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From the Clinical Research Centers |
Division of General and Community Pediatrics (H.J.K), Children’s Hospital Medical Center Cincinnati, Ohio 45229; E. A. Martin Program in Human Nutrition (B.L.S.), South Dakota State University, Brookings, South Dakota 57007; and Institute for Health Policy and Health Services Research (M.H.), University of Cincinnati Medical Center, Cincinnati, Ohio 45267
Address all correspondence and requests for reprints to: Heidi J. Kalkwarf, Ph.D., Division of General and Community Pediatrics, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229. E-mail: heidi.kalkwarf{at}chmcc.org
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The extent to which the classic calciotropic hormones, PTH and 1,25-dihydroxyvitamin D [1,25(OH)2D], and the physiologic action of these hormones, are altered during lactation and the postweaning periods, to conserve calcium and help direct the calcium economy, is unclear; many studies have had contradictory findings (3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15). Some of the discrepancies among studies may be explained, in part, by differences in control populations, calcium intake of study groups, and small sample sizes.
Theoretically, if calcium intake were sufficient to meet the needs for milk production or to facilitate the recovery of bone after weaning, then alterations in calciotropic hormones and physiologic compensations to conserve calcium during lactation would not be needed. This model presumes that the secretion of calcium in breast milk is the stimulus for changes in calcium homeostasis. There is little data on changes in calcium homeostasis during lactation in women with different calcium intakes. Specker et al. (12) compared serum 1,25(OH)2D concentrations between omnivorous and vegetarian women with different calcium intakes. Serum 1,25(OH)2D concentrations were higher in lactating (compared with nonlactating) women, and the increase in 1,25(OH)2D was greater among lactating vegetarian women who had the low calcium intake. Two randomized calcium supplementation trials in lactating women found no effect of calcium supplementation on serum PTH or 1,25(OH)2D concentrations during lactation or after weaning (16, 17). However, neither trial included nonlactating postpartum women, to determine whether these responses would have differed by lactation status.
The objectives of the study reported herein are three-fold: 1) to determine whether calciotropic hormones are increased and urinary calcium excretion is decreased during lactation and after weaning, relative to these measures in nonlactating postpartum women; 2) to determine whether these responses were altered by different calcium intakes; and 3) to compare, temporally, how changes in calciotropic hormones and urinary calcium relate to indices of bone formation and resorption. We investigated these questions as part of a randomized trial designed to examine the effects of calcium supplementation on bone density during lactation and after weaning (2).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Two groups of women, defined by time post partum, were recruited to
participate in this randomized, double-blinded, placebo-controlled
calcium supplementation trial (2, 18). Women were studied either during
the first 6 months post partum (lactation cohort) or second 6 months
post partum (weaning cohort), so that we could examine the effects of
calcium supplementation during lactation and after weaning while
controlling for time post partum. Only women with estimated calcium
intakes (
800 mg/day), as determined by a food frequency
questionnaire, were enrolled, to provide a sensitive population in
which to examine calcium supplementation effects. None of the women had
any disorder that affected calcium or bone metabolism or were taking
chronic medications or hormonal contraceptives, and all had a singleton
pregnancy lasting 
37 weeks and had taken prenatal vitamins during
pregnancy.
Lactation cohort women (97 lactating and 99 nonlactating) were enrolled
at 16 ± 2 days (mean ± SD) post partum and were
followed for 6 months. Only lactating women who were planning to
breast-feed for 6 months and provide one or less formula feeding per
day were recruited. Nonlactating women exclusively formula-fed their
infants from birth. Weaning cohort women (95 lactating and 92
nonlactating) were enrolled at 5.6 ± 0.8 months post partum and
also were followed for 6 months. Lactating women in the weaning cohort
were breast-feeding 5.5 ± 1.1 times/day at enrollment and then
weaned their infant from the breast within the next 2 months.
Intestinal calcium absorption and some biochemical measurements have
been reported previously for a subset of lactating and nonlactating
women studied at 4.6 ± 0.2 (lactation cohort, n = 48) or at
9.6 ± 0.9 months post partum (weaning cohort, n = 48)
(15).
The women in each cohort were randomized to receive 1 g/day of elemental calcium as calcium carbonate (Os-Cal, Marion Merrell Dow, Kansas City, MO) or placebo. The calcium supplement was provided as two 500-mg tablets, and subjects were instructed to consume one tablet with the morning and evening meals. Women were given a daily multivitamin containing 400 IU vitamin D (Dayalets, Abbott Laboratories, North Chicago, IL) to ensure adequate vitamin D nutriture. Compliance with the calcium and multivitamin supplements was assessed by pill counts every 3 months.
Women kept daily logs throughout the study to record the occurrence of menses. Women completed 3-day food records during the 11th and 23rd study weeks to allow estimation of calcium intake, as reported previously (2, 18).
Laboratory methods
A nonfasting blood sample and a 24-h urine sample were collected at baseline and after 3 and 6 months of calcium or placebo supplementation. Methods used for analyses of calcium, phosphorus, and calcium regulatory hormones are described elsewhere (15). Urinary calcium was expressed as total milligrams excreted per 24 h and as a function of glomerular filtrate (19). Tubular phosphorus reabsorption (TRP) was calculated using a standard formula (20). Serum osteocalcin and carboxyterminal propeptide of type I procollagen (PICP), markers of bone formation, and urinary cAMP were measured by commercial RIA kits from INCSTAR Corp. (Stillwater, MN). Urinary deoxypyridinoline, a marker of bone resorption, was measured by an immunoassay (Metra Biosystems, Inc., Palo Alto, CA).
Statistical analyses
Data were analyzed using repeated-measures ANOVA (SAS Institute, Inc., Cary, NC). In addition, two-way ANOVA analyses were conducted at each time point to test the effects of lactation, calcium supplementation, and the interaction between these two factors. Because there were few significant interactions, results are presented as the main effects of lactation and calcium groups unless otherwise stated. Post hoc analyses were conducted to determine whether the menstrual status of lactating women was related to calciotropic hormones and other biochemical measures; only significant differences are presented. All variables were checked for normality before analyses, and nonnormally distributed variables were transformed to better approximate normality. The square root transformation was used in the analyses of urinary calcium and cAMP; the natural logarithm transformation was used for the analyses of PTH, 1,25(OH)2D, deoxypyridinoline, and PICP; and the arcsin transformation was used for the analyses of TRP. P values < 0.10 are presented in the text.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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80% of the pills. In the
lactation cohort, lactating women had higher estimated calcium intakes,
compared with nonlactating women, at baseline (613 ± 187
vs. 530 ± 180 mg/day; P < 0.01), as
determined from the food frequency questionnaire, and during the study
(860 ± 257 vs. 699 ± 234 mg/day;
P < 0.001), as determined from the food records. In
the weaning cohort, lactating women had higher estimated calcium
intakes than nonlactating women at baseline (676 ± 141
vs. 562 ± 186 mg/day, P < 0.001), but
there was no difference during the study after weaning (739 ± 224
vs. 711 ± 217 mg/day). There were marked differences
in length of postpartum amenorrhea between lactating and nonlactating
women. In the lactation cohort, only 26.2% of lactating women,
compared with 100% of nonlactating women, had resumed menses by 6
months post partum. In the weaning cohort, 12.5% of lactating women,
compared with 98.7% of nonlactating women, had resumed menses at
enrollment (i.e. an average of 5.6 months post partum). Lactation cohort: the first 6 months post partum
There were no differences in serum calcium concentrations between
lactating and nonlactating women (Table 1
). In contrast, serum phosphorus
concentrations were higher in lactating (compared with nonlactating)
women at 3 and 6 months (P < 0.001). Serum phosphorus
was lower (P = 0.03) in lactating women who had resumed
menses by 6 months post partum (n = 62), compared with amenorrheic
lactating women (n = 22) (i.e. 3.7 vs. 3.9
mg/dL), but was still higher than those of nonlactating postpartum
women (3.6 mg/day, P < 0.001).
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There were no differences in urinary calcium excretion between lactating and nonlactating women at baseline, but calcium excretion was slightly less in lactating women at 3 and 6 months post partum (P = 0.09 and 0.06, respectively). These results did not change when calcium excretion was expressed relative to urinary creatinine or glomerular filtrate. TRP was lower in lactating (compared with nonlactating) women only at 6 months (P = 0.02). Urinary cAMP was greater in lactating women at baseline (P = 0.001) and 3 months (P = 0.02) but not at 6 months.
Urinary deoxypyridinoline, a marker of bone resorption, changed
dramatically over the course of the study (Fig. 1). For both lactating and nonlactating
women, deoxypyridinoline excretion was highest at baseline (0.5 month)
and decreased thereafter (P < 0.001). Lactating women
had higher deoxypyridinoline excretion (compared with nonlactating
women) at 3 and 6 months (P = 0.03 and
P < 0.001, respectively). At 6 months post partum,
deoxypyridinoline excretion was slightly higher among lactating women
who had resumed menses, compared with those who had not (geometric
means: 6.6 vs. 5.1 mmol/mmol creatinine, P =
0.06).
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). At baseline, PICP
was lower in lactating (compared with nonlactating) women
(P < 0.001). At 3 and 6 months, this trend reversed
and PICP was greater in lactating women (P < 0.001).
Serum concentrations of osteocalcin followed a trend similar to PICP
and were higher in lactating women at 3 and 6 months (P
< 0.001). Calcium-supplemented women had higher serum calcium concentrations (P = 0.03) and lower serum PTH and 1,25(OH)2D concentrations (P < 0.01) at 3 and 6 months post partum than placebo-supplemented women. Urinary calcium excretion increased after calcium supplementation began (P < 0.001). At 6 months, there was a slight interaction between lactation and supplement groups (P = 0.06): the increase in urinary calcium excretion caused by supplementation was 21.9 mg/24 h for lactating women, compared with 70.5 mg/24 h in nonlactating women. TRP was higher in calcium-supplemented (compared with placebo-supplemented) women at 3 and 6 months (P = 0.004 and P = 0.07, respectively). There was no effect of calcium supplementation on serum phosphorus, PICP and osteocalcin concentrations, or urinary cAMP and deoxypyridinoline excretion.
Weaning cohort: the second 6 months post partum
Serum calcium and phosphorus concentrations were higher in
lactating women, compared with nonlactating women, at baseline
(P < 0.001) (Table 2).
Serum calcium and phosphorus concentrations decreased after weaning
(P < 0.001), and there was no differences between
lactating and nonlactating women thereafter.
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There were no differences in urinary calcium excretion between lactating and nonlactating women before (6 months post partum) or after weaning (9 and 12 months). At baseline (6 months post partum), TRP was slightly lower for lactating (compared with nonlactating) women (P = 0.06), but there was no difference between groups after weaning. At 6 months post partum, cAMP was slightly higher among lactating women than nonlactating women (P = 0.08). Urinary cAMP was higher among lactating women who had resumed menses (n = 11), compared with those who had not (n = 61) at 6 months post partum (geometric means: 424 vs. 300 nmol/mmol creatinine, P = 0.001) and at 9 months post partum (n = 55 vs. 17) (282 vs. 237 nmol/mmol creatinine, P = 0.09).
There was little change in deoxypyridinoline excretion in the second 6
months post partum (Fig. 1). Urinary deoxypyridinoline was slightly
greater in lactating (compared with nonlactating) women at 6, 9, and 12
months post partum (P = 0.10, 0.03, and 0.07,
respectively). Serum PICP and osteocalcin decreased over the course of
the study and were higher in lactating women at 6 and 9 months post
partum (P < 0.001) and, to a lesser extent, at 12
months (P = 0.02 and 0.08). At 9 months post partum,
PICP and osteocalcin concentrations were lower (P =
0.02) among lactating women who had resumed menses (n = 55),
compared with those who had not (n = 17) (geometric means: 140
vs. 192 µg/L and 4.0 vs. 5.2 µg/L,
respectively).
Serum calcium, urinary calcium excretion, and TRP were higher (P = 0.05, P < 0.01, and P < 0.01, respectively), and serum PTH and 1,25(OH)2D were lower (P < 0.001 and P = 0.03) in women receiving the calcium supplement, compared with those receiving the placebo, at 9 and 12 months. Calcium supplementation had no effect on serum phosphorus, osteocalcin, or urinary deoxypyridinoline concentrations. At 12 months post partum, PICP concentrations were lower (P = 0.01) among women receiving the calcium supplement, compared with those receiving the placebo.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Lactating women secrete approximately 210 mg/day of calcium in
milk, which, over 6 months, is equivalent to 4% of the total skeletal
reserve of calcium (
900–1000 g). The role of calciotropic hormones
in maintaining serum calcium and directing the calcium economy during
lactation and after weaning has been unclear, especially in relation to
the dynamic changes in bone mineral content. Typically, serum PTH and
1,25(OH)2D increase in times of high calcium need, to
conserve calcium and maintain or increase serum calcium concentrations.
We found that the concentrations of PTH and 1,25(OH)2D
indeed change over the course of lactation and differed from those of
nonlactating postpartum women. However, the changes in PTH, indicators
of PTH activity, and 1,25(OH)2D were discordant and were
not consistent with directing the calcium economy during lactation and
after weaning.
PTH concentrations were lower in lactating than in nonlactating women, a trend opposite to that expected if one assumed that calcium loss in breast milk decreases serum calcium and stimulates a cascade of responses to conserve calcium through classical calcium regulatory pathways. PTH concentrations were suppressed in lactating women during the first 3 months post partum, at a time when bone was rapidly resorbing, a finding consistent with some (3, 7, 13, 16), but not all, other studies (9). PTH increased after weaning, to concentrations similar to those of nonlactating postpartum women; we did not find a further increase that has been reported by others (5, 9).
Despite the decreased PTH concentrations early in lactation, our data on urinary cAMP excretion provide indirect evidence of increased PTH-like activity at this time. Lactating women had elevated urinary excretion of cAMP, which can reflect both PTH and PTH-related peptide (PTHrP) action at the kidney. Serum concentrations of PTHrP are apparently increased during human lactation (8, 23, 24, 25, 26, 27). It has been hypothesized that PTH concentrations are suppressed during lactation, secondary to elevations of PTHrP (23). We did not measure serum PTHrP. Because serum PTH changes were opposite in direction to urinary cAMP, it is possible that cAMP changes reflected PTHrP activity. We also found that lactating women had higher serum phosphorus and lower TRP late in lactation, which resulted in greater urinary phosphorus excretion. The reduction in TRP during lactation is consistent with a previous study (7) and would be expected if PTH were elevated. Because PTH was suppressed, PTHrP action is a possible alternative. PTHrP mimics PTH by stimulating renal calcium conservation and increasing urinary phosphorus excretion (28, 29).
Serum 1,25(OH)2D concentrations increased 28% during the first 6 months of lactation, a finding consistent with other longitudinal studies (7, 11, 14, 16, 30). Despite the fact that 1,25(OH)2D concentrations also increased for nonlactating women during this period, 1,25(OH)2D was 16% higher in lactating women than for nonlactating women at 6 months post partum, and it remained slightly higher for approximately 2 months after weaning, when bone mineral density was increasing (2). Only two other longitudinal studies have included nonlactating postpartum women as a control group, neither of which found serum 1,25(OH)2D concentrations to be higher during lactation, possibly because of smaller sample sizes (7, 9). A small sample size may also explain why we did not observe this increase during lactation in our previous report on a subgroup of these women (15). The few studies that examined changes in serum 1,25(OH)2D after weaning, found concentrations to be elevated (9) or not different (5, 7, 17, 31) from controls.
The stimulus for increased serum 1,25(OH)2D concentrations
during lactation is not clear. Serum PTH concentrations were lower
than, and serum calcium and phosphorus concentrations were higher than,
in nonlactating postpartum women, all of which should have resulted in
lower 1,25(OH)2D concentrations. The rise in
1,25(OH)2D occurred when the majority of lactation-induced
bone loss measured at the lumbar spine had already occurred
[i.e. 3 months post partum (2)], perhaps providing an
alternate mechanism to obtain calcium. Increasing estrogen
concentrations may explain the increase in 1,25(OH)2D.
Estrogen treatment is associated with increased serum
1,25(OH)2D, though its effects are thought to be indirect
and not a direct effect on 1-
hydroxylase activity (32). In support
of this hypothesis, we found that serum 1,25(OH)2D
concentrations were higher in lactating women in the weaning cohort who
resumed menses by 6 months postpartum, compared with those who had not.
We did not observe this relationship in the full lactation cohort, as
we had previously reported for a subgroup of these women (15).
We found only small, nonsignificant differences in urinary calcium excretion between lactating and nonlactating women receiving the placebo during lactation and no differences after weaning (see below for discussion of differences in calcium-supplemented groups). These findings differ from some studies (5, 33, 34) but are in agreement with other studies that used nonlactating postpartum women as controls (3, 7). We found that nonlactating postpartum women were experiencing alterations in calcium metabolism, because they had a 31-mg/day (38%) increase in urinary calcium between 2 weeks and 6 months post partum (P < 0.05). Failure to account for postpartum changes would overestimate the effects of lactation per se. Differences in calcium intake might also explain the discrepancy in results among studies (see below).
Although the markers of bone turnover were elevated in lactating women, there was no marker or combination of markers that could consistently predict changes in bone density over time. In lactating women, temporal changes in serum 1,25(OH)2D concentrations were similar to those of PICP and osteocalcin, perhaps indicating a mechanism for calcium acquisition during bone formation. Deoxypyridinoline was elevated in lactating women, suggesting that bone resorption may be one mechanism that provides calcium needed for milk production. At 2 weeks post partum, bone resorption seemed to be occurring in nonlactating (as well as lactating) women, as indicated by the high deoxypyridinoline in both groups. Rapid bone resorption for a few weeks post partum may explain why we (2) and others (35) have found that nonlactating postpartum women experience a small increase in bone density during the first year post partum.
Effects of calcium intake on calcium regulation during lactation and after weaning
The extent to which the loss of calcium in breast milk per se is a stimulus for changes in calcium regulatory hormones and calcium conservation during lactation is not known. In an observational study of vegetarian and omnivorous women, Specker et al. (12) found that the calciotropic hormone response to lactation was augmented in vegetarian women with a low calcium diet. Measurement of the calcium-regulating hormones in postpartum women, randomized to receive a calcium supplement or a placebo, allowed us to determine to what extent the drain of calcium during lactation is the primary stimulus that affects the hormonal regulators or whether other factors direct the calcium economy and enable the secretion of calcium into breast milk. We found that the model of a calcium drain as a stimulus is not appropriate, because supplementation of lactating women with extra calcium did not alter the calciotropic hormone response to lactation: differences between lactating and nonlactating women persisted in the presence of calcium supplementation. Calcium supplementation had the expected lowering effects on serum PTH and 1,25(OH)2D concentrations in both lactating and nonlactating women. These findings differ from those of Prentice et al., in which calcium supplementation of lactating Gambian women with very low calcium intakes did not affect calciotropic hormones (16). Our findings are consistent with the hypothesis that the calcium-sensing mechanisms were intact and, overall, PTH was secreted appropriately in response to changes in serum calcium concentrations. We speculate that other factors (e.g. estrogen and PTHrP) must be directing the calcium flux out of and into bone and that calciotropic hormones regulate serum calcium concentrations in the face of this process.
We found that the calciuria in response to calcium supplementation was smaller in lactating women than in nonlactating women at 6 months post partum (calcium-by-lactation group interaction P = 0.06). This provides some evidence that lactating women may excrete less calcium than nonlactating women at high calcium intakes, and this is consistent with the findings of one other study (36). The signal to elicit this compensation is not clear, because there were no calcium intake-by-lactation group interactions for calciotropic hormones. Other than this finding, we found that calcium intake, between approximately 750-1700 mg/day in Caucasian adult women nursing a single infant, has little effect on lactation-induced changes in the calcium economy.
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Acknowledgments |
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Footnotes |
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Received June 10, 1998.
Revised October 6, 1998.
Revised October 30, 1998.
Accepted November 2, 1998.
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