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*
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands; and
Centrum for Biostatistics, Utrecht University, 3584 CC Utrecht, The Netherlands
2To whom correspondence should be addressed. E-mail: M.A.Tryfonidou{at}vet.uu.nl.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • True Ca absorption • 45Ca balance studies • age-dependent changes • Ca intake, dogs
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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) is a principal element of bone mineral and is thus of great importance in skeletal mineralization during growth. Ca is absorbed by two different processes in the intestine, i.e., active and passive. Active Ca absorption is a transcellular and saturable process hormonally regulated by 1,25-dihydroxycholecalciferol [1,25(OH)2D], the most biologically active vitamin D metabolite (1
). Passive absorption is a paracellular and nonsaturable process with discrepancy whether it is regulated by 1,25(OH)2D (1
,2
). After birth, Ca absorption is mainly passive. Active absorption has recently been described in suckling pigs as being independent of 1,25(OH)2D (3
). With increasing age and weaning, the contribution of passive absorption to total Ca absorption decreases, and active 1,25(OH)2D-dependent Ca absorption becomes more prominent (4
,5
).
There are no reports to date regarding differences in Ca absorption during growth in species with a large variation in normal growth rate. The domestic dog presents this species-specific disparity in growth rate, and hence mature body size, more dramatically than any other mammalian species as evident by the 100-fold difference in mature body weight that can be achieved across breeds. For example, during the period from weaning (6 wk of age) through 6 mo of age, the Great Dane can gain 
1.5 kg/wk, whereas the Miniature Poodle may gain only 100 g/wk (6
). Both giant and small breed dogs develop pathological fractures due to osteopenia regardless of their relative growth rates, when raised on diets deficient in Ca. However, pathological fractures are observed in Great Danes raised on a diet providing 0.55 g of Ca/100 g of diet on a dry matter basis (7
) and in Miniature Poodles raised on a diet with a Ca content of 0.05 g of Ca but not on a diet providing 0.33 g of Ca/100 g of diet dry matter (8
). In contrast, Great Danes develop osteochondrosis (9
), whereas Miniature Poodles develop only irregularities of microscopic magnitude (8
), when raised on a diet with excessive Ca (3.3 g/100 g diet dry matter). When they are raised on Ca-deficient diets, giant and small breed dogs have elevated plasma 1,25(OH)2D concentrations and fractional Ca absorption rates as high as 80 to 90% after weaning (8
,10
,11
). When raised on a Ca-oversupplemented diet, plasma 1,25(OH)2D concentrations decrease, accompanied by fractional Ca absorption rates as low as 40% (8
,11
–13
). Therefore, dogs of giant and small breeds are expected to be able to regulate their Ca absorption soon after weaning.
The difference in susceptibility to developing skeletal disorders between dogs with rapid and slow growth rates may in part relate to the pathophysiological changes associated with the intestinal Ca transport system during growth and the hormonal regulation of Ca absorption. We therefore studied intestinal Ca absorption in growing dogs with respect to the Ca intake– and age-dependent effects. In addition, the hypothesis was tested that there may be differences in the development and regulation of Ca absorption between breeds of dogs with rapid and slow growth rates and that this may be an important pathophysiological factor in the development of skeletal disorders during imbalanced Ca intake. To test this hypothesis, results were analyzed from 45Ca balance studies carried out in giant and small breed dogs raised on diets with Ca content either deficient or exceeding the recommended amount of 1.0% Ca g/100 g (dry matter) (14
,15
).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The Utrecht University Ethical Committee for Animal Care and Use approved all procedures. The subjects of this study were growing Great Danes and Miniature Poodles who have participated in studies previously published in The Journal of Nutrition (7
,11
,12
,16
) and in ongoing research (17
). During the time of data accumulation, the same techniques were used and all studies were performed at the Department of Clinical Sciences of Companion Animal of the Faculty of Veterinary Medicine, Utrecht University. Sixty-seven Great Danes and 23 Miniature Poodles were assigned to the different groups at 3 wk of age (Table 1
). At this time, partial weaning was started using dry food as gruel. At complete weaning (6 wk of age), pups received diet as their only dry food. Food was restricted or free access was provided (Table 1)
and the actual ingested amount of food was determined daily for each dog during the experiment.
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) and the Association of American Feed Control Officials (AAFCO) (15
). Soluble salts were used, including monocalcium and dicalcium phosphate, potassium phosphate and Ca carbonate to achieve the appropriate Ca and phosphate concentration. Small amounts of phytates and oxalates were in the food and thus did not interfere with Ca bioavailability (18
) as only the starch, gluten and grid components of corn and potato were used. The diets differed only in their Ca concentrations, which ranged from 0.33 to 3.3 g/100 g diet (dry matter). Table 2
shows the analysis of the control diets used in the different studies containing Ca ranging from 0.8 to 1.1 g Ca/100 g of diet (dry matter) according to the NRC (14
) and later reports (19
). The cholecalciferol content of the diets was within the reference range of the AAFCO recommendations for growing dogs, i.e., a minimum of 12.5 and a maximum of 125 µg cholecalciferol/kg diet (dry matter) at an energy density of 3500 kcal/kg diet (dry matter) (15
).
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,12
,20
,21
). Decreased food intake is attributed to the hypercalcemia in combination with hypercalcitoninemia, which influences the satiety center (22
). It is unclear whether low energy intake or the imbalance of minerals decreases the growth rate in these animals (12
). Data from dogs raised on a diet with 3.3 g Ca/100 g diet (dry matter) were included in the study because the actual food intake was measured individually in each dog and the actual Ca ingested per kg of body weight could be calculated to study the relationship between Ca intake and Ca absorption in Ca intakes higher than the recommendations. Protocol.
The results in this report are confined to the absorption efficiency of the actual ingested Ca in these dogs measured in 45Ca balance studies. Measurements of Ca absorption were carried out in the period after weaning (i.e., at 6 wk of age) until the age of 6 mo with an interval of 6 wk between each investigation. In this manner, true absorption of the ingested amount of Ca (Va) was measured in each dog at different ages during a period of constant dietary Ca concentration, excluding data from dogs for which the diet was normalized during the study, i.e., data from 21 and 25 wk of age from the dogs studied by Schoenmakers (12
).
Va was measured using one tracer, i.e., 45Ca as 45CaCl2 in water (specific activity 271.88 MBq/mg; NEN Life Science Products, Boston, MA), by techniques previously described and validated for dogs (7
,12
). The use of only one tracer is justified by the following observations: (a) after intravenous (IV) administration of 45Ca, the endogenous fecal excretion (Vf) of 45Ca is detectable for a maximum of 3 d; (b) after oral administration of 45Ca, the nonabsorbed tracer (VF) is detectable for at most 4 d in the feces; and (c) the contribution of Vf by the tracer to VF is negligible. Therefore, one tracer can be used in the 45Ca balance studies provided that the oral 45Ca dose is given at least 3 d after the IV administration and with the assumption that Ca balance is in a steady state during the 7-d investigation.
Dogs were kept individually in metabolic cages during 45Ca balance studies. The actual food intake was measured and daily Ca intake (VI) was calculated for each investigation period. The Vf was determined by collection of the feces for 3 consecutive days after an IV dose of 45Ca. The Vf was calculated from the quotient of the part of the injected dose (R3) that was excreted in the feces for 3 d and the integral of plasma specific activity according to the formula: Vf = R3/
03 C(t) dt. On the d 4 of each metabolic study, a dose of 45Ca equivalent to the IV dose was orally administrated and feces were collected for 4 consecutive days to determine the VF. Va was calculated by the formula: Va = VI - (VF - Vf). All parameters were expressed as mmol Ca · kg body-1 · d-1. The fractional absorption of the ingested Ca (
) was defined as: = Va/VI · 100%.
Analysis of feces.
Feces were individually collected and pooled for each part of the 3- and 4-d investigation, weighed and homogenized with a known quantity of distilled water by use of a blender. Multiple samples were dried for 24 h at 60°C, weighed, ashed for 6 h at 550°C and resuspended in 10 mL of hydrochloric acid (37% v/v), and distilled water was added to a total volume of 100 mL. The activity of 45Ca was determined in 0.4 mL of the supernatant mixed thoroughly with 4 mL scintillation fluid (Ultima Gold; Packard Bioscience BV, Groningen, The Netherlands) with a liquid scintillation counter (1212 Rackbeta; LKB Wallac, Turku, Finland).
Statistics and model analysis.
Analysis of covariance of the effect of cholecalciferol intake (i.e., 13.4 vs. 27.6 µg/kg diet dry matter) on with VI as covariate revealed that cholecalciferol intake did not have a differential effect (P = 0.094). In addition, the validity of pooling the data were graphically confirmed. The safety of this approach was supported by determination of the relationship among the variables VI, Va and only in the studies with a wide range of VI. The same relationships described here emerged in all separate studies, i.e., the correlation between VI and Va was always positive and between VI and always negative. In the remaining studies, relationships could not be determined safely because the dogs participating were raised only on one certain diet with either optimal or excessive Ca. Separate model analysis of the data would be inconclusive due to a combination of complex models and smaller sample sizes.
A first analysis of the results, including descriptive statistics and bivariate correlations, was performed using SPSS 10.1 (SPSS Inc., Chicago, IL). Food intake and thus VI were related to energy requirements because all dogs were fed at least their maintenance energy requirements based on metabolic body weight (body weight0.75) (23
). The daily available amount (AI) of Ca intake was AI = aI · body weight0.75, and because VI was expressed as mmol · kg body-1 · d-1, VI = AI/body weight = aI · body weight-0.25. Thus, a decrease of VI at increasing body weight should be expected. However, body weight-0.25 is a slowly varying function of body weight, and thus its effects would be detected more easily over a large range of body weight as observed in the fast growing Great Danes. Indeed, VI was significantly related to age in the Great Danes (r = -0.351 with P < 0.01) as well as to Va and , whereas it was not related to any of the parameters in the Miniature Poodles. This observation justified the incorporation of age as an additional variable in the models of analysis. Evaluation of the skeletal development assessed according to techniques described earlier (24
) revealed that Miniature Poodles and Great Danes raised on balanced diets follow comparable developmental patterns, reaching the same stage by the age of 21 wk (unpublished data). Therefore, Miniature Poodles and Great Danes were assumed to be at the same age at a comparable developmental stage for the duration of the study.
Model analysis was performed using the statistical package R (25
). The parameters in the model analysis were Va, VI (mmol · kg body-1 · d-1), breed of dog (0 for Miniature Poodles and 1 for Great Danes) and age (wk). For each dog, two to four measurements of Va and VI at different ages during the fast period of growth (i.e., 6 to 27 wk of age) were available. Va and VI were expressed as mmol · kg body-1 · d-1 and thus the effect of body size was eliminated from the analysis.
Several models, expressing Va as a function of the other parameters, were investigated. The first and second are extensions of the linear model described by Heaney et al. (26
) and of the power function model described by Heaney et al. (27
) by including a possible age and breed dependence:
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and
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The third model is an extension of the model described by Blanchard & Aeschlimann (28
) in which the distinct active and passive components of Ca absorption can be discerned. In their original model, A = (Amax · D)/(Km + D) + P · D, A represents the amount of Ca absorbed, Amax the theoretical maximum absorbed by active transport, D the Ca load, Km the apparent half-saturation constant of the saturable active transport (i.e., the dose corresponding with Amax/2), and P is a composite diffusivity constant describing all nonsaturable passive transport of Ca. Taking into account that both Amax, Km and P may change with age due to the developmental processes of the intestinal Ca absorption system, age and breed were introduced in the model as follows:
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Fitting a model to the data results in an estimation of the coefficients a1, b1, etc. If, for instance, in Model I, c1 does not differ significantly from zero, which implies that Age does not play a role in the model. The actual fitting procedures require knowledge of the distribution of the Va data. The Va data had an asymmetrically right skewed distribution. Inspection of the Va data revealed a considerable increase in the variance (
2) at increasing VI (Fig. 1
) and so the shape was allowed to change with VI according to log(2) = 1 + 2 · VI. It was not possible to incorporate random dog effects in the model. However, because of the large differences in VI among the dogs, this was taken into account by allowing the shape to change with the VI. Several distributions, including the normal, log normal, inverse Gauss, gamma, log gamma, Weibull, Cauchy, Laplace and log Laplace, were fitted with Models I, II and III for the location and the one mentioned above for the shape. Akaike’s Information Criterion (AIC) was employed to judge the fit of the model; a lower value indicated a better fit (29
).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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(r = 0.832 and 0.927 with P < 0.01 in Great Danes and Miniature Poodles, respectively), whereas VI and were inversely related (Fig. 2
) (r = -0.450 and -0.444, with P < 0.01, in Great Danes and Miniature Poodles, respectively).
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Breed did not play a significant role in the fit of either of the models. A similar result was found in Model III. Breed (d3) was not significant, nor were the age effects on Km (b3) and P (c3). Excluding these parameters stepwise from the model improved the AIC from 455.9 to 453.8 (exclusion of d3), to 452.8 (exclusion of d3 and c3) and to 451.8 (exclusion of d3, c3 and b3). Thus, the model was given by the equation:
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In support of the age dependency of Amax, exclusion of a3 substantially worsened the fit, with AIC increasing to 462.8. Results of the model analysis have been included in the Va versus VI plot (Fig. 1)
. Figure 3
illustrates the theoretical relationship between active and passive Ca absorption over the range of VI studied for the median age of the dogs (i.e., 15 wk of age).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,11
,12
,16
), where Ca metabolism has been thoroughly described, including Ca routed to the skeleton and urine. The analysis of several 45Ca balance studies, all performed by the same technique and under the same research conditions, allows for model analysis of Ca absorption in growing dogs. Thus, the three models studied, in a complementary fashion, the effects of the actual ingested Ca defined as VI, and the effects of age and breed on Va. Additionally, Model III studied distinctly passive and active Ca absorption and the possible differences between breeds of dogs in the extremes of the diversity in growth rate in this species.
In the period after weaning until the age of 27 wk, Va had a significant direct relationship to VI in both breeds of dogs. This was supported by the observed direct relationship between Va and VI in Model I and Model II, where Va was directly proportional to a function close to VI0.82. In addition, Model III revealed a slope of 0.53, in other words 53% of the VI was absorbed passively, which is in accordance with studies in growing rats (5
,30
). Consequently, passive diffusion, a process of the concentration gradient, was responsible for a major portion of the total Ca absorbed, reinforcing the direct relationship of Va to VI. The strong direct relationship between Va and VI during the growth phase is a continuation of the need for high Ca retention for mineralization of the growing skeleton (31
). It has been shown earlier that Ca is absorbed and retained to a greater extent in young growing animals than in their older counterparts (30
,32
) and that the Ca absorption system is regulated by the requirements of the life stage of the organism (33
,34
).
The curvilinear characteristics of the relationship between VI and Va (Fig. 2)
and in particular the inverse relationship between VI and (Fig. 1)
indicate the presence of active and passive Ca absorption in weaned growing dogs. The latter is in accordance with the numerous reports on the processes by which Ca absorption takes place in other mammals after weaning (1
,3
–5
). Active Ca absorption played a physiologically important role in the absorption of Ca during low VI, whereas during excessive VI the quantity of Ca absorbed by the active process was negligible compared with that absorbed passively (Fig. 3)
. The inverse relationship between and VI, has also been reported by others (26
,27
) and is mainly attributed to physiological adaptation mechanisms orchestrated by the calciotropic hormones (1
) that act to maintain Ca homeostasis. During low VI, the tendency of plasma Ca concentrations to decrease stimulates the production and secretion of parathyroid hormone (PTH). PTH up-regulates the renal production of 1,25(OH)2D which in turn up-regulates Ca absorption (8
,10
,11
). In the same manner, during increased VI, plasma Ca concentrations tend to increase and the production and secretion of PTH is down-regulated causing a down-regulation of the production of 1,25(OH)2D which in turn down-regulates active Ca absorption (8
,11
–13
). The down-regulation of active Ca absorption during increased VI contributes to the decrease in the total Va; however, this is not sufficient because 53% of the VI is still absorbed passively. Consequently, passive Ca absorption in growing dogs with excessive VI is the driving force stimulating the thyroid C-cells to hypertrophy and produce more calcitonin during the postprandial rise of plasma Ca concentrations (9
,35
), subsequently routing Ca to the skeleton (22
).
From 6 to 27 wk of age, Va and consequently , decreased with age in all models at the same VI indicating a developmental pattern in Ca absorption in dogs. In addition, in Model III it was shown that the age-dependent decrease of was mainly attributable to changes in the active component of Ca transport, in accordance with the developmental pattern reported in rats (5
). In particular, Amax decreased significantly with age at a rate of 3.3% per wk, whereas the Km remained constant during this same period. On the contrary, the mean slope (P) representing the passive component of Ca absorption remained constant at 0.53 for the duration of the study, consistent with a P of 0.50 reported in growing rats after weaning (5
). In addition, in Model III there was evidence of an adaptational component indicated by the inverse relationship between the decreased rate of actively absorbed Ca and VI.
Breed and thus growth rate did not play a significant role in either of the models of Ca absorption and its relationships to VI and age. This analysis rebuts previous assumptions (36
) and revealed that there were no essential differences between giant and small breed dogs concerning the intestinal Ca handling in the period after weaning until the age of 27 wk on diets containing 0.33–3.3 g Ca/100 g diet (dry matter). Consequently, the increased susceptibility for disturbances in skeletal mineralization of giant versus small breed dogs cannot be explained by a difference in intestinal Ca handling, leaving other considerations such as growth rate and disturbance of calciotropic hormones as possible etiological factors (6
,13
).
The effect of the dietary cholecalciferol concentration cannot be addressed in this study; the two-fold difference between control diets did not affect when corrected for VI. This was further supported by the dominance of passive absorption at sufficient VI and thus the limited hormonally regulated Ca absorption at this stage at sufficient VI (37
). To see the effects of cholecalciferol intake on intestinal Ca absorption over a larger range of cholecalciferol intake are warranted accompanied by the determination of the main cholecalciferol metabolites that next to 1,25(OH)2D3 may influence Ca absorption (38
).
In the lower and upper range of VI, there was deviation from the accepted ratio of Ca to phosphate which may influence intestinal Ca absorption. Excessive intake of phosphate may decrease intestinal Ca absorption (39
,40
) by formation of insoluble complexes in the lumen of the intestine and thus by lowering the concentration of soluble Ca (41
). The latter, however, occurs only when excessive phosphate intake is accompanied by sufficient Ca (41
). Thus in the lower range of VI with the recommended phosphate intake, formation of such complexes is not expected and is supported by the striking increase in , i.e., 80 to as much as 100%, supporting the undisturbed bioavailability of Ca. In the upper range of VI with no concomitant increase in phosphate intake, the availability of phosphate may be limited by the formation of insoluble complexes and accompanied by a decrease in active 1,25(OH)2D3-dependent absorption, resulting in relative deficiency in phosphate. The latter is supported by the occurrence of hypophosphatemic hypoparathyroidism and rickets in Great Danes on a diet with excessive Ca (13
).
We conclude that postweaning dogs can regulate Ca absorption during long periods of deficient or excessive VI, irrespective of growth rate. In the period after weaning until 6 mo of age, at the recommended levels of VI, active Ca absorption undergoes developmental changes, whereas passive absorption accounts for 53% of absorption of the VI and is age-independent. The adaptational processes can be challenged at the extremes of VI. During Ca deficiency, active Ca absorption contributes to a large part of the total Ca absorbed whereas active Ca absorption is negligible and passive absorption plays a dominant role during Ca excess. In addition, intestinal Ca handling in dogs is not related to body size and growth rate as revealed by analysis of breeds with dramatically different mature body size.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: 1,25(OH)2D3, 1,25-dihydroxycholecalciferol; , fractional Ca absorption of the VI; AI, available amount of calcium in the intake; Amax, theoretical maximum of actively absorbed Ca; AIC, Akaike’s Information Criterion; Ca, calcium; 45Ca, the radioactive isotope 45calcium; D, amount of Ca present in the intestinal lumen; IV, intravenous; Km, apparent half-saturation constant of the saturable active transport of Ca; ND, not determined; P, diffusivity constant describing all nonsaturable passive transport of Ca; PTH, parathyroid hormone; R3, total fecal content of 45calcium after intravenous administration; 2, variance; Va, true calcium absorption of the VI; Vf, endogenous fecal calcium excretion; VF, total fecal content of 45calcium after oral administration; VI, ingested amount of calcium (calcium intake).
Manuscript received 8 May 2002. Initial review completed 7 June 2002. Revision accepted 9 August 2002.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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