premenopausal women. Am J Clin Nutr 1 9 9 0 : 52: 722-5. 2 3 Heaney RP. Skillman TG. Secretion and excretion of calcium by the human gastrointestinal tract. J Lab Clin Med 1 9 6 4 ; 6 4 : 29-41. 2 4 Matkovic V. Kostial K. Simonovic [. Burina R, Brodarec A, Nordin BEC. Bone status and fracture rates in two regions in Yugoslavia. Am J Clin Nutr 1 9 7 9 ; 32: 540-9. 25 Holbrook TL. Barrett-Connor E, Wingard DL. Dietary calcium and risk of hip fracture: 14-year prospective population study. ILncet 1 9 8 8 : ii: 1046-9. 2 6 National Center for Health Statistics, Carroll MD. Abraham S. Dresser CM. Dietary lntuke Source Data: United States, 1976-80. Vital and Health Statistics. Series 11-No. 231. DHHS Pub. No. (PHS) 83-1681. Public Health Service. Washington: US. Government Printing Office, March 1983. 2 7 Miller 12. Smith DL. Flora L. Peacock M. Johnston CC Jr. Calcium absorption in children estimated from single and double stable calcium isotope techniques. Clin Chim Actu 9 1 8 9 : 183: 107-13. 28 Leitch I, Aitken FC. The estimation of calcium requirement: a re-examination. Nutr Abstracts Rev 1 9 5 9 : 2 9 : 393-407. 29 Miller JZ, Smith DL. Flora L. Slemenda C. Jiang X.Johnston CC Jr. Calcium absorption from calcium carbonate and a new form of calcium (CCM) in healthy mole and female adolescents. Am J Clin Nutr 1 9 8 8 ; 4 8 : 1 2 9 1 4 . 3 0 Matkovic V, Fontana D. Tominac C. Goel P. Chesnut CC Ill. Factors that influence peak bone mass formation: a study of calcium balance and the inheritance of bone mass in adolescent females. Am J Clin Nutr 1990: 52: 878-88. 31 Riggs BL. Wahner HW. Dunn WL. Mazess RB, Offord KP. Melton LJ 111. Differential changes in bone mineral density of the appendicular and axial skeleton with aging. J Clin Invest 1981; 67: 328-35. 32 Davies KM. Recker RR, Stegman MR, Heaney RP, Kimmel DB. k i s t J. Third decade bone gain in women. Bone Miner Res 1 9 8 9 ; 4 : S327. 33 Garn SM. The Earlier Gain and the Later Ims of Cortical Bone. Springfield, Illinois: Charles C. Thomas, 1970. 34 Recommended Dietary Allowances, Subcommittee on the Tenth Edition of the RDAs Food and Nutrition Board, Commission on Life Sciences, National Research Council. Washington DC: National Academy Press, 1989. 35 Nordin BEC. Need AG, Chatterton BE, Horowitz M.Morris HA. The relative contributions of age and years since menopause to postmenopausal bone loss. J Clirr Endocrinol Metab 1 9 9 0 : 70: 83-8. 36 Heaney RP. Estrogen-calcium interactions in the postmenopause: a quantitative description. Bone Miner 1990; 11 : 67-84. 37 Dawson-Hughes B. Dallal GE. Krall EA.Sadowski L. Sahyoung N. Tannenbaum S. A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. N Engl J Med 1 9 9 0 : 323: 878-83. 38 National Institutes of Health Osteoporosis Consensus Development Conference Statement. J Am Med Assoc 1 9 8 4 : 2 5 2 : 799-802. 39 Cumming RC. Calcium intake and bone mass: a quantitative review of the evidence. Calcif Tissue Int 1 9 9 0 : 4 7 : 194-201. 40 Lau E. Donnan S, Barker DJP. Cooper C. Physical activity and calcium intake in fracture of the proximal femur in Hong Kong. BMJ 1988: 297: 1441-3.

180

R. P. HEANEY

41 Cooper C. Barker DJP. Wickham C. Physical activity, muscle strength, and calcium intake in fracture of the proximal femur in Britain. B M J 1 9 8 8 : 297: 1443-6. 4 2 LaCroix AZ, Wienpahl J, White LR et al. Thiazide diuretic agents and the incidence of hip fracture. N Engl J Med 1 9 9 0 : 322: 286-90. 4 3 Ray WA. Griffin MR. Downey W. Melton LJ 111. Long-term use of thiaxide diuretics and risk of hip fracture. IAncet 1989 : i: 687-90. 4 4 Nordin BEC, Heaney RP. Calcium supplementation of the diet: justified by present evidence. BMJ 1990: 300: 1056-60. 4 5 Riis B. Thomsen K, Christiansen C. Does calcium supplementation prevent postmenopausal bone loss? N Engl/ Med 1987: 316: 173-7. 4 6 Ettinger B. Genant HK. Cann CE. Postmenopausal bone loss is prevented by treatment with low-dosage estrogen with calcium. Ann Intern Med 1 9 8 7 : 106: 4 0 4 5 . 4 7 Barrett-Connor E. Diet assessment and analysis for epidemiologic studies of osteoporosis, In: Burckardt P. Heaney RP. eds. Proceedings of an lnternational Symposium on Osteoporosis, Lausanne. May 1991. Raven Press, New York. 4 8 Heaney RP. Davies KM. Recker RR. Packard PT. Long-term consistency of nutrient intakes. J Nutr 1 9 9 0 : 1 2 0 : 869-75. 4 9 van Berensteijn ECH. van't Hof MA, de Waard H et al. Relation of axial bone mass to habitual calcium intake and to cortical bone loss in healthy early postmenopausal women. Bone 1 9 9 0 ; 1 1 : 7-13. 5 0 Beaton GH. Toward harmonixation of dietary, biochemical, and clinical assessments : the meanings of nutritional status and requirements. Nutr Rev 1 9 8 6 : 4 4 : 349-58. 51 Hansen MA, Overgaard K. Riis JH. Christiansen. C. Potential risk factors for development of postmenopausal osteoporosisexamined over a 12-year period. Osteoporosis hit 1991: 1 : 95-102. 52 Riggs BL. Hodgson SF. O'Fallon WM et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1 9 9 0 : 322: 802-9. 53 Ott SM. Chesnut CH 111. Calcitriol treatment is not effective in postmenopausal osteoporosis. Ann Intern Med 1989: 1 1 0 : 2 6 7-74.

54 Storm T. Thamsborg G. Steiniche T. Genant HK. Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in postmenopausal osteoporosis. N Engl J Med 1 9 9 0 : 322: 1265-71. 55 Watts NB. Harris ST. Genant HK et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 1 9 9 0 : 323: 73-9. 56 Riggs BL. Seeman E. Hodgson SF. Taves DR. O'Fallon WM. Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis (comparison with conventional therapy). N Engl J Med 1 9 8 2 : 3 0 6 : 446-50. 57 Holbrook TL. Barrett-Connor E. Calcium intake: covariates and confounders. Am J Clin Nutr 1991 : 53: 7 4 1 4 . 58 Delmi M. Rapin C-H. Bengoa J-M. Delmas PD. Vasey H. Bonjour J-P. Dietary supplementation in elderly patients with fractured neck of the femur. IAncet 1 9 9 0 : 3 3 5 : 1013-6. 59 Heaney RP. Smith KT. Recker RR. Hinders SM. Meal effects on calcium absorption. Am J Clin Nutr 1989 : 4 9 : 372-6. 6 0 Recker RR. Calcium absorption and achlorhydria. N Erigl J Med 1 9 8 5 : 313: 70-73. 61 Heaney RP. Recker RR. Weaver CM. Absorbability of calcium sources: the limited role of solubility. Calcij Tissire Int 1 9 9 0 : 46: 3 0 0 4 . 62 Carr CJ, Shangraw RF. Nutritional and pharmaceutical aspects of calcium supplementation. Am Pharm 1 9 8 7 : NS27: 49-57. 63 Shangraw K. Factors to consider in the selection of a calcium supplement. Public Health Key 1 9 8 9 : Sept-Oct: S46-50. 6 4 Deehr MS. Dallal GE. Smith KT. Taulbee ID. Dawson-Hughes B. Effects of different calcium sources on iron absorption in postmenopausal women. Am J Clin Nutr 1990: 51 : 95-9. 65 HorowitL M . Need AG. Philcox ]C, Nordin BEC. Biochemical effects of a calcium supplement in osteoporotic postmenopausal women with normal absorption and malabsorption of calcium. Mirier Electrolgte Metab 1 9 8 7 : 1 3 : 1 12-6. Received 19 ]uly 1991. accepted 2 October 1991. Correspondence; Professor R.P. Heaney. Creighton University. Omaha, Nebraska, USA.