Pii: s0278-6915(02)00094-7

Food and Chemical Toxicology 40 (2002) 1263–1270 Effects of caffeine on bone and the calcium economy Creighton University, 2500 California Plaza, Omaha 68178 Nebraska, USA Caffeine-containing beverage consumption has been reported to be associated with reduced bone mass and increased fracture risk in some,but not most,observational studies. Human physiological studies and controlled balance studies show a clear but only avery small depressant effect of caffeine itself on intestinal calcium absorption,and no effect on total 24-h urinary calcium excretion.
The epidemiologic studies showing a negative effect may be explained in part by an inverse relationship between consumption ofmilk and caffeine-containing beverages. Low calcium intake is clearly linked to skeletal fragility,and it is likely that a high caffeineintake is often a marker for a low calcium intake. The negative effect of caffeine on calcium absorption is small enough to be fullyoffset by as little as 1–2 tablespoons of milk. All of the observations implicating caffeine-containing beverages as a risk factor forosteoporosis have been made in populations consuming substantially less than optimal calcium intakes. There is no evidence thatcaffeine has any harmful effect on bone status or on the calcium economy in individuals who ingest the currently recommendeddaily allowances of calcium. # 2002 Elsevier Science Ltd. All rights reserved.
Keywords: Caffeine; Calcium intake; Calcium absorption; Bone mass; Milk the probable importance of caffeine as a contributor tothe osteoporosis disease burden.
Caffeine and the related methyl xanthines are widely In this review the possible mechanisms whereby any distributed in plants throughout the world. All stable ingested agent (such as caffeine) may alter bone strength indigenous cultures having access to these plant products are discussed,and then the evidence that may be available have developed drinks containing these stimulants. Thus for each with regard to caffeine is examined. The present caffeine is probably the most commonly consumed phar- analysis gives primary weight to investigator-controlled macologically active compound in the world,certainly in studies such as randomized,controlled trials and physi- Europe and North America. Probably it is partly for ological experiments under careful metabolic controls, that reason that caffeine has often been a target of as contrasted with observational studies. Where there opportunity for investigators seeking to identify envir- are discordances,plausible explanations are offered.
onmental factors that may contribute to the burden ofchronic disease. The first publication showing a negativeeffect of caffeine on the calcium economy came from 2. Mechanisms whereby caffeine might affect bone strength this author’s laboratory (Heaney and Recker,1982).
Shortly thereafter,Massey and colleagues (Massey and There are four principal ways an agent may increase Wise,1984; Massey and Hollingbery,1988; Bergman et al., fracture risk and/or skeletal fragility (Heaney,1996): (1) 1990) showed that a caffeine-induced diuresis increased an increase in fall frequency and/or an interference with urinary calcium loss acutely. On these grounds,caffeine postural reflexes that protect the body during falls; (2) a came very quickly to be included in everyone’s list of risk reduction of body fat over bony prominences; (3) an factors for osteoporosis. However,later work,summar- interference with the bone remodeling process designed to ized in what follows,led to substantial modifications of detect and repair fatigue damage in bone structures; and(4) a decrease in bone tissue mass either globally or in keyarchitectural elements (such as trabecular connections).
There are no recognized data relating caffeine to the Abbreviations: ECF,extracellular fluid; PTH,parathyroid hormone first two mechanisms. The third mechanism is itself still * Corresponding author. Tel.: +1-402-280-4029; fax: +1-402-280- inadequately explored for bone generally,and its impor- E-mail address: rheaney@creighton.edu (R.P. Heaney).
tance for osteoporotic fractures remains undefined.
0278-6915/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
P I I : S 0 2 7 8 - 6 9 1 5 ( 0 2 ) 0 0 0 9 4 - 7 R.P. Heaney / Food and Chemical Toxicology 40 (2002) 1263–1270 However,fatigue damage is a major cause of failure in induced a significant acute calcium diuresis. However, all engineering structures; it occurs in bone on normal subsequent studies showed that this renal effect was use as well as with sporadic overloading and it is highly biphasic (Kynast-Gales and Massey,1994); that is,the likely that it contributes to bony weakness with aging.
acute increase was followed by a later fall in urinary Its importance in this context is that the consequent calcium. While this late fall did not completely obliter- fragility need not be associated with a decrease in bone ate the acute increase reported by the investigators, mass. Thus,absence of an effect on calcium balance would earlier estimates of the net negative effect of caffeine not,ipso facto,absolve a putative agent from guilt in this consumption had to be lowered substantially.
context. However,as with falls and padding,there are no Barger-Lux and Heaney,in two further studies,were studies implicating caffeine in tissue-level surveillance able to find no effect at all of caffeine on total 24-h calcium loss. In the first (Barger-Lux et al.,1990),a double-blind, The best studied (but not necessarily the most impor- randomized,placebo-controlled,cross-over metabolic tant) of the causes of skeletal fragility is decrease in balance study,subjects consumed only decaffeinated bone tissue mass. Such decrease can be brought about coffee,but with each cup they also took a capsule con- either by direct effects on the feedback control system taining either caffeine or placebo. No significant differ- that regulates bone density,or by alteration in the supply ence in calcium balance was found between placebo of critical minerals (e.g. calcium and phosphorus,but in consumption and 400 mg caffeine/day administered for this context most likely calcium). Most of the available 19 days. The sample size was small,and the study did evidence implicating caffeine has focused on possible not have sufficient power to find a balance effect as effects on calcium balance or its integral bone mass.
small as 5 mg of calcium per cup of coffee,but the Calcium availability,in turn,can be affected by altering urinary calcium component of the balance was suffi- ingested intake,by altering absorption,by altering ciently sensitive to detect a small effect,and here no hint digestive juice calcium content,or by altering sweat of caffeine-induced calciuria was found. In fact,the and/or urinary calcium losses. It will be along the lines mean 24-h urinary calcium was non-significantly greater of this approach (i.e. effects of caffeine that may reduce during the placebo period than during the caffeine period.
bone tissue mass) that most of the evidence available in A similar conclusion was reached in an expanded ana- regard to caffeine will be evaluated. However,the other lysis of the original group of women from this labora- mechanisms are mentioned not just for the sake of tory,now involving over three times as many balance completeness,but because they may need to be exam- studies as previously,with caffeine consumption once ined in explaining discordances between conclusions again in the form of tea or coffee. No significant influ- ence of caffeine-containing beverages could be found oneither urinary calcium loss (Barger-Lux and Heaney,1995) or on endogenous fecal calcium loss (Heaney and 3. Effects on the calcium economy and on bone tissue Recker,1994). However,the negative balance effect persisted in this analysis,and in the expanded data setwas estimated to amount to approximately 4 mg of cal- cium lost/cup of coffee. In multiple regression modeling,this effect was localized to a slight but significant The first published study (Heaney and Recker,1982) decrease in calcium absorption efficiency. Calcium showing an effect of caffeine-containing beverages on the intake in these women averaged only about 660 mg/day, calcium economy in humans was performed on 170 heal- or roughly half of current recommendations. (The sig- thy,middle-aged women,and involved careful control of nificance of this point will be discussed further,below.) and/or measurement of intakes of calcium,phosphorus, Three other human experimental studies have been protein and caffeine-containing beverages,and full col- published. In one,eight premenopausal women were fed lections of all excreta under metabolic balance conditions.
a diet containing either 1.4 l diet cola per day (and no In multiple regression models,caffeine intake (in the form other source of caffeine),or an equivalent,caffeine-free of tea and coffee consumption) was significantly asso- beverage for 2 weeks (Smith et al.,1989). No effect was ciated with a slight negative balance effect,amounting found on 24-h urine calcium. In a second study (Massey to a loss of less than 5 mg of calcium per cup of coffee et al.,1994),no effect of caffeine consumption was consumed,or equivalent. There was a suggestion that found for total serum calcium,24-h urine calcium or the caffeine effect might have been exerted through hydroxyproline excretion in 25 women,both pre- and increased urinary calcium and/or through increased postmenopause. In the third study (Hasling et al.,1992), endogenous fecal calcium loss. This work was followed calcium balance was measured in 85 women with post- shortly by a series of studies by Massey and colleagues menopausal osteoporosis. In multiple regression models (e.g. Massey and Wise,1984; Massey and Hollingbery, both calcium intake and coffee intake were significantly 1988; Bergman et al.,1990),showing that caffeine and independently correlated with balance,the latter R.P. Heaney / Food and Chemical Toxicology 40 (2002) 1263–1270 negatively. Although coffee rather than caffeine intake intake and bone mineral density,while 13 similar stud- was measured,they calculated a negative balance shift ies (Hansen et al.,1991; Lacey et al.,1991; Cooper et al., of 6 mg/day for each 100 ml coffee consumed. This is 1992; Johansson et al.,1992; Glynn et al.,1995; Hansen, somewhat larger than the 4 mg/cup figure of Barger- 1995; Travers-Gustafson et al.,1995; Lloyd et al.,1997; Lux and Heaney (1995),who used very similar methods, Grainge et al.,1998; Maini et al.,1996; Packard and but in a much larger group of women.
Recker,1996; Picard et al.,1988; Hannan et al.,2000) The only other controlled studies of the mechanism of found no significant association. Two additional studies calcium loss with caffeine exposure involved rats fed a (Barrett-Connor et al.,1994; Harris and Dawson- high coffee diet. In one (Yeh and Aloia,1988),rats were Hughes,1994) found an effect,but as noted above,only fed a diet containing 4% instant coffee by dry weight,in in individuals consuming low calcium intakes. Five which increases in both digestive juice calcium and studies evaluated change in bone mineral density; four urinary calcium were found. The relevance of these data (Reid et al.,1994; Lloyd et al.,1998; Hannan et al., to human coffee consumption is doubtful. In a second 2000; Lloyd et al.,2001) found no effect of caffeine and study (Sakamoto et al.,2001) using diets with somewhat a fifth (Harris and Dawson-Hughes,1994) reported an lower,but still high coffee contents (0.62 and 1.36%), effect but,as already noted,only at low calcium intakes.
no effect was found at either intake level on indices of Five case-control studies have been reported,one using bone remodeling or on levels of cytokines implicated in osteoporosis as the defining criterion (Blaauw et al., 1994),and four using hip fracture (Nieves et al.,1992; Thus,the best available human experimental evidence Cumming and Klineberg,1994; Tavani et al.,1995; indicates that,in individuals ingesting inadequate cal- Kanis et al.,1999). Only one showed a significant dif- cium intakes,caffeine leads to a small negative calcium ference in caffeine consumption between cases and con- balance,through a weak interference with calcium trols (Kanis et al.,1999),and that one specifically a absorption efficiency. The magnitude of the effect is lower risk of hip fracture in tea drinkers (but not coffee such that it has been estimated that it could be offset by addition of only 1–2 tablespoons of milk to a cup of Finally,four prospective studies evaluated caffeine as coffee (Barger-Lux and Heaney,1995). This conclusion one of several risk factors for incident fracture (Kiel et was not tested directly with respect to caffeine,but pre- al.,1990; Hernandez-Avila et al.,1991; Cummings et al., vious studies had shown that reduced absorption from 1995; Meyer et al.,1997). All four reported a significant any cause can be offset by increased calcium intake association. In the largest of these studies,utilizing the (Heaney et al.,1975). Moreover,two of the observa- Framingham cohort,the increase in hip fracture risk tional studies,discussed further below,found an effect was nearly three-fold. However,the highest age in the of caffeine-containing beverages only in individuals with cohort was 65,and there were few fractures overall. In low calcium intakes (Barrett-Connor et al.,1994; Harris the Norwegian study (Meyer et al.,1997) fracture risk and Dawson-Hughes,1994). Hence the bulk of the evi- was increased only for individuals consuming nine or dence points to a dependence of the caffeine effect on more cups of coffee per day,with no dose–response relationship at lower coffee intakes. In the Study ofFractures (SOF) project cohort (Cummings et al.,1995), the authors were able to identify 17 independent riskfactors,caffeine being one of the weaker [odds ratio Following the original report of a caffeine effect,and (OR)=1.2,95% confidence interval (CI)=1.0–1.5]. In in parallel with the controlled trials and physiological several of these prospective study reports the authors measurements summarized above,associations were emphasise the uncertainty of the causal connection and sought in observational studies in which bone mass and/ note that caffeine-containing beverage consumption or fracture rate were measured and correlated with esti- may be a marker for other unidentified causal factors mates of caffeine intake developed by asking people about their consumption of caffeine-containing bev- The two studies showing a beneficial effect in tea erages. At least 32 such studies (summarized in Table 1) drinkers (Kanis et al.,1999; Hegarty et al.,2000) are have been reported in the past several years,involving difficult to interpret in isolation. Hegarty et al. attrib- altogether many thousands of individuals. Seven showed uted the benefit to other factors in tea (e.g. flavonoids), a negative effect of caffeine-containing beverages on the but lacking experimental evidence of such an effect,this calcium and bone economies,three a partial effect,21 conclusion can be only speculative. Most of the other showed no effect,and two a beneficial effect specifically studies lumped tea and coffee consumption in their estimates of caffeine intake,and it is not possible speci- Four cross-sectional studies (Bauer et al.,1993; Her- fically to dissect out tea effects from coffee effects. Con- nandez-Avila et al.,1993; Krahe et al.,1997; Rubin et trolled trials of tea-drinking need to be conducted to al.,1999) found a negative association between caffeine R.P. Heaney / Food and Chemical Toxicology 40 (2002) 1263–1270 Table 1Observational studies of caffeine effects on bone Neg effect only at < 1 serving milk/day SOFb cohort; one of 12 factors; effect weak Neg effect at only one of five bone sites SOFb cohort; one of 17 factors; 20% inc. in risk Framingham cohort; older subset than in Kiel et al.,below Neg. effect only at Ca intakes < 744 mg/day Pos. effect; tea drinkers had higher BMD Weak neg association at one bone site,not others Nurses Health Study; 3x increase in hipfx risk prior to age 65 years No effect for coffee,small positive effect for tea Framingham subset; risk incr. above 2 cups coffee/day Neg correlation between caffeine and hip BMD; not spine Effect only at 9 or more cups coffee/day Neg. correlation between caffeine and hip BMD; not spine a X=cross-sectional; P=prospective; CC=case-control.
b Study of fractures.
If these observational studies constituted the only Barger-Lux and Heaney,1995). This is both because of evidence,one would have to conclude that the data were the common reciprocity of choices relating to the two far from consistent or conclusive,and that the effect, beverages,and because total fluid intake is itself less found in only a minority of studies,might be spurious.
variable than intake of its beverage components. (As Observational studies,as is generally recognized,cannot one source goes up,others tend to go down.) The effect establish causality for relationships when detected. By of calcium intake on bone status,of course,is well the same token,negative epidemiological studies cannot established,with more than 50 randomized,controlled exclude a relationship. Inevitable errors in estimating trials showing a positive effect of high calcium intake on exposure both obscure real effects and lead to some- bone mass,and a negative effect on fracture rate. (See: times complex interactions of the putative independent Dietary Reference Intakes for Calcium,Phosphorus, variables. Usually in epidemiological studies of nutri- Magnesium,Vitamin D,and Fluoride,National Acad- ents,none of the possible responsible factors is directly emy Press,Washington,DC,1997 for a summary and measured,but is instead estimated from such instru- analysis of these studies,as well as Heaney,2000.) Thus, ments as,in this instance,food frequency questionnaires.
estimates of caffeine intake tend to be inverse surrogates The errors and bias that such methods introduce are for calcium intake,a factor known to influence bone immense and have been explored in detail elsewhere mass. While not all observational studies have been able (Barrett-Connor,1991; Heaney,1991; Heaney,1997).
to discern this inverse relationship between calcium and One example of a mechanism capable of producing an caffeine intake (e.g. Kiel et al.,1990),it is likely that apparent association is the likely inverse relationship intake estimation errors are responsible for this failure.
between intake of milk and consumption of caffeine- The principal study clearly reporting an inverse associ- containing beverages (e.g. Heaney and Recker,1982; ation was performed under metabolic balance controls, R.P. Heaney / Food and Chemical Toxicology 40 (2002) 1263–1270 where intakes of both caffeine-containing and calcium- et al. (1997),in directly analysing caffeine content, containing beverages were measured,rather than found that food table values were high by more than 50%. A systematic overestimation of this sort would not When a significant association is found,as in the case affect the correlational analyses described above,but it of caffeine and bone,the purported independent vari- would influence comparison with dosing studies,such as able may be only a marker for the actually responsible that of Barger-Lux et al. (1990),who treated subjects with (but sometimes unmeasured) causal factor. Also,whe- a pharmacologic caffeine preparation in a measured dose ther a factor emerges as significant in various studies of 400 mg/day. This was considered equivalent to an depends not just on its actual influence,but on the intake of 2–3 cups of brewed coffee per day. If,as Lloyd relative accuracy of the estimates of exposure to the et al. (1997) suggest,standard coffee contains less caf- given variable,and all others in the model. Those vari- feine than had been thought,then the study of Barger- ables with less estimation error can emerge as significant Lux et al. (1990) was carried out at an intake equivalent if they are more precise surrogates for the actual causal to 3–5 cups of coffee daily. Their conclusion about the factor than are estimates of exposure to that factor itself absence of an effect on 24-h urinary calcium excretion (Hassager et al.,1991). For example,if caffeine intake is would thus apply to a higher level of caffeinated beverage inversely correlated with calcium intake,and if caffeine intake is either estimated more accurately than calciumintake or is more stable over extended periods of time, then caffeine will displace calcium from various stepwiseregression models,even if it has no effect in its own Caffeine and the other methyl xanthines act in a variety right. As estimate accuracy will vary from variable to of tissues,generally by interfering with the action of variable,and from study to study,one can reach no phosphodiesterase and thereby potentiating the activity conclusion generally applicable to all epidemiological of agonists acting through the adenylate cyclase–cAMP pathway. At sufficient doses,therefore,they could the- Another illustration,undoubtedly applicable to some oretically exert effects directly on the cellular apparatus extent in the studies summarized here,is the problem of controlling bone remodeling. In high enough doses caf- confounding. An example is provided by the study of feine interferes with fetal rat skeletal development Johansson et al. (1992) in 619 70-year-old men and (Nakamoto et al.,1989; Schneider et al.,1990) but has women. While a significant bivariate inverse correlation no effect on calcium release from 2-day fetal mouse cal- was found between intake of caffeine-containing bev- varial cultures (Bergman et al.,1988; Lerner and Mell- erages and bone mass (P < 0.01),the relationship dis- stron,1992). Moreover,very high doses given to adult appeared in a multivariate model adjusting for such rats for 8 weeks (equivalent on a body weight basis to other factors known adversely to affect bone,such as 60–70 cups of coffee/day in adult humans) had essen- tially no effect on bone remodeling,as measured by Thus,while observational studies can point to possi- histomorphometry (Glajchen et al.,1988). Similarly, ble relationships for testing in stronger designs,they Sakamoto et al. (2001) found no effect of high-coffee can,themselves,neither establish nor exclude the sought diets on biochemical markers of bone metabolism or on for causal connection. Moreover,in this case,given the cytokines implicated in bone loss in adult rats. However, evidence of an effect already available from physi- Ohta et al. (1999) found slight,but significant reductions ological studies,observational studies are redundant in bone strength in ovariectomized adult rats fed very today,or at best only confirmatory. As already noted, high doses of caffeine (20 mg/kg body weight) for 90 days.
the observational studies are not the only basis for Concentrations required to produce direct skeletal effects in attributing to caffeine an effect on the calcium economy.
animals are higher than experienced by bone in human Metabolic balance studies do show a weak negative adult caffeine consumers,and it is unlikely,therefore,that effect of caffeine on calcium absorption,and the most any of the detected effects in humans operate through plausible way to harmonize all of the data is to conclude direct skeletal mechanisms. That was the conclusion (1) that the effect is real and (2) that the negative pre- reached by Glajchen et al. (1988). However,effective caf- ponderance of the observational studies is due to the feine concentrations can be relatively high at the gut smallness of the effect size and to the weakness of the mucosa during absorption from a caffeine-containing methods available for estimating exposure,both to meal,and it may be that the observed absorptive inter- caffeine itself,and to other important covariates.
ference reflects a direct effect of caffeine (during its ownabsorption) on the transport system for calcium.
Finally,as noted earlier,an agent affecting propensity to fall,soft tissue padding,or repair of fatigue damage Most of the foregoing studies have used food and could also explain an increase in skeletal fragility,apart beverage table values to estimate caffeine intake. Lloyd from any effect on the calcium economy itself. While these R.P. Heaney / Food and Chemical Toxicology 40 (2002) 1263–1270 effects cannot be excluded,it does not seem necessary to component of the system,namely the calcium content of invoke such mechanisms in this setting. Fracture studies and bone mass studies are approximately concordant.
Similarly,a sudorific effect of caffeine (increasing sweat 1,25(OH)2vitamin D level yields much more calcium calcium losses) could explain a bone mass effect in the from a high than from a low calcium diet. At low cal- absence of measurable changes in absorption or non-der- cium intakes,the ECF [Ca2+] deficit is still satisfactorily mal outputs. However,such an explanation is also unne- offset because the renal and osteoclastic effects of PTH cessary,since the physiological studies do show a small compensate for the decreased absorption potential.
effect on absorbed calcium input,probably sufficient to Thus ECF [Ca2+] is maintained (although at a cost to explain the small effects on bone mineral density bone). But,at high intakes,for example those in the range of current recommendations (NIH Consensus In brief,the weak effect found on fracture rate in the Conference,1994; Dietary Reference Intakes for Cal- studies summarized in Table 1 is entirely concordant cium,Phosphorus,Magnesium,Vitamin D,and Fluo- with the weak effect on bone mass found in the epide- ride,National Academy Press,Washington,DC,1997), miological studies of Table 1,and both effects are con- the extra few milligrams needed can be easily extracted cordant with the weak effect found on the calcium from the otherwise large surplus of unabsorbed calcium in ingested food residue. At 1200–1500 mg calciumintakes,extraction of an additional 10 mg means anabsorptive increase of only approximately 0.8%,while at a 300 mg intake [approximately the bottom quartilein the several National Health and Nutrition Evaluation Substantial further help in harmonizing the data Survey studies (Carroll et al.,1983; Alaimo et al., comes from the observed dependence,in at least two 1994)],the absorptive increase would have to be many studies,of the effect of caffeine on low calcium intake in times larger—for at least two reasons: (1) because 10 is a the subjects concerned (Barrett-Connor et al.,1994; larger fraction of 300 mg ingested than of 1200; (2) Harris and Dawson-Hughes,1994). Because the prob- because at low intakes there is less unabsorbed dietary able basis for the effect is an interference with calcium calcium residue available from which to extract further absorption efficiency (Barger-Lux and Heaney,1995), calcium. Additionally,because absorption is already this interaction with calcium intake reveals an important operating close to its maximal efficiency,there is less feature of the underlying relationships.
As background,it is useful to recall that calcium ion It is likely that these quantitative aspects of the reg- concentration in the extracellular fluid (ECF) is exqui- ulatory system reflect the high calcium intakes that pre- sitely regulated; that is,departures from the reference vailed during hominid evolution (Eaton and Konner, level are met with hormonal responses designed to cor- 1985). In any event,as just noted,the feedback control rect them. The result is that even large swings in inputs system,operating to maintain constancy of ECF [Ca2+] and outputs over the course of a day are associated with concentration,is ‘‘satisfied’’ when the decrement is off- only tiny fluctuations in ECF [Ca2+]. The miniscule set. There is no known mechanism that ‘‘informs’’ the decrease in ECF [Ca2+] produced by an external nega- control system where the needed calcium came from, tive balance of only a few mg/day (the effect size of 3–4 such as whether from otherwise untapped calcium in the cups of coffee,as estimated by Barger-Lux and Heaney, digestate,or from internal stores (bone). In brief,the 1995) would be expected to evoke a small increase in higher the calcium intake,the more readily will the body parathyroid hormone (PTH) secretion. PTH,in turn, adjust to extra demands for calcium,to increased losses, activates not one,but three effector mechanisms designed to raise ECF [Ca2+] and to restore it to its priorlevel. These are: (1) increased synthesis of 1,25(OH)2vitamin D (and hence an improvement of absorption efficiency for ingested calcium); (2) increased renal tub-ular reabsorption of calcium (and hence a reduction of James Lind,the Scottish naval surgeon who is cred- urinary calcium losses); and (3) increased bone resorp- ited with eradicating scurvy in the British Navy,noted tion,brought about both by direct effect of PTH on the that onset of symptoms of scurvy was hastened among resorptive apparatus and indirectly by enhancement of sailors performing heavy physical work. The solution, osteoclastic work efficiency through PTH-induced low- of course,was not to decrease the work load of British ering of ECF phosphate concentration. Internally,ECF sailors,but to provide them a source of what would [Ca2+] is returned to the reference level. But the net come to be recognized,nearly 200 years later,as an effect on external calcium balance of these three essential nutrient,vitamin C. So,too,with caffeine’s mechanisms depends entirely on the one unregulated exposure of the bone-wasting effect of inadequate calcium R.P. Heaney / Food and Chemical Toxicology 40 (2002) 1263–1270 intake: the solution is not to decrease the caffeine intake Grainge,M.J.,Coupland,C.A.,Cliffe,S.J.,Chilvers,C.E.,Hosking, of the Western world,but to provide adequate sources D.J.,1998. Cigarette smoking,alcohol and caffeine consumption, and bone mineral density in postmenopausal women. OsteoporosInternational 8,355–363.
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AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 17, Number 1, 2001, pp. 35–43 Mary Ann Liebert, Inc. The Antiviral Drug Docosanol as a Treatment for Kaposi’sSarcoma Lesions in HIV Type 1-Infected Patients: MICHAEL J. SCOLARO,1 LUCY B. GUNNILL,2 LAURA E. POPE,2 M.H. KHALIL,2 ABSTRACT Docosanol inhibits a broad spectrum of lipid-enveloped viruses in vitro including HSV-1, HSV-2, VZV, CM


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