Journal of the American College of Nutrition, Vol. 20, No. 90005, 403S-409S (2001)
Published by the American College of Nutrition
Constructive Interactions among Nutrients and Bone-Active Pharmacologic Agents with Principal Emphasis on Calcium, Phosphorus, Vitamin D and Protein
Robert P. Heaney, MD
John A. Creighton University Professor, Creighton University, Omaha, Nebraska
Address correspondence to: Robert P. Heaney, MD, John A. Creighton University Professor, Creighton University, 601 North 30th Street-Suite 4841, Omaha, NE 68131. E-mail: rheaney{at}creighton.edu.
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ABSTRACT
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Current and emerging bone active pharmacologic agents are capable of producing substantial gains in bone mass. However, nutrition must be adequate if this potential is to be realized. Calcium and vitamin D supplementation, for example, have both been demonstrated to augment substantially the skeletal response to estrogen therapy in postmenopausal women. The bisphosphonates and selective estrogen receptor modulator (SERMs) have all been tested only in the context of supplemental calcium and vitamin D. Therefore, it cannot be assumed that these bone active agents would be effective in the absence of these nutrients. Adequate protein intake has also been demonstrated to protect bone mass in the elderly and to improve recovery from osteoporotic fractures. Phosphorus intake, less extensively studied, may be more important than currently recognized, particularly in elderly individuals living alone, eating little meat, and receiving anti-osteoporosis treatment agents.
Key words: osteoporosis, bone mass, calcium, vitamin D, protein, phosphorus, bisphosphonates, SERMs, fluoride, parathyroid hormone, estrogen
Key teaching points:
• Bone gain in response to current and pending bone active agents creates a high requirement for calcium, phosphorus, and protein, which rivals that occurring at the adolescent growth spurt.
• Physiologic adaptability at mid life and thereafter is less than during growth.
• This is the reason for the higher intake requirements for calcium and vitamin D after age 50 to maintain the skeleton.
• Bone building agents impose an intake requirement higher than current DRIs, for at least calcium and possibly for protein and phosphorus as well.
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INTRODUCTION
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The concept of constructive interactions between nutrients and bone active agents has rich ramifications. On the surface it may seem to relate solely to the special nutrient requirements of a therapeutic regimen. But it also addresses, and perhaps uncovers, what may be serious nutritional inadequacies that accompany the disease being treated. Yet again, the needs elucidated by a treatment regimen may provide insights into fundamental nutrient requirements for everyone. In brief, I take "constructive interactions" to mean, essentially, what happens with optimal nutrition.
The principal bone active agents of interest are estrogen, the selective estrogen receptor nodulations (SERMs), the bisphosphonates, calcitonin, intermittent parathyroid hormone (PTH), and fluoride. In addition to other possible effects, the first four agents are generally considered to be anti-resorbers, and the last two, osteoblast stimulators. All agents are used for either the prevention or treatment of osteoporosis, and it is in connection with this disorder that I shall focus my remarks. All agents were initially developed to halt bone loss or to produce bone gain, under the premise that low bone mass explains most or all of the skeletal fragility of osteoporosis.
While this premise remains at least partially correct, it has become clear that the anti-fracture efficacy of all these agents is not easily explainable by their effect on bone mass. This somewhat complicates the evaluation of interactions with nutrients, since data, such as are available for nutrients, relate mainly to effects on bone mass, while bony fragility is now recognized to be also due to such diverse factors as reduced trabecular connectivity, reduced collagen cross-linking, and failure to repair fatigue damage in a timely fashion. At least two of these factors represent osteoblast dysfunctions and have nutritional correlates in animal systems, although they have not yet been implicated in human osteoporosis.
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BACKGROUND
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The nutrients exhibiting constructive interactions include calcium, phosphorus, vitamin D, and protein. A few background facts for each will help establish the context in which nutrient-drug interactions can best be appreciated.
Calcium
Calcium is the principal cation of bone and the most abundant mineral cation in the body. Primitive human and primate diets had very high calcium nutrient densities [1]. Over the course of evolution, human physiology was optimized to prevent calcium intoxication, not to cope with chronic calcium deficiency. Calcium deficiency did occur, of course, but it was at times of total food shortage. Under such circumstances, the skeleton served as the body’s nutrient reserve for calcium and phosphorus. The body accessed these minerals by increasing bony resorption and scavenging the calcium and phosphate ions released in the process. Then, when food supplies were once again plentiful, the skeletal loan was repaid. Agricultural societies, by contrast, have diets with low calcium densities because they are based on seed foods, which have the lowest calcium content of all the plant parts.
Several factors mitigated the impact of the inherently low calcium density of seed foods. For example, domestication of dairy animals resulted in augmentation of the diet by dairy calcium. Also, grain-milling practices prior to the Iron Age introduced substantial quantities of calcium carbonate into milled flour or meal, effecting an inadvertent but fortuitous calcium fortification of various bread foods.
Modern humans, living longer and faced with low calcium diets, must adapt continuously, dealing with calcium shortage by using the mechanisms evolved for food shortage—and either limiting bone acquisition early in life or withdrawing calcium from the skeletal reserves in the later years (i.e., decreasing bone mass). One consequence of this lifelong adaptation is parathyroid hyperplasia and serum PTH levels that rise progressively with age. McKane et al. [2] showed that three years of calcium supplementation, sufficient to bring total calcium intake to 60 mmol (2400 mg)/d in healthy older women, reduced parathyroid secretory reserve (effectively parathyroid cell mass) by 30% to 40%. This intake density, probably close to that of the primitive diet, reduced circulating PTH levels to young adult normal values, but did not lower PTH concentrations below normal. In other words, even at this high calcium intake, there was still need for PTH to offset daily hypocalcemia.
Now, a common feature of aging mammals—and surely the aging human—is a decrease in the reserve capacity of all systems, in this case of the system that allows some measure of adaptation to low calcium intake early in life. Thus, the calcium requirement is said to rise with age. However, what is really changing is not so much the calcium requirement, but rather the ability to adapt to insufficiency. Failure to understand this age-related change has led to some ineffective stabs at hormone and perhaps also pharmacologic treatment of older individuals with reduced bone mass.
Phosphorus
Phosphorus, in the form of phosphate, accounts for more than half of the mass of bone mineral. Additionally, it is involved in cellular energy metabolism and plays numerous other vital roles in cell function. Osteoblasts are unique among all other cell types in that they create a mineral trap in bone matrix after it has been deposited. This trap depletes the extracellular fluid (ECF) around the osteoblast of both calcium and phosphorus, and if the local concentration of phosphorus drops too low, osteoblasts become phosphorus-starved. This is probably the basis for most of the osteoblast dysfunction in the various osteomalacias.
Because of its protoplasmic importance, most tissues, whether plant or animal, contain relatively abundant quantities of phosphorus. Seed foods are particularly rich in phosphorus. Thus, if one is getting sufficient protein in the diet, it is likely that phosphorus needs will be met as well. Nevertheless, if either total food intake or protein intake is restricted, phosphorus availability may be limited. In NHANES-II, 
30% of women over age 65 were receiving less than two-thirds of the currently recommended phosphorus intake [3]. Growth requires a serum phosphorus level higher than usual adult values, and bone repair with bone-active agents may resemble growth in its dependence on an adequate phosphorus intake.
Vitamin D
The importance of vitamin D for bone health is so well recognized as to require little additional comment. By conversion first to 25(OH) D and then to the hormonal form of the vitamin, 1,25(OH)2 D, vitamin D mediates active calcium transport at the gut, and thus augments dietary absorption during times of need or reduced calcium intake. It is likely that 25(OH) D exerts several functions in its own right, although these are inadequately understood. It is not known whether circulating 25(OH) D level is simply a convenient indicator of vitamin D status or whether maintaining a certain 25(OH) D level is advantageous in its own right. Hence the quantity of vitamin D needed remains an unsettled issue. Parfitt [4] has described three stages of vitamin D deficiency osteopathy. In the first and most common stage there is mainly calcium malabsorption and a consequent reduction in bone mass without histological evidence of osteomalacia.
Under primitive conditions vitamin D would have been synthesized in the skin in quantities probably exceeding 1000 IU/d, and perhaps several times this figure [5], despite the damping effect of skin pigmentation on the photoconversion of 7-dehydrocholesterol to pre-vitamin D. Dark-skinned agricultural workers in the tropics typically have serum 25(OH) D levels of 150 nmol/L or higher [5], in contrast to levels prevailing in light-skinned adults in Europe and North America, which are one-third or less this value. Solar vitamin D synthetic efficiency declines both with latitude and with age. Hence the elderly of the industrialized nations are at high risk for vitamin D deficiency. In recognition of this fact, the Food and Nutrition Board in 1997 tripled the 1989 RDA (from 200 IU/d to 600 IU/d) for all individuals over age 70 [6].
Protein
Protein comprises half the volume of the bony substance. It is evident therefore that protein intake must be adequate to support bone-building therapies. However, in addition to supplying the bulk material of bone, protein intake likely influences bone building as well (and perhaps mainly) by optimizing IGF-1 concentrations. IGF-1 is generally considered osteotrophic. Protein intake tends to drop in the elderly, particularly if they live alone. Serum albumin and IGF-1 concentrations are reduced in elderly hip fracture patients [7,8]. Thus protein deficiency at least co-exists with osteoporosis and may play a role in the poor outcomes from osteoporotic fractures.
This very brief overview helps clarify why repairing nutritional deficiencies might be expected to augment response to bone-active hormones in drugs. Available evidence is supportive of this prediction. At the same time, it must be said that the evidence is still very incomplete.
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CALCIUM
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Bisphosphonates and SERMs
All of the agents concurrently approved for treatment of osteoporosis in the U.S. and Canada have been tested only along with varying amounts of calcium (as the carbonate) and vitamin D [9–13]. Table 1 lists the co-therapeutic nutrients used in the trials of each agent. It is not possible to say whether any of these agents would have achieved either their associated bone mass increase or their remodeling suppression and fracture reduction without the added nutrients. By extrapolating from the better-studied situations, to be described below, it may be safe to assume that these agents would have been less effective, and perhaps substantially so.
Estrogen
Interactions between calcium and estrogen are perhaps the best studied. Bone loss occurs at menopause because of estrogen lack, and estrogen replacement therapy (ERT) can prevent this loss. However, it has long been recognized that, if ERT is delayed, further bone loss can be prevented, but the lost bone is not restored. By contrast, estrogen exposure at menarche results in a prompt increase in trabecular bone density. It seems likely that a part of the explanation for these different responses lies in the failure to recognize both the need for calcium and the rather large changes in the settings of the calcium economy that occur between menarche and menopause. Table 2 summarizes these changed settings and gives the quantitative information needed to see why what may be possible at menarche may not be possible at menopause [14–16]. In brief, the pubertal girl is able to manage net absorption of 212 mg calcium from her diet, while a menopausal woman can extract only 42 mg calcium from hers. The former, while not optimal for growth, nevertheless permits mineral accretion and net bone growth. But the latter is less than even the daily urinary calcium loss, and hence cannot support appreciable mineral accretion, no matter how much the replaced estrogen may reduce urinary calcium loss.
The importance of calcium supplementation as co-therapy with ERT was demonstrated in a meta-analysis of 31 randomized controlled trials of estrogen by Nieves et al. [17]. Ten of the trials used no calcium supplementation, and daily calcium intake in those trials averaged 589 mg—close to the mean intake values for U.S. women in NHANES-II [3]. Twenty-one of the trials used some additional calcium, with intakes averaging 1183 mg/d—close to the currently recommended intake for postmenopausal women. Fig. 1 shows the dramatic difference in response to standard ERT in the presence and absence of extra calcium.
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Fig. 1. Change in bone mineral density at three skeletal sites with estrogen replacement in postmenopausal women, both with and without supplemental calcium. (Redrawn from the meta-analysis of Nieves et al. [17]; copyright Robert P Heaney, 2000. Used with permission.)
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The importance of adequate nutrient support is further illustrated in the experience of trials of low dose ERT. Because many women are unwilling to take full dose ERT for long, there has been interest in developing lower dose regimens. Five such trials have been published to date [18–22], and their results are summarized in Fig. 2. The two oldest trials, which found essentially no protective effect of estrogen in doses of 0.3 mg conjugated equine estrogen or equivalent per day, used no supplemental calcium. The trials of Speroff et al. [19] and Genant et al. [21] did use extra calcium and found protection from bone loss. Most recently, the trial of Recker et al. [22] found very large gains. In this trial, all women were supplemented with sufficient calcium to produce intakes above 1000 mg/d and sufficient vitamin D to produce serum 25(OH) D levels above 75 nmol/L.
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Fig. 2. Bone mineral density change on low dose estrogen regimens reported from five studies [18–22]. The bottom two trials used neither supplemental calcium nor vitamin D; the third and fourth trials up used calcium only, and the top trial used both supplemental calcium and vitamin D. (Copyright Robert P Heaney, 2000. Used with permission.)
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Calcitonin
Calcitonin has been studied less extensively in a nutritional context, and generally produces a smaller bone mass gain than can be achieved with any of the other agents described above. Nevertheless, in a meta-analysis of published trials involving calcitonin, Nieves et al. [18] reported greater bone gain in individuals supplemented with calcium than in those in whom no additional calcium was provided.
Fluoride
Fluoride, an agent approved for the treatment of osteoporosis in many countries around the world, is capable of producing a 10% to 15% per year increase in central bone mass, but with inconsistent anti-fracture efficacy. This degree of bone anabolism, of necessity, creates a very large calcium demand. In the face of inadequate absorbed calcium intake, this demand will evoke a compensatory increase in PTH and a corresponding increase in total skeletal remodeling, as well as intrabody shifts of bone mass from peripheral to central skeletal regions. This would be predicted to weaken bony regions less directly affected by the anabolic action of the fluoride, and may be part of the reason for the variable anti-fracture efficacy of fluoride. Dure-Smith et al. [23] showed convincingly that individuals with such exuberant osteoblastic response have substantial bone hunger and require in excess of 2500 mg Ca/d by mouth to keep up with the demand of bone mineralization.
Parathyroid Hormone
Human PTH, now pending approval for treatment of osteoporosis in the U.S., is another agent capable of direct osteoblastic stimulation and a corresponding increase of central skeletal bone mass amounting to 5% to 10% per year [23a]. Slovik et al. [24] showed that this effect could not be produced without providing large transfers of calcium from the gut into blood, which they ensured by giving 1,25(OH)2D.
With both fluoride and PTH, the bone building stimulus is quantitatively the largest that these individuals would have experienced since their own adolescent growth spurts. At the age of those who typically suffer from osteoporosis, the gut is not capable of the absorptive response that it would have been able to make at puberty. This is the reason why potent bone-building agents require either a very large calcium intake or pharmacologic dosing with 1,25(OH)2D.
In brief, the body builds bone out of mineral, not out of drugs or hormones. If the mineral is not present in adequate quantities, either the amount of net bone building is limited, or other skeletal regions are compromised to support central demands. In either circumstance, provision of adequate nutrition is necessary to support the therapeutic effect of a potent bone-active agent.
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VITAMIN D
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Vitamin D interactions are much less well studied than calcium. The low dose estrogen study conducted by Recker et al. [22], cited above, differed from the less effective trials of Genant et al. [21] and Speroff et al. [19] mainly by virtue of its normalizing of vitamin D status in the treated subjects. Both of the two most impressive of the calcium supplementation trials used supplemental vitamin D as well—one at 700 IU/d [25] and the other at 800 IU/d [26]. Both trials produced substantial reductions in fracture incidence. Peacock et al. [27], in a three-armed trial of calcium alone, vitamin D alone, and placebo, found complete protection against bone loss with calcium alone, and only partial protection with vitamin D alone, indicating that vitamin D, without extra calcium, is not sufficient. On the other hand, it must be noted that his subjects, with serum 25(OH)D levels averaging 62.5 nmol/L, were substantially closer to vitamin D sufficiency than were the subjects in the trial by Chapuy et al. [26], in whom serum 25(OH)D levels were less than half that value.
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PROTEIN
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The issues surrounding protein interactions are complex, perhaps unnecessarily so. The facts, so far as they can be briefly summarized, are as follows. The primitive human diet would have been high in both total protein (up to 35% to 40% of total energy), and specifically animal protein [28,29]. Early hominid skeletal remains are generally robust and give no hint that a high protein intake was in any way harmful. Moreover, well preserved Canary Island cave burial remains indicate that the skeleton was more robust in those individuals with evidence of high protein intake [30]. Hannan et al. [31], in their analysis of the Framingham cohort, found exactly this same relationship in contemporary living humans. Their data are reproduced in Fig. 3, which shows a stepwise decrease in loss of bone mineral density as protein intake rises from the lowest to the highest quartile.
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Fig. 3. Change in bone mineral density plotted by quartile of calcium intake. (Redrawn from the data of Hannan et al. [31]; Copyright Robert P. Heaney, 2000. Used with permission).
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It is also true that high protein diets increase urinary calcium loss and that low calcium intakes can create a situation in which high protein intakes contribute to negative calcium balance [32]. This is probably because calcium absorption efficiency at low intakes is already close to maximal and cannot be augmented sufficiently to offset additional obligatory loss. At high calcium intakes, by contrast, calcium absorption efficiency is down-regulated and thus still has considerable reserve capacity to increase in response to demands such as produced by protein-mediated calciuria.
In this instance we are not dealing with a constructive interaction with pharmacologic agents. Rather we see a constructive interaction between nutrients: the closer all of them are to optimal intake levels, the clearer the beneficial effect of each one, considered individually, becomes.
Additionally, protein supplementation in elderly hip fracture patients has been demonstrated in at least two randomized controlled trials [7,33] to improve salvage dramatically, in terms of death, length of hospital stay, and return to independent living. The effect is associated with elevation of IGF-1 levels [8,34]. The high protein intake in these patients not only aids recovery, but also slows or stops bone loss in the contralateral hip [34]. This constitutes another instance of constructive interaction between adequate nutrition and (in this case) surgical therapy.
The protein issue is unfortunately complicated by an obfuscation campaign mounted by animal rights activists and militant vegans who oppose all use of animal products and who employ results of isolated observational studies to scare the public. So vocal and effective have these groups been that they now, to some extent, influence the research agenda of mainline nutritional science [35]. This societal trend needs to be borne in mind when evaluating seemingly negative reports about protein and bone.
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PHOSPHORUS
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Phosphorus is, in a sense, like the bastard at the family picnic—undeniably related but not entirely welcome either. This unsavory reputation is difficult to explain, but some of it may trace back to the development of osteolytic lesions in horses fed the extremely high phosphorus diets that are used to support milk production [36] in dairy cows. Another explanation could be a latent nutritional Puritanism based on the fact that colas, which taste good, contain phosphoric acid. High phosphorus intake has been hypothesized as a cause of osteoporosis (without plausible human evidence) [37]. The federal Food and Drug Administration convened at least one special panel in the past 20 years to address the presumed problem associated with increased entry of phosphorus into the modern American diet [38]. No cause for concern was found. When the Food and Nutrition Board [6] addressed the hazards of high phosphorus intake in its recommendations concerning bone active nutrients, it concluded that high phosphorus intakes, in the range plausible for humans, were without potential for harm. Additionally, it noted that the phosphorus density of typical human diets is lower, by a factor of two or more, than that of laboratory or household companion animals, including non-human primates.
As already noted, bone building requires an adequate bulk supply of phosphate as well as of calcium. Phosphorus availability is expressed at the osteoblast worksite as the concentration of inorganic phosphate (Pi) in the ECF. Low ECF Pi values will not support growth. It is likely that it is the 24-hr serum integrated Pi which is important here, and the tendency in human testing to measure only fasting morning values probably gives us little insight into the average day-long concentration that the osteoblast experiences. Hence, little is known about the effects of bone-building regimens on this important variable in the elderly, who are the usual recipients of such treatments. It is of possible relevance that the most effective of the calcium supplementation trials reported to date used tricalcium phosphate as the calcium supplement salt [26]. Although calcium was undoubtedly responsible for much of the benefit, it cannot be ruled out that the phosphate contributed significantly in its own right.
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CONCLUSION
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Bone building requires an adequate supply of not only the bulk nutrients from which bone mass is built, but also the nutrients supporting osteoblast work. In general, this amounts to at least good total nutrition. But there also may be an additional component related specifically to the needs for literal bone growth which, with some new agents, may approach, in the elderly, the demands experienced earlier during the adolescent growth spurt. Bone-building therapies are most often utilized in older individuals who, as a group, are less likely to be receiving adequate nutrition even for maintenance. Hence the use of current and emerging bone active agents requires special additional attention to ensure adequate nutrition, attention that may not be so evidently necessary in treating other chronic disorders in an aging population. While optimal response to bone-active agents demands good total nutrition, special emphasis needs to be placed on calcium, vitamin D, protein, and phosphorus.
Received April 26, 2001.
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E. Segal, L. Dvorkin, A. Lavy, G. S. Rozen, I. Yaniv, B. Raz, A. Tamir, and S. Ish-Shalom
Bone Density in Axial and Appendicular Skeleton in Patients with Lactose Intolerance: Influence of Calcium Intake and Vitamin D Status
J. Am. Coll. Nutr.,
June 1, 2003;
22(3):
201 - 207.
[Abstract]
[Full Text]
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TOP
ABSTRACT
INTRODUCTION
