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Creighton University, Omaha, Nebraska
Purdue University, West Lafayette, Indiana
Address reprint requests to: Robert P. Heaney, M.D., Creighton University Medical Center, 601 N. 30th St., Suite 4841, Omaha, NE 68131. rheaney{at}creighton.edu
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ABSTRACT |
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 TOP ABSTRACT IntroductionDietary Calcium and Childhood...Dietary Calcium, Physical...Calcium, Bone Remodeling, and...ConclusionsREFERENCES |
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Change in bone mass and size during growth are dependent on both calcium intake and exercise, with the largest differences being observed in prepubertal children who have both high exercise levels and high calcium intakes. Much of this benefit is expressed as increased bone diameter (and hence stiffness). Fracture risk peaks at about the time of puberty and is inversely related to bone mass. However, even prepubertally, children with low calcium intakes have been reported to have a fracture rate 2.7x that of their birth cohort.
Bone remodeling triples from age 50 to 65 in typical women and is now recognized to have primarily a homeostatic basis. While remodeling improves bone strength by repairing acquired defects, homeostatic remodeling, while necessary to maintain blood calcium levels, contributes only structural weakness to bone. High calcium intakes in postmenopausal and older women reduce this homeostatic remodeling to approximately pre-menopausal values and improve bone strength immediately, well prior to any appreciable change in bone mass.
Key words: calcium, dairy, bone quality, bone remodeling, fracture, growth
Key teaching points:
• Low bone mass is associated with increased fracture risk in children, just as in adults.
• Low dairy intake is one of the causes of reduced bone mass during growth.
• Physical activity and calcium intake interact during growth, with the largest accumulation of bone being concentrated in children with high physical activity and high calcium intakes.
• Bone remodeling, necessary to repair or reshape bone, also serves calcium homeostasis; on prevailing diets, homeostatic remodeling is larger than structural remodeling, tripling in magnitude from the premenopausal years to age 65.
• Homeostatic remodeling, while it provides needed calcium ions to the extracellular fluid, weakens bone locally, wherever in the skeleton it occurs. Available evidence suggests that excessive remodeling is a major cause of osteoporotic bony fragility.
• Reduction in bone remodeling by high calcium intakes produces an immediate reduction in fracture risk, well before perceptible change in bone mass can occur.
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Introduction |
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TOPABSTRACTIntroductionDietary Calcium and Childhood...Dietary Calcium, Physical...Calcium, Bone Remodeling, and...ConclusionsREFERENCES |
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Although there remain some isolated pockets of disagreement (e.g., ref. 6), there is now a broad consensus that a calcium intake of 1000–1500 mg/d is needed to ensure skeletal optimization across the population at all ages after childhood. The policy statements cited review the now massive body of evidence supporting this consensus. Our purpose here is to highlight new information on the relation of calcium intake to childhood fractures, on the interaction of dietary calcium and physical activity in skeletal health, and on the still evolving understanding of the role played by bone remodeling in bony fragility and its interaction with calcium intake.
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Dietary Calcium and Childhood Fractures |
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TOPABSTRACTIntroductionDietary Calcium and Childhood...Dietary Calcium, Physical...Calcium, Bone Remodeling, and...ConclusionsREFERENCES |
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Childhood fractures are often attributed mainly to the "clumsiness" and risky behaviors of youth. However, Goulding’s report [8] on the association of fracture with low bone density in 3–15 year old girls living in New Zealand showed that fracture incidence even during childhood was related to a property of bone, i.e. massiveness, modifiable by lifestyle choices. Although calcium intakes in children with fractures and healthy controls were not significantly different for Goulding’s cohort of girls or in a subsequent cohort of boys [9], Goulding’s group subsequently reported that children under age 10 who were milk avoiders had significantly less bone and were shorter than a birth cohort of more than 1000 from the same city ( 10). In her population, the odds ratio for a fracture in those with low bone density compared to matched controls was 2.3 for the radius, 2.4 for the spine, and 2.0 for the hip. The milk avoiders had total skeletal bone mineral content (BMC) Z-scores averaging –0.45, which was significantly different than the distribution in the healthy population (Z-scores represent deviation from the age-adjusted mean normative data). A subsequent evaluation of their relative fracture incidence showed that one in three of the 50 milk avoiders had reported fractures, with 18 of their 22 fractures occurring before age 7 [11]. This fracture rate was 175% greater in the milk avoiders than expected from their birth cohort. Interestingly, the milk avoiders also had a higher risk of being overweight. Given that the most common site of fracture was the forearm, being overweight could exacerbate the impact load on the arm during a fall.
Vulnerability to fracture is not uniform across childhood. There is a transient increase in porosity of cortical bone during puberty as a result of a phase lag between achievement of peak height and peak bone mass [12]. The timing of this decrease in bone density was recently characterized in a group of Canadian children studied longitudinally by annual bone density scans through puberty [13]. In girls, average peak height velocity occurred at age 11.8 and average peak BMC velocity occurred at age 12.4, a lag of 0.7 y. Similarly, in boys the lag occurred between an average peak height velocity of 13.4 y and to a peak BMC velocity of 14.1 y.
Fig. 1 profiles the incidence of forearm fracture with age in the Midwestern U.S. [14]. The peak incidence of fracture occurs slightly before the period of increased bone porosity predicted by Bailey et al. [15]. In girls, the highest rate of bone turnover occurs during the 2 years preceding onset of menses and declines after onset of menses [16]. Bone strength expressed as fracture incidence may relate as much to bone turnover rate as to bone mass, as we discuss later. The peak incidence of fracture in girls aged 8–11 and boys aged 11–14 would fall close to peak bone turnover rates associated with pubertal growth. However, neither a dip in bone mineral density (BMD) nor accelerated bone turnover, suffice to explain the frequency of fracture at ages younger than 7 years in milk-avoiding New Zealand children [11].
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Dietary Calcium, Physical Activity, and the Growing Skeleton |
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TOPABSTRACTIntroductionDietary Calcium and Childhood...Dietary Calcium, Physical...Calcium, Bone Remodeling, and...ConclusionsREFERENCES |
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1 g/day randomized to exercise intervention had improved BMD at the spine [19] and tibia and hip [20] compared to calcium alone. However, the interaction between dietary calcium and physical activity in the growing skeleton remained uncertain because of lack of intervention trials and the inability of then available bone densitometry to capture bone geometric characteristics (beyond measurement of BMD and BMC) which contribute to strength in the growing skeleton. Two important intervention trials have been reported since 2002 that shed light on the interaction of dietary calcium and physical activity in growing bone. Specker and Binkley [ 21] studied 239 children aged 3–5 y for 1 year who were randomized to 1 g/d calcium or placebo and to two exercise regimens, gross motor (weight bearing) or fine motor (sitting). Leg BMC gain, determined by dual energy X-ray absorptiometry (DXA), was significantly higher only in the combined calcium and weight-bearing exercise group. However, peripheral quantitative computed tomography (pQCT) of the 20% tibia, which measures geometry of the leg, gave additional information about bone strength.
As shown in Fig. 2, weight-bearing exercise alone increased tibia periosteal and endosteal circumferences (P = 0.05) which raised bone strength by increasing cross-sectional moment of inertia, even though there was no increase in bone mass. Cross-sectional moment of inertia is a measure of the distribution of material around a given axis. The contribution of bone mass to strength is proportional to its squared distance from the axis around which bending occurs. Thus small increases in diameter can have profound positive effects on the bending strength of a bone. There was a significant interaction between weight-bearing exercise and calcium supplementation for leg BMC (P = 0.05) and tibial cortical thickness and cortical area (P 
0.02), resulting in the largest bone gain. With only BMC from DXA, the strength advantage from greater bone circumferences due to exercise alone was not apparent. The increased calcium intake allowed greater bone mineralization of the larger bone area stimulated by exercise. This insight was achieved through the use of a factorial design and bone imaging technology.
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Main effects of calcium intake and physical activity on bone gain have been reported in a number of randomized, controlled trials in children [7]. The effects may differ at bone sites which differ in cortical vs. trabecular bone, the stage of maturity of the growing skeleton, or the interdependency of calcium intake and physical activity. Cortical-rich bone regions have responded more to calcium supplementation in most trials than trabecular-rich regions [24]. On the other hand, activity trials in children have shown significant increases in trabecular bone [25] as well. Mechanical loading stimulates trabecular number and size [26]. Activity trials usually are more effective in prepubertal children possibly because of a synergistic activity between exercise and growth hormone [27]. Findings on the benefits of calcium supplementation in prepubertal vs. pubertal children have been inconsistent. In the only calcium supplementation trial that has spanned puberty, the benefits of calcium on bone were greater during the pubertal growth spurt than during bone consolidation [28]. The lack of main effects of calcium and exercise and positive interaction of the two in the Specker and Binkley [21] study suggest that part of the inconsistency among trials of either calcium or activity alone may be the failure to appreciate this interaction.
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Calcium, Bone Remodeling, and Skeletal Fragility |
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TOPABSTRACTIntroductionDietary Calcium and Childhood...Dietary Calcium, Physical...Calcium, Bone Remodeling, and...ConclusionsREFERENCES |
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Both types share a common feature: bone mineralization in the formation phase of remodeling takes calcium and phosphorus out of the circulating blood, creating a mineral deficit in the ECF which constitutes the principal systemic basis for stimulating parathyroid hormone (PTH) secretion. PTH in turn is the principal determinant of the quantity of bone resorption occurring throughout the skeleton. In this sense, bone mineralization "pulls" bone resorption. In parathyroidectomized animals and in humans with hypoparathyroidism, total bone remodeling drops to levels less than one-sixth the value found in intact organisms. The result, however, is usually hypocalcemia.
During periods of fasting or low calcium intake, PTH secretion rises, and with it bone resorption (and, thereby, total remodeling). From a homeostatic perspective, such remodeling provides the calcium needed to maintain ECF [Ca2+]. However, structurally, homeostatic remodeling contributes only weakness, since bone at sites being remodeled is reduced in mass and hence in strength. This strength reduction is illustrated diagrammatically in Fig. 3, which makes the point that a resorption cavity in the side of a load-bearing bone trabecula produces local weakness out of proportion to the modest reduction in mass. Over the short term, this loss in strength is trivial, but if inadequate calcium intake is continuous, then remodeling remains high and fragility increases. The numbers of these compromised trabeculae accumulate and ultimately bone mass declines as well. It is important to note that the increase in fragility precedes appreciable loss of mass, and is due, as Fig. 3 illustrates, to compromised structures.
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The remodeling transient has to be factored into any interpretation of the results of interventions that alter bone remodeling, particularly if one is interested in the effects of the intervention on steady state bone balance [31, 32]. But until recently, the transient was seen mainly as something that got in the way of discerning the "true" effect of the agent on bone [32]. It is now likely that the remodeling change is substantially more important than the mass change - at least over the short term when the remodeling change is fully expressed but the mass change is just getting under way.
This conclusion first became apparent in the analysis of osteoporosis treatment trials, in which BMD change was found to explain less than half of the fracture reduction at the end of the trial [33]. Even more to the point, the fracture reduction produced by bisphosphonates and selective estrogen receptor modulators (SERMs) was noted to begin immediately after starting treatment, before there was time for an appreciable mass difference to develop [34,35]. But calcium also functions as an antiresorptive agent. It does not antagonize PTH action on bone as do estrogen, the SERMs, and the bisphosphonates, but reduces remodeling by directly reducing PTH secretion. McKane et al., for example, showed that high calcium intakes in healthy postmenopausal women reduced 24-hr PTH levels by 40% [36]. Moreover, analysis of the fracture risk curves reported for two major calcium and vitamin D intervention studies [36, 37] shows clearly that the fracture risk reduction occurs almost immediately after starting treatment. Fig. 4 is a replot of some of the fracture data of these two trials, showing forcefully the prompt reduction in fracture risk that is produced by supplemental calcium and vitamin D.
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Although most of the data on this effect of remodeling have been developed in studies of the elderly, similar conclusions seem applicable to studies in young people. Fig. 5 is a schematic redrawing of the data from the calcium intervention trial of Johnston et al. in adolescents [39], and its follow-up, post-intervention, by Slemenda et al. [40]. The figure shows the curvilinear positive remodeling transient at the onset of supplementation, and the corresponding negative transient at its withdrawal. Bone mass in both the treated and untreated groups was increasing, as these were rapidly growing young people. The research question had been "Would this bone accumulation be greater in the calcium-supplemented group?". Such gain would have consisted of a combination of coincident growth, calcium augmentation (if any), and the remodeling transient, with the latter now recognized to be the largest of the three, at least over the short term. Unfortunately, the remodeling transient had not entered into design considerations at the time this trial was performed, and it was the total increase that was the design endpoint.
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As this example illustrates, the transient has come to be seen mainly as an important confounding factor. However, with the insight derived from the fracture efficacy trials in the elderly, it now seems clear that, in both young and old, the transient itself, or more properly, the remodeling suppression that produces it, is a part of the benefit - and indeed, perhaps the larger part [41]. Both the increased mass and the reduced remodeling during calcium augmentation are now understood to increase bony strength.
Wastney et al. [16], using short duration calcium kinetic studies in children, showed that increases in calcium intake suppress bone resorption without affecting bone formation (at least over the life of one remodeling cycle). The role of remodeling adjustment in calcium homeostasis was beautifully exemplified in this study, as increased absorption from food was matched, milligram for milligram, by decreased calcium release from bone by decreased resorption.
There are two features of remodeling suppression that deserve special comment. First, the symmetry of the two remodeling transients, i.e., going on and coming off supplementation (shown for example, in Fig. 5), has been used to argue that the bone gain on supplementation should not be considered evidence that the calcium requirement is higher than prevailing intakes. The bone gain is not permanent - so the argument goes - and thus the response to supplementation is not a true nutrient effect. This argument limps at very best. Supplying a needed nutrient to a deficient individual will always result in a benefit that is only temporary if the nutrient is subsequently withdrawn and the deficiency state returns. As virtually everyone knows, nutritional health is an ongoing affair.
The second feature is the level of remodeling itself, and the associated questions of what rate is optimal, and whether suppressing remodeling is a good thing to do. In adults, bone turns over at a rate estimated to be in the range of 8–12%/yr, with cancellous bone regions in contact with red marrow being replaced at 2–3x that average rate, and the cortical bone of long bone shafts, at perhaps half that rate or lower. Remodeling is known to repair fatigue damage and hence has generally been considered to be a positive factor for bone strength, overall. Moreover, remodeling had been assumed initially to be driven largely by this need for structural repair. Thus, reduced remodeling, by allowing fatigue damage to accumulate, had been predicted to increase bony fragility. For this reason it came as a surprise when reduced remodeling was found not to increase fragility, but to reduce it, and in fact to be the probable reason for reduced fracture risk [33,41] in the osteoporosis treatment trials.
The explanation now considered most likely is that most remodeling in First World adults is homeostatic, not structural. Homeostatic remodeling, as already noted, while it contributes calcium, decreases local bone strength. Moreover, recent research quantifying remodeling has shown that cancellous bone remodeling doubles across menopause, and by the mid-60s is about 3x the premenopausal level [42]. This change, almost certainly not driven by mechanical need, is now thought to be the likely cause in postmenopausal women of the greatly increased fragility of that life stage. The premenopausal rate, measured histomorphometrically, is about 6–7%/yr at the iliac crest. By contrast, Parfitt has recently estimated that a remodeling rate of 2%/yr should be sufficient to repair fatigue damage [43]. Whatever the optimal structural rate may be, it now seems certain that there is a relatively large excess of remodeling in ostensibly healthy, First World, adult humans that has its basis not in structural repair, but in calcium homeostasis. To the extent that this remodeling is a source of weakness, it follows that remodeling reduction will strengthen bone - which is what the data show.
The reasons for what is now recognized as a high level of homeostatic remodeling are only partially understood. Two explanations, pertinent to the focus of this paper, are low calcium and vitamin D intakes. Both, as already noted, lead to elevated PTH secretion and hence to increased bone remodeling. Thus it is logical and, in retrospect, predictable, that elevating calcium and vitamin D intakes should promptly decrease bony fragility. It is worth recalling that PTH secretion drops immediately when extra calcium and vitamin D are given, and bone resorption responds virtually immediately, as well [16]. Thus, pre-existing resorption cavities are filled in day by day, while new ones are being created at a reduced rate, leading to an improvement in strength within days of starting remodeling suppressive therapy.
But contemporary low intakes of these two key nutrients can be only a part of the explanation for high remodeling. The study of McKane et al. [36], previously mentioned, pushed total calcium intakes in healthy postmenopausal women to 2400 mg/d, and did succeed in lowering 24-hr average PTH and bone remodeling rates - but only to premenopausal levels which, if Parfitt is correct, are still substantially higher than needed to maintain mechanical integrity of the skeleton.
An additional, possible explanation is the shift to a seed-based diet at the time of the agricultural revolution. Seed foods today account for about two-thirds of the energy intake of the global population, while our hunter-gatherer ancestors typically got less than 5% of total calories from such sources. (This is probably the largest shift in diet in the history of the human race.) Seed foods are typically low in calcium and potassium, and high in sulfur-containing amino acids; all these characteristics are known to be associated with increased PTH secretion. Abbott et al. [44], examining static remodeling indices in skeletal remains from pre- and post-agricultural populations, found an approximate doubling of remodeling across the agricultural revolution. Additionally, the agricultural revolution, by producing surplus energy, permitted a human population explosion that forced migration to higher latitudes, where vitamin D status became problematic.
Whether these factors, taken together, constitute a fully adequate explanation for the elevated remodeling of modern humans is uncertain. Nevertheless the new appreciation of the importance of remodeling enhances the rationale for ensuring an adequate calcium intake.
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Conclusions |
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TOPABSTRACTIntroductionDietary Calcium and Childhood...Dietary Calcium, Physical...Calcium, Bone Remodeling, and...ConclusionsREFERENCES |
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TOPABSTRACTIntroductionDietary Calcium and Childhood...Dietary Calcium, Physical...Calcium, Bone Remodeling, and...ConclusionsREFERENCES |
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