Kovacs CS. Maternal Mineral and Bone Metabolism During Pregnancy, Lacta-
L
tion, and Post-Weaning Recovery. Physiol Rev 96: 449 547, 2016. Published
February 17, 2016; doi:10.1152/physrev.00027.2015.During pregnancy and
lactation, female physiology adapts to meet the added nutritional demands of
fetuses and neonates. An average full-term fetus contains 30 g calcium, 20 g
I. INTRODUCTION 449 ash weight and mineral content of fetal cadavers between
II. SKELETAL AND MINERAL PHYSIOLOGY... 451 24 wk and term. Multiple studies have demonstrated that
III. DISORDERS OF BONE AND MINERAL... 471 the average full-term fetus has 30 g calcium (77, 196, 289,
IV. SKELETAL AND MINERAL PHYSIOLOGY... 486 332, 868, 930, 982984, 1022), 20 g phosphorus (289,
V. DISORDERS OF BONE AND MINERAL... 510 984, 1022), and 0.80 g magnesium (289, 332, 984, 1022).
VI. CONCLUSIONS 521 However, that fetal mineral content is not obtained at a
constant rate during pregnancy; instead, at least 80% of the
I. INTRODUCTION calcium, phosphorus, and magnesium present in a human
term fetus is accreted during the third trimester (77, 196,
During pregnancy and lactation, female physiology must 332, 868, 930, 982, 984, 1022). This corresponds to a
adapt to meet the added nutritional demands of the fetus mean calcium transfer rate of 100 150 mg/kg per day (77,
and neonate. How much of a demand is there for delivery of 332, 868, 930, 983, 984, 1022), which, for an average-sized
calcium and other minerals? What adaptations are invoked fetus, is 60 mg/day at week 24 and 300 350 mg/day
during pregnancy and lactation to meet these demands? Do between the 35th and 40th week of gestation (1022). Sim-
these adaptations alter normal biochemical and hormonal ilarly, the rate of phosphorus transport is 40 mg/day at
parameters of mineral and skeletal metabolism? What im- week 24 and increases to 200 mg/day over the last 5 wk of
pact do these adaptations have during pregnancy and lactation gestation (1022). The rate of magnesium transfer increases
on preexisting disorders of mineral and bone metabolism? Are more modestly from 1.8 to 5.0 7.5 mg/day over the last 5
there any long-term beneficial or adverse consequences of wk (1022). When expressed as hourly rates, during the
pregnancy and lactation on the skeletal health of women? All third trimester the fetal demand for calcium and phospho-
of these questions are addressed in this review. rus represent between 5 and 10% of the amounts present in
the mothers plasma (196, 982). This means that the fetal
The fetal requirement for mineral, which the pregnant demand for calcium and phosphorus has the potential to
woman must supply, has been determined by measuring the provoke maternal hypocalcemia and hypophosphatemia.
449
MINERAL METABOLISM DURING PREGNANCY AND LACTATION
The neonatal requirement for mineral, which may be sup- cium daily (430). However, the output of milk on an indi-
plied through breastfeeding, has largely been inferred from vidual basis is determined by the suckling demands of the
studies in which healthy neonates are weighed before and neonate and can certainly markedly exceed these values.
after each feed; a few studies have measured change in Women who nurse twins and triplets can have, respectively,
weight of the mother or the volume of milk that can be more than double and triple the milk output of women
manually expressed. The calcium intake has been the main nursing singletons (233, 792). Individual cases of women
parameter considered in these calculations. Such studies nursing singletons have documented milk output of up to
reveal an average intake of 780 ml of human milk per day 2.4 3.1 liters per day that was sustained for more than 12
(20, 138, 376, 653), which, combined with an average cal- mo of lactation (583, 838). The composition of milk is
cium content in milk of 260 mg/l during the first 6 mo similar between women with average and high outputs
postpartum (41), reveals a total calcium intake of 200 (233, 792), and so producing more milk will cause greater
mg/day. Estimates of fractional calcium absorption from maternal losses of calcium.
metabolic balance studies have shown that neonates absorb
60 70% of calcium from human milk (5, 8, 289, 382), Between 6 and 12 mo of age, more infant nutrition comes
thereby making 120 140 mg of calcium available for the from solid food despite continued breastfeeding. Fewer
the 50th percentile for calcium intake ranges from 800- The original data are described and cited in necessary detail
1,000 mg daily in both populations (430), for an expected to justify the conclusions, but each section is followed by a
fractional absorption of 200 250 mg daily. The 25th per- short summary so that the reader can glean key points at a
centile of intake is 600 700 mg daily, while the 5th per- glance.
centile is about 400 mg daily, in both populations (430).
Consequently, if normal intestinal calcium absorption were The term phosphorus is used for consistency and simplicity,
relied upon, most women do not consume sufficient calcium and because that is what is measured. It is acknowledged
to meet the combined needs of their babies and themselves. that in serum phosphorus largely exists as inorganic phos-
phates (dihydrogen and monohydrogen phosphate), in
However, increased intakes are not required in women who bone it is largely in the form of hydroxyapatite, while in soft
consume adequate calcium because of several adaptations tissues and extracellular fluid there are an abundance of
that are invoked during pregnancy and lactation. During organic phosphates complexed with carbohydrates, lipids,
pregnancy, the efficiency of intestinal calcium absorption and proteins (53).
doubles to meet the fetal requirement for calcium, whereas
during lactation, skeletal resorption increases to provide
150.0
Prolactin
(ng/ml)
*Women with low calcium or high phytate intakes have normal or increased PTH.
(WT) mice consumed a standard 1% calcium diet, there was Serum phosphorus remains normal during pregnancy in
no change in the ionized calcium or the serum calcium dur- rats (117, 314, 718) and mice (477, 478, 580), but may be
ing pregnancy (296, 477, 478, 992, 994). One study mea- modestly reduced in guinea pigs (958), sheep (21, 57), goats
sured the ionized calcium every other day in the same mice (21, 55), and cows (21). It is especially low during milk
from the time of mating and noted no change during preg- fever of cows (613). One study of pregnant rats differed by
nancy (827). Fewer studies have assessed the serum albu- reporting a reduction in serum phosphorus (425). Serum
min, but it was unchanged in pregnant mice compared with magnesium has been less commonly measured but is unal-
nonpregnant controls and did not decline during the last 7 tered in pregnant rats (315, 425), mice (580), and goats
days of pregnancy (154, 175, 197). (55).
Physiologically important hypocalcemia can occur during B) HUMAN DATA. The earliest studies in pregnant women
pregnancy when the fetal demand for calcium exceeds the found a progressive 510% decrease in serum calcium such
mothers ability to maintain her own serum calcium. This that the mean value fell below the normal range, thereby
may be especially true in rats where the hourly fetal demand indicating biochemical hypocalcemia (641, 674). Such re-
for calcium almost equals the amount of calcium present in sults confirmed what had already been observed in animal
the maternal circulation (196). Consistent with this, in- models, and suggested that the human fetus drains calcium
creased litter number and weight are associated with a from the maternal circulation in sufficient amounts to pro-
lower serum calcium in the mother (90), while pregnant rats voke maternal hypocalcemia and secondary hyperparathy-
fed a low-calcium (0.1%) diet experienced a marked decline roidism (15). It was not until later that it was better appre-
in both serum calcium and ionized calcium during the last ciated that the serum albumin falls during pregnancy due to
several days before delivery (321). A low-calcium diet sim- normal expansion of the intravascular volume, thereby pro-
ilarly provoked hypocalcemia in pregnant ewes compared voking a decline in the albumin-bound fraction of calcium
with consumption of a usual and a high-calcium diet (69). (720). The decline in the albumin-bound fraction of serum
In pregnant or lactating cows, such hypocalcemia is termed calcium is physiologically unimportant.
milk fever when it occurs near parturition or during lacta-
tion and provokes symptoms such as paresis (21). During When it became possible to measure the ultrafiltrable frac-
milk fever the serum calcium can be 50% of normal or even tion of serum calcium (which includes both complexed and
lower despite a compensatory rise in PTH (613); the cal- ionized calcium, but not albumin-bound calcium), no
cium demand of the fetuses is the precipitating factor. Sud- change was seen when prepregnancy and pregnancy mea-
den deaths during late pregnancy from presumed severe surements were compared (471). Later innovations resulted
hypocalcemia have occurred in rats rendered severely vita- in the ability to measure the ionized calcium with ion-spe-
min D deficient (359, 361363), and in Vdr null (296, 502) cific electrodes. Both cross-sectional (210, 227, 324) and
and Cyp27b1 null mice (330) maintained on a normal 1% longitudinal studies (221, 294, 721, 739, 791, 809, 813)
calcium diet. have shown that the ionized calcium does not change during
human pregnancy, even though the mean serum calcium volume is doubled in normal pregnant rats compared with
simultaneously drops 10% into the hypocalcemic range virgins (784, 842), while in vitro studies suggest that, for
(221). any level of extracellular calcium, parathyroids from preg-
nant rats secrete more PTH than those from virgin rats
The albumin-corrected serum calcium is a reasonable sub- (806). In addition to the obvious effect of the varying cal-
stitute for the ionized calcium, as several longitudinal and cium content of the rodent diets, there may be additional
cross-sectional studies have shown it to remain stable across variability between studies due to rats strains, and differing
all three trimesters, despite the concurrent fall in serum NH2-terminal or COOH-terminal radioimmunoassays
albumin (85, 599, 632, 646, 778). (RIAs) that were designed to detect human PTH. In most of
these studies the serum calcium alone was measured with-
Twin pregnancy does not impair the ability of a woman to out correction for the lower serum albumin. But a 0.4%
maintain a normal serum calcium, as shown in a compara- calcium diet provoked a decrease in the ionized calcium
tive study of women bearing twins versus singletons (646).
together with an increase in PTH in pregnant rats (90),
while more marked hypocalcemia and secondary hyper-
Serum phosphorus shows no change in most studies during
parathyroidism developed when pregnant rats were chal-
PTH radioimmunoassays measured multiple biologically The influence of PTH in regulating mineral metabolism dur-
inactive fragments of PTH (725, 959). ing pregnancy is further discussed in subsequent sections
that address the synthesis of calcitriol (sect. IIA4) and the
Two-site immunoradiometric (IRMA) PTH assays are more adaptations that occur in the intestines (sect. IIB), kidneys
sensitive and accurate (725). In cross-sectional studies of (sect. IIC), and bone (sect. IID). PTHs role is also illumi-
North American and European women consuming a diet nated by data on the effects of primary hyperparathyroid-
adequate in calcium, PTH is typically suppressed to the ism (sect. IIIB), hypoparathyroidism (sect. IIID), and pseu-
lower end of the normal range during all three trimesters dohypoparathyroidism (sect. IIIE) during pregnancy.
(207, 227, 294, 324, 791, 809, 905). In longitudinal studies
from North America, Europe, and Asia, the mean PTH level 3. Parathyroid hormone-related protein
was suppressed to the lower end of the normal range or
A) ANIMAL DATA. Parathyroid hormone-related protein
below it during the first trimester, and either remained sup-
(PTHrP) was first cloned in 1987 from human tumors that
pressed or increased to mid-normal by the end of pregnancy
cause humoral hypercalcemia of malignancy (593, 882,
(33, 85, 207, 221, 304, 632, 739, 813). Twin pregnancy did
889). It is a prohormone that is processed into several moi-
not change the serum PTH value compared with women
increased in pregnant goats beginning a day or two before PTHrP174 in plasma of patients with humoral hypercalce-
expected delivery and even further during parturition (744, mia of malignancy, but PTHrP136 was not assayed in that
771) compared with nonpregnant animals. Most of the study (137)]. This problem may be less of a concern in
measurements were with assays designed to detect human rodents since there is no alternative splicing and only one
PTHrP1 86 (364, 744, 956) rather than species-specific as- full-length form. A PTHrP134 assay should detect each of
says, and such assays will not detect the potentially more PTHrP136, PTHrP1139, PTHrP1141, and PTHrP1173, and
abundant (and biologically active) PTHrP136 (this issue is may be the preferred assay to use but only with optimally
discussed in more detail in the next section). collected and processed plasma samples.
B) HUMAN DATA. Before discussing data on circulating PTHrP As noted earlier, there are predicted mid-molecular and
values during human pregnancy, it is important to review COOH-terminal forms of biologically active PTHrP. In the
common problems of sample collection and preparation, human these include PTHrP3894, PTHrP38101, PTHrP107139,
and available assays. and possibly PTHrP141173, each of which may have its own
receptor and distinct role (494, 682, 712, 996). The clini-
First, PTHrP is rapidly cleaved and degraded in serum. Ap- cally available PTHrP134 and PTHrP1 86 assays do not
trated by two clinical cases. One woman experienced a The high levels of estradiol may be contributing to stimula-
late-term hypercalcemic crisis with a high plasma concen- tion of PTHrP production during pregnancy. In vitro stud-
tration of PTHrP; an urgent C-section was followed within ies have demonstrated that estradiol increases PTHrP
6 h by symptomatic hypocalcemia and an undetectable mRNA expression from cultured human myometrial cells
PTHrP level (270). A second woman with known hypo- (160), but it did not stimulate mammary epithelial cells to
parathyroidism was able to gradually eliminate use of cal- produce PTHrP (808).
citriol and halve the dose of calcium taken during her preg-
nancy. Immediately after delivery, she developed sudden There are no data on blood levels or potential roles of
and symptomatic hypocalcemia that resolved after breast- mid-molecular and COOH-terminal PTHrP during preg-
feeding was initiated (890). In both cases, removal of pla- nancy. Fetal-placental calcium transport is regulated by
cental PTHrP was the likely factor causing a rapid fall in mid-molecular PTHrP within the fetal circulation, but
serum calcium, and in the first case a rapid and marked whether maternal PTHrP plays a role in regulating this
process is unknown (2, 152, 500).
decline in circulating PTHrP was confirmed.
That the rise in PTHrP during normal pregnancy is physio-
Other clinical cases have demonstrated that the breasts are
shown to be upregulated two- to fivefold from in vitro anal- fetus and placenta likely do not contribute substantial cal-
ysis of homogenates obtained from kidneys of pregnant citriol to the maternal circulation, because maternal cal-
rabbits and guinea pigs (282, 512). Consequently, the ma- citriol levels are very low during pregnancy and similar to
ternal kidneys are likely the source of increased production nonpregnant values, even when bearing heterozygous fe-
of calcitriol, as they are in the nonpregnant adult. tuses that produce calcitriol (520, 521). Furthermore, in a
preliminary study, Cyp27b1 null mice had calcitriol levels
However, the maternal decidua, placenta, and fetus are also near the detection limit during prepregnancy, and these val-
potential sources of calcitriol due to expression of Cyp27b1 ues were not significantly different during pregnancy de-
in these tissues (334, 346, 896, 977, 978). The placenta has spite the presence of Cyp27b1/ placentas (330). Addi-
often been assumed to account for the rise in maternal cal- tionally, the expression of Cyp27b1 mRNA is 35-fold
citriol during pregnancy, but this appears to be incorrect. higher in maternal kidneys during pregnancy compared
The same gene is responsible for renal, decidual, placental, with placentas obtained from the same mouse (478). This
and fetal expression of Cyp27b1 (334). The ability of non- suggests that the relative activity of Cyp27b1 in the placenta
renal tissues to contribute to the production of calcitriol has is too low to account for the rise in calcitriol in the maternal
been tested by administering tritiated 25-hydroxyvitamin D circulation. However, the expression of Cyp24a1 (24-hy-
the peak calcitriol level during pregnancy in parathyroidec- protein during pregnancy, and the decline in serum albu-
tomized rats and Pth null mice may be the result of in- min, indicate that free calcitriol is likely increased in all
creased 24-hydroxylation of calcitriol and 25OHD, and not three trimesters (33, 399, 599, 764, 1019).
reduced synthesis of calcitriol (478, 658). Therefore, al-
though PTH is the dominant stimulator of Cyp27b1 in In a large cross-sectional study, serum calcitriol increased
nonpregnant rodents, it clearly does not have this role dur- threefold in women with singleton and twin pregnancies,
ing pregnancy. and there was no difference between the two groups (646).
There was also no difference in vitamin D binding protein
If not PTH, what stimulates the renal expression and activ- and albumin levels, which means that singleton and twin
ity of Cyp27b1 during pregnancy? Among known hor- pregnancies likely resulted in identical increases in free cal-
mones that could be potential regulators are PTHrP, estra- citriol (646). A smaller longitudinal study also found no
diol, calcitonin, placental lactogen, and prolactin. How- difference in serum calcitriol between twin and singleton
ever, very few studies have tested the roles of these pregnancies at any time point during pregnancy (746).
hormones. As mentioned, PTHrP mimics the actions of
PTH on the PTH/PTHrP receptor and likely contributes to PTH is normally the dominant regulator of Cyp27b1 in
25OHD of about 60 nM (24 ng/ml) prior to being random- C) SUMMARY. Total and likely free levels of calcitriol begin to
ized to receive up to 4,000 IU of vitamin D per day (399, increase in the first trimester and may reach triple or more
966). Conversely, two longitudinal studies found a modest the nonpregnant value by the third trimester. This increase
but significant decline in total 25OHD (33, 1019) or calcu- likely contributes to upregulation of intestinal calcium ab-
lated free 25OHD values (1019) during pregnancy. These sorption during pregnancy and, indirectly, to suppression
latter studies were smaller and may have been influenced by of PTH. Increased production of calcitriol comes almost
seasonal and late-pregnancy alterations in sunlight expo- entirely from maternal kidneys and not the placenta or fe-
sure and diet. The bulk of the data indicate that maternal tus, but the factors that stimulate renal Cyp27b1 during
25OHD is not substantially drained into the fetal circula- pregnancy remain to be elucidated. 25OHD levels are stable
tion, or consumed by conversion into calcitriol. during pregnancy despite increased conversion to calcitriol
and transplacental passage of 25OHD to the baby, and
A large cross-sectional study found that the maternal even in the face of a twin pregnancy. Conversely, 25OHD
25OHD was also stable across all trimesters in both single- has been shown to decline by 50% in rats that bear large
litters, with more modest to no change in animals bearing
ton and twin pregnancies; however, the 25OHD level was
several pups (pigs) or singletons (sheep).
30% lower in women carrying twins at all time points
Higher estradiol, estrone, and estriol levels during preg- Longitudinal studies in several mouse models have shown
nancy may stimulate calcitonin synthesis. This is supported that FGF23 increases twofold during pregnancy over non-
by the observation that in reproductive-age women, mean pregnant values (198, 478). The physiological significance
plasma calcitonin was three to five times higher in women of this increase is unclear given that serum phosphorus
who were pregnant or taking oral contraceptives, compared shows no change during pregnancy in mice. Moreover, al-
with nonpregnant women who did not use oral contracep- though increased levels of FGF23 have been shown to re-
tives (388). Moreover, treatment of postmenopausal duce serum calcitriol in nonpregnant Phex (Hyp) null mice
women with either estradiol or a synthetic estrogen (ethi- (564) and in Fgf23 overexpressing mice (531), no effect on
nylestradiol) resulted in a significant increase in plasma cal- calcitriol concentrations was seen from increased or de-
citonin (877). creased FGF23 during pregnancy. Specifically, the serum
calcitriol was no different among pregnant Phex null, WT,
The thyroid C-cells are often assumed to be the only site of or Fgf23/ mothers (581, 679).
calcitonin synthesis, but the breast and placenta become
significant production sites during pregnancy (52, 131). B) HUMAN DATA. No published data are available on intact
This has been most clearly demonstrated in women who FGF23 levels during human pregnancy. One study did re-
becomes suppressed (174). IGF-I may decrease to as low as mid-pregnancy (173). When the absorption of 45Ca in 15
50% of basal values during the second trimester before min across an in situ isolated loop of duodenum was mea-
rising two- to threefold above nonpregnant values by term sured, the value was increased 30% at day 14 and doubled
(85, 174, 632, 649). In one study the rise in IGF-I during the at day 20 of pregnancy, similar to the results of the meta-
third trimester correlated with the increase in bone turnover bolic balance studies (735). 45Ca absorption across everted
markers, and the rise in placental lactogen paralleled the gut sacs in rats also revealed that calcium absorption at day
increase in IGF-I, leading the authors to infer that placental 20 of pregnancy was double that of nonpregnant controls
lactogen was driving the increases in IGF-I and bone turn- (360).
over (649). Oxytocin shows a slow but modest increase
during pregnancy to reach peak levels near term (231). An increase in intestinal calcium absorption beginning at
mid-pregnancy may enable the pregnant rodent to accrete
Prolactin and placental lactogen have been shown to stim- mineral in advance of the peak demands that occur during
ulate synthesis of PTHrP in human cultures of extraembry- late pregnancy and lactation. Balance studies have shown
onic membranes (262). Beyond this, no clinical studies have pregnant rats to achieve a net gain in calcium at mid-preg-
tested whether these pregnancy-related hormones play an nancy that is sustained to term (339). Consistent with this,
(1021), these findings are compatible with the doubling of ity to make calcitriol, has shown a 45% increase in bone
intestinal calcium absorption being the result of increased mineral content by DXA, a marked lessening of secondary
calcitriol-mediated effects. However, the increase in intesti- hyperparathyroidism, and normalization of serum calcium
nal calcium transport precedes the rise in calcitriol by at and phosphorus (330). Intestinal calcium absorption has
least 1 wk in pregnant rats (735), and in another study the not yet been measured but is likely to be increased, based on
increment in calcitriol was concluded to be insufficient to these observed changes. The Cyp27b1 null mice had been
explain the magnitude of increase in intestinal calcium maintained on the same diet since 3 wk of age, so all of the
transport during pregnancy (360). improvements in skeletal mineral metabolism are attribut-
able to pregnancy.
Calcitriol regulates that paracellular or passive route of cal-
cium absorption by stimulating the expression of claudin-2 Not all studies agree with the findings of skeletal improve-
and claudin-12, which form tight junctions between intes- ments during pregnancy in severely vitamin D-deficient
tinal epithelial cells (181). These claudins are expressed in rats, Vdr null mice, and Cyp27b1 null mice. Two histomor-
the jejunum, ileum, and colon, but most abundantly in the phometric studies in pregnant vitamin D-deficient rats
ileum where the bulk of calcium is absorbed (298, 406). found significant decreases in mineralized bone, increased
mechanism appeared to be through increased production of precedes the more marked increase in calcitriol and free
calcitriol, rather than being independent of it (436). calcitriol during the third trimester, which may indicate that
the early increase is not wholly driven by calcitriol. More-
The implication of these studies is not to suggest that cal- over, the extremes of severe vitamin D deficiency or genetic
citriol plays no role in upregulating intestinal calcium ab- disorders of vitamin D physiology in the mother do not alter
sorption during pregnancy. Instead, it is quite likely that the serum calcium, ionized calcium, phosphorus, PTH, or skel-
two- to fivefold increase in calcitriol contributes to the dou- etal mineral content of the baby, as detailed in the compan-
bling in the efficiency of intestinal calcium absorption in ion review (492). These normal fetal parameters imply that
normal, vitamin D-replete animals. Additional factors (pos- maternal delivery of mineral is normal, or that the placenta
sibly prolactin, placental lactogen, placental growth hor- is capable of extracting needed mineral regardless of a def-
mone) likely contribute to the normal upregulation of intes- icit in the maternal supply.
tinal calcium absorption during pregnancy. What may be
indicated by these findings in severe vitamin D-deficient 3. Summary
rats, Vdr null mice, and Cyp27b1 null mice is that in the
absence of calcitriol (or the inability to respond to it), these Intestinal calcium absorption increases twofold beginning
are fasted overnight (478, 580). This supports that absorp- The Ca/Cr ratio in a random spot urine has been used in
tive hypercalciuria also occurs in pregnant mice. Additional several recent randomized trials that studied the apparent
evidence in support of this comes from pregnant Vdr null safety of high-dose vitamin D supplementation during preg-
mice, which had significantly increased urine calcium/cre- nancy. No adverse increase in Ca/Cr ratio was reported
atinine ratios, concurrent with their increase in intestinal when 5,000 IU vitamin D per day was compared with pla-
calcium absorption (296). cebo (778), when 4,000 IU daily and 400 IU daily were
compared (399), or when 4,000 IU daily and 2,000 IU daily
Prolactin and placental lactogen reduce urinary calcium ex- were compared (966). These findings have been interpreted
cretion in nonpregnant rabbits (135, 136). Whether these to mean that high-dose vitamin D supplementation does not
hormones are helping the kidneys conserve calcium during cause hypercalciuria during pregnancy (399, 778, 966).
pregnancy has not been tested. An increase in urine calcium However, since it is absorptive hypercalciuria that occurs
excretion during pregnancy suggests that the kidneys are during pregnancy, and random spot urines are neither sen-
not conserving calcium; the suppressed PTH levels may be a sitive enough nor timed appropriately to detect absorptive
contributing factor. This is supported by the observation hypercalciuria, the available data have not adequately ex-
that urinary calcium excretion was no different in pregnant cluded whether hypercalciuria worsens during pregnancy
However, plasma concentrations and placental expression a mild uncoupling in favor of resorption during pregnancy
of placental lactogen are not reduced in preeclamptic in mice, as indicated by normal to modestly increased de-
women (73, 74, 561, 595, 623, 675, 1027). oxypyridinoline and CTX, normal P1NP, and decreased
osteocalcin (296, 477, 478, 580, 994). A decline in osteo-
Numerous clinical trials have been carried out to assess the calcin has also been noted during pregnancy in guinea pigs
efficacy of calcium supplementation at preventing pre- (958) and sheep (277), and contrasts with increased osteo-
eclampsia or pregnancy-induced hypertension, and a net calcin found in rats during early pregnancy and at term
benefit has been seen for women with the lowest intakes of (816, 961).
calcium, whereas no effect is evident for women with ade-
quate calcium intake (398). In multiple clinical trials, no The effect that pregnancy has on bone mass or mineraliza-
effect of high-dose vitamin D supplementation has been tion has been serially assessed by DXA measurements done
seen on the incidence of preeclampsia in pregnant women every day (827) and every other day (993) during reproduc-
(183, 184, 399, 710, 966). tive cycles in outbred Black Swiss mice. There is a progres-
sive 10 20% increase in whole body mineral content that
3. Summary begins early in pregnancy and reaches a peak on the day
D. Altered Skeletal Turnover and Mineral Apart from serial assessment of bone mineral content by
Metabolism DXA at multiple time points during pregnancy in Black
Swiss mice, most studies in rodents have simply compared
1. Animal data end-of-pregnancy BMC or BMD to prepregnancy in the
same mice, or to age-matched virgin mice, without deter-
The maternal skeleton is a storehouse of mineral that can be mining whether any changes in bone mass occurred earlier
resorbed during pregnancy if needed to provide mineral to in pregnancy. This approach has shown that bone mass or
the fetuses. Earlier it was cited that 92% of fetal skeletal mineral content at the end of pregnancy varies significantly
calcium content has been estimated to come from the ma- by skeletal site and genetic background in mice. Outbred
ternal diet of the rat during pregnancy (974). Additional Black Swiss mice consistently show a 10 20% increase in
radioisotope studies have confirmed that some calcium in whole body bone mineral content at the end of pregnancy,
the maternal skeleton will be resorbed to enter the fetal the lumbar spine remains unchanged, and the hindlimb may
skeleton, especially during the last few days of gestation gain 10 15% (296, 478, 827, 994). Conversely, inbred
(706). However, much less 45Ca from the maternal skeleton C57BL/6J mice show a 5% decline in whole body bone
ends up in the fetuses compared with how much enters the mineral content, a 15% drop in lumbar spine bone mineral
milk and the pups during lactation, which confirms that content, and a 10 20% gain in the hindlimb (477, 580).
skeletal resorption during pregnancy is quite modest com- CD-1 mice show no significant changes in mineral content
pared with that during lactation (706). during pregnancy at any skeletal site (35, 956). Rats
showed no change in whole body BMD and nonsignificant
The extent to which bone turnover is altered during preg- declines in BMD of femora and tibiae at the end of preg-
nancy may be deduced from relative changes in biochemical nancy (816), whereas another study found a modest but
markers of bone formation and resorption. These measure- significant decline in lumbar spine BMD (920), and a third
ments are fraught with confounding problems of changes in study found a gain in femoral and vertebral BMC and BMD
intravascular volume and glomerular filtration rate (dis- (888). Another study found that femoral calcium content at
cussed in section IID2). In most studies they were measured the end of pregnancy was linearly related to the calcium
in late pregnancy only. The available indices suggest at most content of the diet (818). Overall, apart from the serial
studies in Black Swiss mice, none of the other studies in and reduced trabecular bone volumes of the tibiae (107), all
rodents can confirm or refute whether bone mass increases in Sprague-Dawley rats with no correlation to the dietary
earlier in pregnancy before declining. calcium content. A microCT study found that C57BL/6
mice consuming 2% calcium increased cortical area and
Static and dynamic histomorphometry have been carried trabecular volume of the femora at day 16 of pregnancy
out in the femora of pregnant rats and compared with age- compared with day 9 (489).
matched virgins. The results are inconsistent across studies
and not clearly explainable by variations in the calcium The available data discussed in this section may seem incon-
content of the diet or the strain of rat. One reported marked sisent and contradictory. For example, within some of these
increases in bone resorption (osteoclast number, resorptive studies there is histomorphometric evidence of markedly
surfaces) and bone formation (osteoblast number, osteo- increased bone turnover in late pregnancy but little or no
blast surface, osteoid volume) during pregnancy in Cobs change in bone mass. A problem contributing to the incon-
rats consuming a 0.45% calcium diet (598). Another found sistency is the comparison of a single time point (end of
that osteoclast parameters increased three- to sixfold while pregnancy) to prepregnancy or age-matched virgins, with-
bone formation parameters were unchanged in Sprague- out any assessment at intermediate time points. If a net
when subjected to rotational stress (548). Two studies from absence of data on bone mass, structure, or mineralization
the same investigator provided contradictory results in that at this time point.
load to failure in the three-point bend test was increased
(216) and reduced (217) at the end of pregnancy in Wistar Some maternal bone resorption during late pregnancy may
rats compared with age-matched virgins. The work to fail- contribute mineral to the fetus. This has shown by study of
ure did not differ between pregnant and age-matched vir- women living near the Techa River in Russia, who inadver-
gins in both studies (216, 217), suggesting that there was no tently ingested 90Sr from water contaminated by nuclear
real change in bone strength. waste during the 1950s. Years after the exposure ended,
90
Sr could be detected in the skeletons of their fetuses,
Although there may be no net change or modest changes in which could only have come from resorption of 90Sr that
bone mass by the end of pregnancy when a calcium-replete had been previously fixed in the maternal skeleton (921,
diet is consumed by rodents, there is other evidence that the 922). But women who ingested 90Sr during pregnancy, es-
macro structure of bone may be altered. In Sprague-Dawley pecially during the third trimester, gave birth to babies with
rats, an increase in femoral cortical bone volumes, radii, 10-fold higher 90Sr content, consistent with dietary absorp-
and cortical thickness have been found at the end of preg- tion of mineral being responsible for much more of the
increased GFR and altered creatinine excretion affecting nancy. An early study used X-ray spectrophotometry of the
urinary measurements, possible contributions from pla- radius and femur during the first or second trimester and
centa and other tissues, increased degradation or clearance found that trabecular but not cortical bone density had
by the placenta (confirmed to affect osteocalcin, Ref. 769), decreased by the time of a postpartum measurement (526).
and lack of fasted or diurnally timed specimens. Several prospective studies used single- or dual-photon ab-
sorptiometry (SPA or DPA) of the forearm serially during
Given these caveats, several markers of bone resorption and after pregnancy (18, 185, 468), or of the femur before
[urine N-telopetide (NTX) or C-telopeptide (CTX), serum and after a planned pregnancy, and found no significant
CTX, tartrate-resistant alkaline phosphatase, deoxypyr- changes in cortical or trabecular bone density (858). An-
idinoline/creatinine, pyridinoline/creatinine, and hydroxy- other study compared preconception SPA and DPA mea-
proline/creatinine] have been found to be low in the first surements to those taken 6 wk postpartum and found a
trimester but to increase steadily thereafter, rising to as 2.4% decrease in the femoral neck, a 2.2% decrease in
much as twice normal in the third trimester (85, 206, 207, radial shaft, a 3.4% increase in the tibiae, and no change in
304, 461, 632, 695, 764, 1002). Correcting for the decline lumbar BMD (256).
in serum albumin obliterated the apparent fall in serum
relevant peripheral ultrasound at the heel or a finger during lactation. Decades have passed in some cases between the
pregnancy is for revealing changes in bone mass or miner- reproductive years and the time of the first BMD measure-
alization at the spine or hip is uncertain. Notably, although ment or fracture, such that confounding factors and events
bone mass declines significantly during lactation, with the in the elapsed time may have influenced the outcome. Such
most marked changes in the lumbar spine (see sect. IVE), confounding may be less likely in the NHANES study in-
ultrasound of the os calcis and mid-tibial shaft showed no volving women ages 20 25 since the pregnancies were only
changes (533, 917, 1015). a few years earlier, wherein no detrimental effect of parity
was seen. Overall, it seems most likely that parity has no
Overall, available data suggest that bone turnover increases long-term adverse effect on BMD or fracture risk for most
during pregnancy, especially during the third trimester. women. It is not recognized as a significant factor for esti-
There are real but small declines in BMD throughout the mating 10-yr risk of fracture in FRAX (929). However,
skeleton that require a sufficiently large cohort to be de- there may be a subset of women in whom parity does ad-
tected with confidence. versely affect bone mass. These may include women in
whom significant nutritional deficiencies lead to increased
Are there any long-term impacts of skeletal changes induced skeletal resorption during pregnancy to meet the fetal min-
have a protective effect against low BMD and future risk of tive disorders, and vitamin D deficiency) is likely to induce
fractures. resorption of the maternal skeleton during the third trimes-
ter. A recent report described a woman with a calcium
intake of 229 mg daily, who developed multiple vertebral
III. DISORDERS OF BONE AND MINERAL
compression fractures during pregnancy (501). Since that
METABOLISM DURING PREGNANCY
amount was insufficient for her own nonpregnant needs,
the normal upregulation of intestinal calcium absorption
A. Osteoporosis in Pregnancy during pregnancy would not have benefited her. Significant
skeletal resorption was an inevitable consequence of her
1. Animal data pregnancy.
Fragility fractures do not normally occur as a result of preg- Another potential cause of physiological bone loss during
nancy in animal models. This is consistent with upregula- pregnancy is greater than normal release of PTHrP from the
tion of intestinal calcium absorption usually being sufficient placenta and breasts. The gradual rise in plasma PTHrP
to meet the mineral requirements of the fetuses, and the (sect. IIA3) likely contributes to upregulation of calcitriol
creased risk of vertebral and other fractures in subsequent the obturator nerve are among the theories proposed to
pregnancies. explain its occurrence in pregnant women (112, 147,
218, 335, 499, 571). It is considered separately here be-
Many uncontrolled treatments [nasal calcitonin (263, 687, cause, unlike the vertebral and other fractures that some-
885), bisphosphonates (43, 143, 178, 263, 438, 475, 671, times occur during pregnancy, it does not seem to result
677, 685, 799, 885, 897), strontium ranelate (897, 1016), from systemic bone resorption. It also has different epi-
and teriparatide (98, 178, 377, 527, 544, 885)] have been demiological characteristics, including that it can occur
reported in various case series. Most of the authors of these in any pregnancy, and it has recurred in the other hip
reports evidently did not appreciate that substantial spon- either during a subsequent pregnancy or when not preg-
taneous recovery of bone mass occurs even in women who nant.
fractured, with BMD increases in the range of 20 70% in
individual cases. For example, a 50% increase in BMD On the other hand, some patients who clearly had transient
demonstrated by QCT in a woman who presented with a osteoporosis of the hip also had very low spine BMD, ver-
compression fracture 1 wk postpartum (556). Therefore, tebral fractures, severe vitamin D deficiency, and prolonged
the attributable effect of pharmacological therapy may have pregnancy/lactation cycles that may have caused general-
found that it occurred in 0.03% of reproductive age women includes nephrocalcinosis, nephrolithiasis, urinary tract in-
who underwent routine screening of serum calcium (391). fections, acute pancreatitis, and increased bone loss (508,
Several hundred cases have been described in English-lan- 824). Fractures are uncommon but have occurred with
guage medical journals (354, 391, 466), while the authors more severe primary hyperparathyroidism and parathyroid
advice has been sought for several cases each year by clini- carcinoma (381, 651). In up to 15% of cases women pre-
cians around the globe. Primary hyperparathyroidism is sented with pancreatitis during the second or third trimester
10 20 times more likely to occur in women over age 45 (153, 186, 205, 429, 508, 511). Hypercalcemic crises have
than in women of child-bearing age (373, 980), but in two occurred during the third trimester (153, 186, 662, 795),
case series, 1% of all parathyroidectomies were done in which coincides with peak release of PTHrP by the placenta
pregnant women (466, 490). The pathology is similar to and breasts. There are risks to the fetus and neonate that
nonpregnant cases: a predominance of single adenomas fol- must be considered, including miscarriage, stillbirth, and
lowed by four-gland hyperplasia (267, 466). hypoparathyroidism, and these are discussed in more detail
in the companion review (492).
The dilutional fall in serum albumin and calcium (see sect.
IIA1) and suppression of PTH (see sect. IIA2) during nor- This historic view has led to a general preference for para-
Historically, primary hyperparathyroidism had been con- A recent retrospective analysis of a database registry found
sidered to be an adverse condition that should be dealt with 1,057 reproductive-aged women with primary hyperpara-
during pregnancy. Older cases series suggested that signifi- thyroidism, of whom 60% had been pregnant before the
cant maternal morbidity and mortality occurred in up to diagnosis and 15% had been pregnant after the diagnosis
67% of mothers, while up to 80% of fetuses and neonates (3). Compared with 3,171 age-matched women, there was
experienced morbidity or mortality (803). Hypercalcemia no apparent difference in the incidence of spontaneous
causes nonspecific, constitutional symptoms that are diffi- abortions, but the rate of C-sections was twice that of con-
cult to distinguish from normal symptoms encountered dur- trols in women who had a pregnancy after the diagnosis
ing pregnancy, including nausea, hyperemesis, constipa- was known (3). That study is limited because no data were
tion, fatigue, weakness, and mental symptoms (508). More available on the mothers during the pregnancies or on neo-
marked hypercalcemia during pregnancy has been associ- natal complications. Another retrospective study reported
ated with hyperemesis, weight loss, seizures, and pre- on 74 women with primary hyperparathyroidism who had
eclampsia (418, 466, 490). Additional maternal morbidity had 134 pregnancies and who were compared with 175
normocalcemic women who had experienced 431 pregnan- ciuria, and nonsuppressed PTH (122). It is asymptomatic
cies over the same interval (391). There was no difference in because its origin in utero causes all tissues to be fully adapted
the rate of spontaneous abortions or pregnancy-related to a higher level of calcium, while the relative hypocalciuria
complications between women with and without primary protects against nephrocalcinosis and nephrolithiasis. The hy-
hyperparathyroidism during pregnancy, but neonatal com- percalcemia with elevated PTH persists during pregnancy as
plications were not reported (391). Additional cases suggest expected (727); however, increased intestinal calcium absorp-
that the rate of still birth, neonatal death, and neonatal tion during pregnancy causes absorptive hypercalciuria and
tetany are far less with modern compared with older case not the expected diagnostic finding of hypocalciuria (638,
series (824). But even in modern cases fetal death still oc- 968). Consequently, the diagnostic criteria for FHH can be
curs, such as in 30/62 medically managed cases that ended confounded during pregnancy by results that suggest primary
in a late spontaneous abortion (the risk correlated with the hyperparathyroidism may be present. Pregnancies in affected
level of maternal serum calcium), whereas no complications women are uneventful; in fact, many documented cases in-
were seen in 15 cases operated upon during the second volve the diagnosis being made in the mothers only after their
trimester (667). Neonatal hypocalcemia and tetany still oc- babies presented with neonatal hypocalcemia or seizures (727,
cur after supposed mild primary hyperparathyroidism in 913, 914). This neonatal hypoparathyroidism originates in
FHH is caused by autosomal dominant, inactivating muta- The role that PTH might play in regulating maternal min-
tions in CASR that lead to chronic hypercalcemia, hypocal- eral and bone homeostasis during pregnancy has been in-
vestigated by studies in parathyroidectomized rats and Pth A set of studies done in 1936 remain illuminating. When para-
null mice. thyroidectomized rats from an unspecified strain consumed a
1.2% calcium diet with low phosphorus content, the serum
When hypocalcemic, parathyroidectomized Sprague-Daw- calcium at term was normal or elevated (94). On the other
ley rats maintained on a 1.2% calcium diet became preg- hand, when a 0.45% calcium diet was provided, the serum
nant, the serum calcium increased to near-normal, serum calcium in pregnant parathyroidectomized rats was 50% of
phosphorus reduced to normal, and intestinal calcium ab- the value of intact rats on the same diet (94).
sorption more than doubled compared with nonpregnant,
parathyroidectomized rats (425). In fact, the increased rate Collectively these studies support that PTH-independent
of intestinal calcium absorption during pregnancy was not upregulation of calcitriol synthesis and intestinal calcium
significantly different between intact and parathyroidecto- absorption occur during pregnancy, but they differ in
mized rats (425). Similarly, studies in pregnant Pth null whether the parathyroidectomized rodents ability to main-
mice consuming a 1% calcium diet found that serum cal- tain her own serum calcium is improved or worsened during
cium increased to normal, serum phosphorus normalized, pregnancy. Since late pregnancy is the interval when rapid
serum calcitriol increased over fivefold, and bone mineral fetal accretion of calcium is occurring, it is clear that flux of
portant factor, as it is in the rodent models, with the ideal ciate that the serum calcium normally falls during preg-
minimum intake considered to be 1.2 g daily based on the nancy.
Institute of Medicine guidelines (774). In half of the reports
in which hypoparathyroidism appeared to worsen during The variability in responses to pregnancy may be related to
pregnancy, either no supplemental calcium or at most 300 the calcium content of the diet, contributions of PTHrP and
mg daily was being taken, and the dietary intake of calcium other pregnancy-related hormones to regulating maternal
was unknown (96, 411, 434, 510, 600, 669, 790, 936). mineral homeostasis, and genetic or ethnic differences. Sig-
Lack of adequate intake of calcium in the first half of preg- nificant maternal hypocalcemia must be avoided during
nancy likely prevents the net positive calcium balance being pregnancy because it increases the risk of fetal mortality
achieved that most women experience during pregnancy, (spontaneous abortion and still birth) and severe secondary
and increases the likelihood of problems in the third trimes- hyperparathyroidism with fractures in the fetus and neo-
ter. There may be variations in the degree to which PTHrP nate. Iatrogenic hypercalcemia should also be avoided. The
release from breasts and placenta, or increases in other albumin-corrected or ionized calcium should be monitored
pregnancy hormones (placental lactogen, oxytocin, etc.), for certainty about when a change in therapy is needed.
contribute to regulating maternal mineral homeostasis dur-
thyroidism complicated by severe nausea and vomiting, a women suggests that whether or not the expected pregnan-
woman experienced an asymptomatic drop in the unad- cy-related increase in serum calcitriol occurs during the
justed serum calcium during a first pregnancy that third trimester predicts whether pseudohypoparathyroid-
prompted an increase in both calcium and calcitriol, while ism objectively improves or worsens during pregnancy.
during her second pregnancy she proved intolerant of more
than 500 mg calcium per day and had a modest decline in In addition to the possibility that hormones of pregnancy
the ionized calcium during the third trimester (668). In the stimulate Cyp27b1 or intestinal calcium absorption di-
second report a woman who was diagnosed to have type II rectly, it is possible that the hormonal changes during preg-
pseudohypoparathyroidism years after her two pregnan- nancy (such as higher estradiol levels) could improve post-
cies, recalled that worsening of hypocalcemic-like symp- receptor signaling. The level of calcium intake is likely an
toms had occurred during the second half of each preg- important variable. In the four pregnancies in which pseu-
nancy, and a single low value of serum calcium from the dohypoparathyroidism objectively improved, 1 g supple-
second pregnancy (left untreated) was found in an old doc- mental calcium was taken throughout (110), whereas in
ument to corroborate her statement (793). She had not four of the pregnancies where it worsened, the women took
taken any calcium supplements during those pregnancies. no supplemental calcium (793, 814), and in the remaining
Gs activity in the proximal tubule of women with pseudo- similar to PTH, this confirms that the breasts must have
hypoparathyroidism. been the sustained source of PTHrP, and not (as the authors
of that report inferred) the placenta. Another pregnant
The goal of management during pregnancy should be to woman presented with marked hypercalcemia (serum cal-
maintain a normal ionized or albumin-corrected serum cal- cium 4.00 mM) associated with high calcium intake and
cium in the mother, thereby minimizing the risk of fetal and elevated PTHrP of 34.9 pM (639). The hypercalcemia re-
neonatal complications from maternal hypocalcemia or hy- solved promptly, and she did not breastfeed, but the ele-
percalcemia (492). This means expectant management with vated PTHrP did not become undetectable until 3 mo post-
appropriate increases or decreases in calcium and calcitriol partum.
as required during each pregnancy.
Pseudohyperparathyroidism also occurs during lactation,
and the ability of breast-derived PTHrP to normalize min-
F. Pseudohyperparathyroidism eral homeostasis in lactating women with hypoparathy-
roidism is further validation of the importance of the
1. Animal data breasts as a physiologically relevant source of PTHrP (see
mice is rescued by expressing Vdr in intestinal cells (555, modestly greater weights and slightly increased lengths,
1000), whereas selective ablation of Vdr from intestinal compared with vitamin D-sufficient mothers (563). The diet
cells (555) or dietary calcium restriction create the rachitic was deficient in vitamin D but not enriched in calcium. No
phenotype (555). Moreover, ablating Vdr from chondro- mention was made as to whether maternal vitamin D defi-
cytes, osteoblasts, or osteocytes, or Cyp27b1 from chon- ciency led to a reduced conception rate, and no measure-
drocytes, do not cause rickets either (555, 606, 644, 1006). ments of bone mass or mineralization were performed. The
Also, a high calcium diet bypasses the need for calcitriol and placentas from vitamin D-deficient pregnancies were of
intestinal expression of its receptor, and normalizes serum identical weight but had smaller diameters, and histological
chemistries, skeletal morphology, and skeletal mineral con- evidence of reduced vascular diameters within the labyrin-
tent in severely vitamin D-deficient, Cyp27b1 null, and Vdr thine placenta, compared with pregnancies from vitamin
null models (28, 102, 103, 224, 241, 273, 553, 554, 693, D-sufficient mothers (563).
874, 875, 948, 1011). However, remaining evidence for a
direct role of calcitriol or VDR in regulating bone cells is As noted earlier, severely vitamin D-deficient rats, Vdr null
that Cyp27b1/Vdr null double mutants have a skeletal phe- mice, and Cyp27b1 null mice achieve significant gains in
notype that is not fully prevented by a high-calcium diet bone mineral content during pregnancy, with reduced sec-
impair intestinal calcium absorption until the 25OHD level ternal benefit of vitamin D repletion. A greater weight gain
is below 20 nM (650). and a small increase in the unadjusted serum calcium were
observed in the vitamin D-treated group, but no other ob-
What evidence is there that maternal vitamin D deficiency, stetrical benefit was seen (121).
or genetic disorders causing loss of calcitriol or VDR, affect
maternal mineral metabolism and obstetrical or fetal out- Cockburn et al. (191) randomized 164 women to 400 IU
comes? vitamin D versus placebo beginning at the 12th week of
pregnancy, and achieved maternal 25OHD of 42.8 vs.
Unfortunately, no study has measured intestinal calcium 32.5 nM (17 vs. 13 ng/ml) at term, but no obstetrical
absorption during pregnancy in vitamin D-deficient com- benefit was described (191). Mallet et al. (588) random-
pared with vitamin D-sufficient women, so it remains un- ized 77 women to receive 1,000 IU vitamin D2 daily
known whether or not intestinal calcium absorption dou- during the third trimester, or 200,000 IU vitamin D2 at
bles in pregnant, vitamin D-deficient women. the start of the third trimester, or no supplementation
(588). The respective maternal 25OHD levels were 25.3,
The most robust clinical data generally come from large, 26.0, and 9.4 nM (10, 10.4, and 3.8 ng/ml) with no effect
Yu et al. (1013) randomized 180 women in London to pared. There were no differences in any obstetrical out-
receive unblinded treatment beginning at week 27 of preg- comes, including mode of delivery, gestational age at deliv-
nancy: 800 IU vitamin D2 per day, a single dose of 200,000 ery, preterm birth, preterm labor, preeclampsia, and infec-
IU vitamin D2, or no treatment (1013). Mean 25OHD in- tion (399, 963).
creased to 42 and 34 nM (16.8 and 13.6 ng/ml) in the
respective treatment groups at term compared with 27 nM A second study by Hollis and Wagner and co-workers (966)
(10.8 ng/ml) in the untreated women. There was no effect reported on 160 women (NCT00412087) randomized at
on preterm delivery and no other obstetrical outcomes. 1216 wk to receive 2,000 or 4,000 IU vitamin D3 daily.
Achieved maternal 25OHD was 90.5 nM (36.2 ng/ml) and
Roth et al. (778) randomized 160 women in Bangladesh 94.8 nM (37.9 ng/ml), respectively. There was no effect on
(NCT01126528) to receive 35,000 IU vitamin D3 per week any obstetrical outcome, including mode of delivery, pre-
or placebo beginning at 26 29 wk. Maternal 25OHD was term labor, preterm delivery, hypertension, infection, ges-
134 nM (53.6 ng/ml) in the supplemented women versus 38 tational diabetes, or combinations of these outcomes (966).
nM (15.2 ng/ml) in the placebo group. There was no effect
on maternal serum calcium, but a borderline significant Hollis and Wagner have subsequently carried out several
(anthropometric and body composition parameters within ulate intestinal calcium absorption and potentially induce
48 h of birth). No obstetrical benefit was reported. A post- osteoclast-mediated bone resorption.
hoc analysis, which was not prespecified in the clinical trial
registrations (ISRCTN 82927713 and EUDRACT 2007- On the basis of associational studies, vitamin D deficiency
001716-23), suggested a possible benefit on bone mineral has been suggested to have nonskeletal effects during preg-
content of winter-born babies. If the apparent benefit on nancy, such as increasing the risk of preterm delivery, C-
winter-born babies is real and not a chance result, it may sections, low birth weight, preeclampsia/pregnancy-in-
not be an indication of an effect on the fetus but instead a duced hypertension, and vaginal infections. One can find
postnatal effect, since (as noted earlier) the neonatal skele- approximately as many studies suggesting these associa-
ton should gain 100 mg calcium per day over the first 14 tions (46, 95, 370, 622, 768, 832) as there are studies indi-
days after birth. A measurement at 14 days does not indi- cating no association (47, 276, 294, 618, 726, 810, 823).
Each of these studies has low power and are confounded by
cate bone mineral content at term.
factors that may lead to lower 25OHD levels and the out-
come in question, including race/ethnicity, maternal over-
Overall, these studies have largely examined women who,
weight/obesity, lower socioeconomic status, poor nutrition,
prior to the intervention, had 25OHD values well above the
sites of calcitonin synthesis during pregnancy, including the thyroid hormone to reduce the risk of cancer recurrence,
mammary glands and placenta. In pregnant goats or rats, but even in those studies bone loss has not been consistently
calcitonin deficiency was created by a complete thyropara- found (476, 543). None of these studies looked at the effects
thyroidectomy followed by parathyroid gland autotrans- of pregnancy, during which the women may not have been
plantation and treatment with exogenous thyroid hormone calcitonin deficient anyway.
(55, 58, 163, 551, 900). Serum calcitonin, TSH, PTH, and
ionized calcium were not measured, so it is uncertain It is notable that with modern calcitonin assays, the basal
whether a calcitonin-deficient, euthyroid, euparathyroid calcitonin level is unchanged before and after total thyroid-
state was achieved. In three studies the animals were killed ectomy in patients without medullary thyroid cancer; it is
the day before expected delivery (55, 58, 163), whereas two only the calcium-stimulated or pentagastrin-stimulated cal-
other studies reporting a pregnancy-related effect must be citonin that is lost (513). This suggests that extrathyroidal
excluded because the animals were killed after 3 wk of calcitonin sources are functional in nonpregnant, nonlac-
lactation (551, 900) (see sect. VH). Among the three preg- tating women.
nancy studies, the ash weight and calcium content were
510% lower in thyroidectomized compared with sham- 3. Summary
intake of less than 420 mg were in a positive calcium bal- during pregnancy regardless of its potential teratogenic ef-
ance in all three trimesters (830). A lower calcium intake is fects. In about half of case reports, the babys outcome is
more likely to induce bone loss during pregnancy (10) and not mentioned, but the cord blood calcium is likely to be
has been associated with increased risk of osteoporosis de- high and followed by neonatal hypocalcemia and tetany.
veloping during pregnancy (501). Whether the mother ob-
tains the needed mineral from her diet or skeleton may be of Treatment options include debulking or curative surgery,
no consequence to the fetus, although a randomized trial hydration, diuresis, and possibly calcitonin or bisphospho-
found that 2 g of supplemental calcium versus placebo im- nates. There are potential teratogenic effects of calcitonin
proved the BMC of babies whose mothers were in the low- and bisphosphonates (492), but they have been used during
est quintile of dietary calcium intake (600 mg/day) (488). pregnancy to treat this condition.
Significant maternal hypocalcemia impairs the delivery of
calcium to the fetuses, who may develop secondary hyper- 3. Summary
parathyroidism, skeletal demineralization, and fractures, as
has occurred in cases of poorly treated maternal hypopara- Hypercalcemia of malignancy causes severe and potentially
thyroidism during pregnancy (492). The lowest quintile of terminal maternal hypercalcemia; if the baby survives, it is
principle is to maintain calcitriol and phosphorus supple- 584). Individual women were identified who had sustained
mentation throughout pregnancy to ensure adequate deliv- production of up to 3 liters of milk per day during 6 12 mo
ery of phosphorus to the fetus (538). of lactation (419, 583, 838); analysis of their milk revealed
daily calcium losses of 500-1,200 mg (419, 838). However,
There are no published reports on pregnancies in women manual expression of milk can yield much greater volumes
with hyperphosphatemic disorders caused by deficiency of than a suckling baby demands, thereby overestimating milk
FGF23 or its co-receptor. Large case series of pregnancies in production. Further bias was introduced by studying
women on dialysis have shown increased obstetrical risks of women known to produce large volumes of milk, some of
gestational hypertension, preeclampsia, eclampsia, and ma- whom were employed as wet nurses.
ternal mortality, and increased adverse fetal outcomes in-
cluding premature birth, intrauterine growth restriction, As noted in the overall introduction, more recent studies
low birth weight, stillbirth, and neonatal mortality (139, have relied on weighing the baby before and after feeds,
594, 656). These outcomes may relate more to the maternal whereas analyses of milk calcium content at different stages
renal failure than the hyperphosphatemia per se. No data of lactation revealed similar results to older studies. An
have been reported about cord blood chemistries or skeletal average daily output of 780 ml milk (20, 138, 376, 653)
Hypophosphatemic and hyperphosphatemic disorders in These are average amounts, and it is recognized that indi-
the pregnant mother have the potential to adversely affect vidual daily losses can vary considerably. Losses have been
the fetus. There are insufficient human data to know for much higher in the more extreme examples cited above, and
certain, but the limited animal data are reassuring that fetal in women nursing twins who generally produce about dou-
mineral and bone metabolism may be unaffected by ex- ble the amount of milk of women who nurse singletons
tremes of low and high serum phosphorus in the mother. (233, 792). The composition of milk also varies within and
between feedings (536, 654), between an individuals
IV. SKELETAL AND MINERAL PHYSIOLOGY breasts (654), and between mothers and different ethnic
DURING LACTATION AND POST- groups (536). The calcium content of milk is higher at 3 mo
WEANING RECOVERY than at 6 mo postpartum (459, 536, 856, 957), but the
volume of milk per feed is higher at 6 mo (856). Conse-
In their widely quoted seminal text The Parathyroid Glands quently, daily maternal loss of calcium could be greater at 6
and Metabolic Bone Disease (15), Albright and Reifenstein mo and beyond, compared with the first 3 mo of lactation
used data from several sources (77, 407, 836) to estimate (856). However, the number of feeds is usually fewer after 6
that maternal losses of calcium are fourfold higher during 9 mo, thereby leading to an overall decline in daily calcium
mo of lactation than in pregnancy, or 80 g in milk versus losses.
20 g in the fetal skeleton. This means an output of more
than 300 mg of calcium in milk each day. However, the Maternal milk output also increases in proportion to litter
authors misread source data that showed closer to 30 g of number and weight in lactating animals, thereby maintain-
calcium in a term fetus (77), used an overestimate of milk ing a similar weight of pups regardless of their number. In
production (407), and lacked any skeletal calcium content mice, for example, the weight of individual pups at 12 days
data at 9 mo. Modern studies, referred to earlier in the of age shows 10% variation from a litter of 4 versus a
overall introduction, have shown that the average full-term litter of 12. But the combined weight of a litter of 12 is three
fetus has 30 g of calcium and that another 30 g (100 times that of a litter of 4, confirming that a larger litter
mg/day) is added by 9 mo. Consequently, the calcium re- means a greater maternal output of milk and calcium (87).
quired by the neonate during 9 mo of lactation equals that A similar constancy of neonatal pup weight has been seen in
required by a fetus during all of pregnancy and does not pigs whose litter sizes range from 5 to 12 at 8 wk of age (87).
exceed it. However, as explained in the following para- Ewes suckling twins produce about double the amount of
graphs, maternal losses of calcium during 9 mo of lactation milk of ewes nursing singletons (970).
are about double that of pregnancy.
To meet the mineral requirements of lactation, maternal
Other older studies similarly overestimated average daily adaptations might include increased intestinal absorption
loss of calcium into milk due to overgenerous estimates of of calcium, renal conservation of calcium, and increased
milk volumes. In a large study of 200 women who ex- skeletal resorption of calcium. Studies reviewed in this sec-
pressed milk manually for 24 h, the volume ranged from 0.8 tion reveal that the main adaptation is a temporary demin-
to 1.8 liters for a mean daily loss of 400 mg calcium (582, eralization of the skeleton, which appears to meet the cal-
0.0 A) ANIMAL DATA. The serum calcium of lactating rats has been
20.0
quite variable in published reports, and not clearly ex-
plained by the calcium content of the diet: hypercalcemia on
Calcitonin
(pmol/l)
low calcium or high phytate intakes and may even rise above normal.
(ng/ml)
*Women with low calcium or high phytate intakes have normal or increased PTH.
Differences in rat strains, litter sizes, and whether the sam- measured every other day in the same mice from the time of
ples were drawn fasted or not likely contribute to the vari- mating, and no change occurred during pregnancy or lac-
ation in results. Greater demands for milk production (such tation (827, 992). These findings suggest that a normal
as larger litter number and combined weight of all pups) mouse may be more capable of maintaining her serum cal-
provoke a lower maternal serum calcium (90, 320, 567, cium in the normal range than a rat during reproductive
708). Abrupt weaning causes the serum calcium to rebound cycles. However, CD1 mice maintained on a 1% calcium
into the hypercalcemic range for several days (76, 86, 396, diet showed a modest but statistically significant decline in
718). This is likely due to sudden loss of the outflow of serum calcium during lactation (34). Consequently, there
calcium into milk while increased bone resorption and in- may be strain differences in the ability of mice to maintain
testinal calcium absorption persist (see sect. IV, B and E). normal serum calcium during lactation. More marked hy-
An increase in serum calcium after abrupt weaning oc- pocalcemia was provoked in CD1 mice on a 0.01% calcium
curred even when dietary intake of calcium was negligible diet (37).
on a 0.02% calcium diet (396), which confirms that in-
creased skeletal resorption is a driver of the post-weaning In lactating ewes serum calcium rose after delivery and de-
rebound in calcium.
clined as lactation progressed, with a low-calcium diet caus-
ing a steeper decline in serum calcium (69). Deer maintained
Serum calcium declined a greater amount during lactation
an increased albumin-corrected serum calcium during lac-
in vitamin D-deficient rats (91), indicating that vitamin D
tation (170). Serum calcium remained normal in lactating
deficiency impairs the ability of the mother to maintain her
goats (55).
serum calcium during lactation. This contrasts with preg-
nancy in which the same vitamin D-deficient rats achieved a
significant increase in serum calcium (915). In the first 3 Serum phosphorus has also shown widely variable re-
days after weaning, serum calcium rebounded twofold sponses in lactating rats, with increases above normal (320,
higher to near-normal values in severely vitamin D-deficient 568, 718), normal values (76, 114, 337, 568), and signifi-
rats before declining significantly to the prepregnancy value cant decreases (86, 319). Phosphorus rose during the first
(915). This is also consistent with persistent upregulation of several days after abrupt weaning, simultaneous with the
intestinal calcium absorption and bone resorption for some spike in serum calcium (86, 718). It either remained normal
days after the outflow into milk has ceased. or declined modestly in lactating mice (477, 478, 580),
declined in lactating goats (55), and increased above normal
In multiple studies from the authors laboratory wherein in deer (170).
WT Black Swiss or C57BL/6 mice consumed a standard 1%
calcium diet, there was no change in the ionized calcium or Serum magnesium is unaltered or modestly reduced in lac-
the serum calcium during lactation regardless of whether tating rats (86, 132), and unchanged in mice (580) and
the samples were drawn nonfasting or fasting (296, 330, goats (55). Magnesium also increases abruptly after forced
477, 478, 580, 992, 994). The ionized calcium was also weaning in rats (86).
B) HUMAN DATA. Multiple cross-sectional and longitudinal diet (337). A low-calcium diet (320, 321) and nursing larger
studies have consistently shown that the serum calcium, litters (320, 708) cause higher PTH concentrations,
whether adjusted for albumin or not, is normal or slightly whereas if only three pups are nursed PTH is normal (320).
increased in breastfeeding women (9, 156, 157, 164, 168, After weaning, PTH falls within 6 h and becomes normal by
207, 221, 348, 349, 385, 453, 454, 468, 470, 558, 641, 24 48 h (321).
721, 757, 764, 805, 871); one exception is a study that
found a decrease in the albumin-adjusted serum calcium In contrast to the studies in rats, longitudinal studies of
(632). The ionized calcium has similarly been shown to be Black Swiss and C57BL/6 mice consuming a 1% calcium
either increased slightly (221, 251, 470, 497, 757) or un- diet have found that PTH is suppressed during lactation
changed (157, 294, 453, 558, 721, 805, 871) in lactating from prepregnancy values, and similar to low values of
women compared with themselves or with controls. Moth- pregnancy (330, 477, 478, 994). A 2% calcium diet sup-
ers nursing twins had higher serum calcium than mothers presses PTH further (330, 478), whereas fasting overnight
nursing singletons in one study (347) but not in another leads to nonsuppressed PTH (580). Conversely in lactating
report (646). In studies in which serum calcium and ionized CD1 mice consuming a 1% calcium diet, the serum PTH
calcium were modestly but significantly increased, mean was no different than in virgin mice, whereas a 0.01% cal-
address the synthesis of calcitriol (sect. IIA4) and the adap- VH), is unknown. Serotonin increases during lactation in
tations that occur in the intestines (sect. IVB), kidneys (sect. mice (101) and may stimulate mammary gland PTHrP,
IVC) and bone (sect. IVD). PTHs role is also illuminated by since increased dietary intake of a serotonin precursor
data on the effects of hyperparathyroidism (sect. VB) and raised PTHrP mRNA and protein expression in the mam-
hypoparathyroidism (sect. VD) in breastfeeding women. mary glands, and also increased plasma PTHrP significantly
(530). Conversely, deletion of tryptophan hydroxylase-1 in
PTH rises to normal (206, 558) or above normal (207, 470, mice results in global serotonin deficiency, and reduced
632, 871) during the post-weaning interval. This elevation PTHrP expression in mammary tissue during lactation
corresponds to the time when bone mineral is restored to (380). This was reversed in a dose-dependent fashion by a
the skeleton (see sect. IVG) (27, 410). serotonin receptor agonist and worsened by a serotonin
receptor antagonist (380).
C) SUMMARY. PTH is generally suppressed in lactating mice
unless the samples are drawn fasting, whereas PTH is al- Local factors are important for stimulating PTHrP, since
most invariably elevated in lactating rats regardless of the milking one goat mammary gland increases the PTHrP con-
calcium content of the diet. In largely Caucasian women centration in milk from that gland but not the contralateral
breastfeeding, which suggested the presence of a PTH-like tion (90, 567). The fall in serum and ionized calcium and
factor during lactation (see sect. VD). rise in PTH, observed in most studies of lactating rats, likely
contribute to the increase in calcitriol. This increase is also
In section IIA3B, the inherent problems with measuring influenced by the diet, rising higher with a 0.1% calcium
PTHrP in serum as opposed to plasma, and limitations of diet and being prevented by a 1.6% calcium diet (568). In
the available assays, apply to published studies of lactating that study PTH was no different between lactating and
women. Despite these problems, and with few exceptions nonlactating rats despite the three different diets, indicating
(473), most studies have found the circulating PTHrP1 86 that the changes in calcitriol were independent of changes in
or PTHrP134 level to be significantly increased in lactating PTH (568). Another set of analyses also indicated that PTH
women vs. nonpregnant women or bottle-feeding controls is not a significant predictor of the calcitriol level in lactat-
(251, 349, 497, 558, 863). An assay directed against a mid- ing rats (90, 567). But PTH must account for some of the
region sequence (PTHrP6377) also found PTHrP to be ele- increase in calcitriol during lactation since two studies
vated in the blood of lactating women (130). found that serum calcitriol in lactating parathyroidecto-
mized rats was only half the concentration of lactating in-
Circulating PTHrP increases after suckling (251, 557, 558); tact rats, although the achieved level was at least double
A) ANIMAL DATA. Serum calcitriol increases twofold or more C) SUMMARY. Calcitriol remains elevated in lactating rats and
in lactating rats (90, 92, 93, 114, 718, 1021), and higher mice, whereas in breastfeeding women the level promptly
levels are achieved with larger litters or more intense lacta- declines to nonpregnant values. These differences between
rodents and women are consistent with indications that mon warning in prescribing information that calcitonin
rodents require increases in both intestinal calcium absorp- should not be used in breastfeeding women because of its
tion and skeletal resorption to meet the mineral require- potential to inhibit lactation.
ments of lactation, whereas women require only increases
in skeletal resorption (see sect. IV, C and E). C) SUMMARY. Calcitonin may be normal or increased in lac-
tating rodents and breastfeeding women. Although largely
5. Calcitonin considered a vestigial hormone, there is convincing evi-
dence from animal models that calcitonin protects against
A) ANIMAL DATA. Similar to serum calcium and PTH, serum excess skeletal resorption during lactation (sects. IVE and
calcitonin levels in lactating rats have been quite variable, VH). It surges to high levels at weaning, which may point to
including low values on a 1.4 and 1.5% calcium (86, 627); a functional role in inducing osteoclast apoptosis, or it may
high levels on 1.2% and 0.9% calcium (76, 926) and an simply be responding to the post-weaning spike in serum
unspecified diet (201); and normal values on an unspecified calcium. Calcitonin can also inhibit prolactin and lactation
diet (337). Calcitonin levels are higher in fed versus fasted in women and animal models when administered at phar-
lactating rats (201). In ewes, calcitonin drops to nonpreg- macological doses.
The effect of calcitonin to inhibit prolactin in rodents, and Prolactin levels surge during early lactation as it exerts its
similar findings in human studies (155, 431), led to a com- role in initiating milk production; dopaminergic agents in-
hibit prolactin and stop milk production. Prolactin and pro- progesterone, testosterone, inhibins, and activins. Whether
lactin receptor null mice cannot be studied because they are these play direct or indirect roles in regulating maternal
infertile, but loss of one allele of the prolactin receptor skeletal metabolism during lactation is uncertain.
causes impaired lactation (465). Prolactin has been pro-
posed to directly stimulate osteoblasts and osteoclasts dur-
ing lactation, but inhibiting prolactin with bromocriptine
B. Calcium Pumping and Secretion in
achieved inconsistent results (888). Moreover, inhibiting Mammary Tissue
prolactin does not necessarily test a direct role of prolactin
on bone, since loss of prolactin will inhibit milk production, 1. Animal data
reduce ovarian suppression, and reduce PTHrP production
by mammary tissue. The process by which calcium enters mammary epithelial
cells and is eventually secreted into milk is incompletely
Oxytocin is required to cause contraction of myoepithelial understood (FIGURE 3). Calcium appears to enter the baso-
cells within mammary tissue, thereby causing milk ejection. lateral membranes of mammary epithelial cells via stretch-
Oxytocin has also been proposed to regulate osteoblasts activated and other calcium channels. A low concentration
Basolateral
surface ADP FIGURE 3. Calcium transport across mam-
Ca2+ ATP mary epithelial cells into milk. The basolateral
Ca2+ Mammary (left) and apical (right) basement membranes
Ca2+ PMCA1 epithelial cell Apical of a mammary epithelial cell are depicted.
Ca2+ surface
Ca2+ Calcium enters the cell through channels that
Ca2+ have not been defined; TRPV6 and TRPV5
Ca2+
Ca2+ Ca2+ are not expressed. About 20 30% of cal-
Ca2+
Ca2+ cium destined for secretion into milk is
Ca2+ Ca2+
pumped into the Golgi apparatus via PMCA1,
Ca2+ Ca2+ Ca2+ Ca2+ wherein it is packaged into secretory gran-
Ca2+ Ca2+
Ca2+ Ca2+ ules containing proteins (casein and -lactal-
~2.2 mM <1 mM ~3 mM bumin) and complexes of calcium with phos-
[Ca2+] in blood [Ca2+] in cytoplasm Ca2+ [Ca2+] in milk phate and citrate. These granules are ex-
truded from the Golgi apparatus into milk
Ca2+ through transepithelial secretion at the apical
Ca2+
Ca2+ Ca2+ Ca2+ membrane. About 70 80% of calcium en-
2+ tering the cell becomes bound to carrier pro-
Ca2+ Ca2+ Ca2+ Calbindin-D9k Ca2+ Ca2+ Ca
progesterone, low dietary calcium, systemic hypocalcemia, Further studies that examined the effect of calcimimetic
high prolactin, and suckling (737, 906, 910, 916, 940, 952, agents, and selective deletion of the calcium receptor, have
956, 1003, 1004). Each of these stimulatory factors sup- clarified the role of PTHrP within mammary tissue. It is the
ports a role for PTHrP in regulating mammary gland and calcium receptor, expressed by mammary epithelial cells,
mineral physiology during lactation. On the other hand, an which appears to directly regulate production of PTHrP,
early study failed to detect a change in milk calcium content and the fluid and calcium content of milk (36, 591, 952).
when lactating mice were passively immunized with anti- While a low calcium diet increases mammary production of
PTHrP antibody (620). PTHrP, this effect is blocked by a calcimimetic drug, which
activates the calcium receptor to downregulate PTHrP
The role of PTHrP has been further explored through the (952). Ablation of the calcium receptor globally, or selec-
use of gene deletion models in mice. Selective deletion of tively within mammary epithelial cells, upregulates mam-
Pthrp from mammary epithelial cells at the onset of lacta- mary gland PTHrP expression and reduces calcium trans-
tion resulted in reduced milk calcium content (953). How- port into milk (36, 591). Moreover, selective ablation of the
ever, this may have been an indirect effect because the sup- calcium receptor from mammary epithelial cells raises the
ply of calcium to mammary tissue was also reduced, as plasma PTHrP level, induces hypercalcemia, and causes in-
indicated by reduced bone turnover markers and less bone creased bone resorption and net loss of bone by the end of
resorbed by the end of lactation (953). Conversely, signifi- lactation (591). But despite systemic hypercalcemia and in-
cant upregulation of PTHrP mRNA and protein occurred creased bone resorption, the milk calcium content remains
within mammary epithelial cells of Ctcgrp null mice (which low because of loss of the calcium receptors actions to
lack calcitonin), and the milk calcium content was signifi- promote calcium entry into milk (591).
cantly doubled at day 14 of lactation (994), and nonsignifi-
cantly increased at day 7 of lactation (992). Again, this may The calcium receptor also upregulates expression of
have been an indirect effect because in these mice the supply PMCA2, expressed on the apical plasma membranes of
of calcium to mammary tissue was significantly increased, mammary epithelial cells, to stimulate calcium secretion
as shown by increased bone turnover markers and a dou- into milk (952, 954). The importance of PMCA2 has been
bling of net bone lost by the end of lactation (992, 994). revealed by a spontaneous loss of function mutation of
Pmca2 in deafwaddler mice, which produce milk of low when the calcium supply is insufficient (FIGURE 4). In this
calcium content (753, 954). Deletion of the calcium recep- model, PTHrPs role is to maintain systemic delivery of
tor from mammary epithelial cells did not affect expression calcium to the mammary epithelial cells by resorbing cal-
of PMCA2, thereby confirming that it is loss of the calcium cium from the skeleton and reabsorbing calcium from the
receptor function that specifically leads to the low calcium kidney tubules. Thereby, PTHrP plays an indirect but key
content of milk (591), perhaps by reduced activity but not role in determining the calcium content of milk.
expression of PMCA2.
This model implies a negative feedback loop that will enable
Studies in goats have revealed that the calcium receptor and milk production to decrease or cease if the serum calcium
PTHrP may play opposing roles with respect to mammary becomes dangerously low for the mother (955). However, it
epithelial cell survival. Activation of the calcium receptor by is not a fail-safe loop because hypocalcemia leading to tet-
calcium or a calcimimetic drug inhibited proliferation and any and death can occur during lactation in rats and mice
induced apoptosis of mammary epithelial cells, whereas that nurse large litters, and in dairy cows (milk fever).
overexpression of PTHrP had the opposite effect to inhibit Blocking the effect of PTHrP to resorb bone through use of
apoptosis and promote proliferation (552). a bisphosphonate or osteoprotegerin (OPG) treatment in
Ca2+
Ca2+
Ca2+
Ca2+ Ca2+
Ca2+
Ca2+ Ca2+
Ca2+
H2O Ca2+ H2O
+ +
Calcium and H2O Ca2+ Calcium and H2O Ca2+
PTHrP Ca2+ PTHrP Ca2+
(milk) Ca2+ (milk)
Ca2+
Ca2+ Ca2+
Ca2+
PTHrP PTHrP
PTHrP PTHrP
(maternal plasma) (maternal plasma)
FIGURE 4. The role of PTHrP and calcium receptor (CaSR) within the lactating breast. The calcium receptor
(represented schematically) is expressed by lactating mammary epithelial cells. It monitors the systemic
concentration of calcium to control PTHrP synthesis and, thereby, the supply of calcium to the breast. An
increase in serum calcium or administration of a calcimimetic inhibits PTHrP expression (A), whereas a
decrease in serum calcium or ablation of the calcium receptor from mammary epithelial cells stimulates PTHrP
expression (B). The calcium receptor also directly regulates the calcium and fluid composition of milk indepen-
dent of PTHrP. Administration of a calcimimetic stimulates calcium and water transport into the breast, while
ablation of the calcium receptor results in low milk calcium despite increased PTHrP and systemic hypercal-
cemia. PTHrP produced by mammary epithelial cells enters the maternal circulation to stimulate maternal
bone resorption and renal calcium conservation. It also enters milk at 1,000- to 10,000-fold higher concen-
trations, from where it may influence neonatal accrual of calcium.
measured. Moreover, several additional physiological obser- calcium in Vdr null mice may mean that this effect of cal-
vations suggest that the mammary gland calcium receptor has citriol is not mediated by VDR. Additional studies in se-
quite limited ability to prevent systemic hypocalcemia. In se- verely vitamin D-deficient mice and rats also found that the
verely vitamin D-deficient rats, which have a serum calcium calcium content of milk was normal (19, 119).
50% of normal, the calcium content of milk was unchanged
compared with normocalcemic, vitamin D-sufficient mothers Phosphorus is also subjected to regulated pumping and se-
(91). In cows, the calcium content of milk is unaffected by low, cretion into breast milk, although less is known about the
normal, or high dietary calcium content, or low to high milk regulatory factors involved. The FGF23 target NaPi2b is
output (204). coexpressed with VDR in mammary epithelial cells of the
goat and mouse (417, 631, 643), and NaPi2b expression
Notably, the effect of the calcium receptor to inhibit mam- decreased in response to lower dietary phosphorus intake
mary gland production of PTHrP is reversed in certain ma- (643). Expression of Klotho and FGF receptors by lactating
lignant breast cancers, such that altered G protein coupling mammary tissue has evidently not been studied. Systemic
causes the calcium receptor to stimulate rather than inhibit hypophosphatemia in Phex/Hyp mice did not alter the
the production of PTHrP (592). This may explain why a phosphorus or calcium content of milk (240), but this dif-
Two cases of women with hypophosphatemia due to XLH tion, since severely vitamin D-deficient rats increase duode-
found that the phosphorus content of milk was reduced to nal calcium absorption to a value equal to that of vitamin
about half the normal value (447, 745). The reduced serum D-sufficient rats; they also raise their serum calcium signif-
phosphorus in these women may explain the low phospho- icantly but not to normal (93, 360). When these severely
rus content of milk, without requiring a direct role of vitamin D-deficient rats were also parathyroidectomized
FGF23 to regulate the phosphorus content of milk. and transferred to a high-calcium diet, an increased rate of
intestinal calcium absorption was maintained despite ab-
3. Summary sence of both calcitriol and PTH, and it was no different
from the rate achieved in intact, vitamin D-sufficient rats
The calcium receptor appears to directly control the cal- (93). Moreover, ketoconazole treatment reduced serum cal-
cium content of milk by inhibiting PTHrP and stimulating citriol by half in lactating rats, but this had no effect on the
PMCA2. There is also evidence that PMCA2 may be locally efficiency of intestinal calcium absorption (92), confirming
regulated by PTHrP, serotonin, and calcitriol. PTHrP is that calcitriol is not necessary for an increased rate of ab-
expressed by mammary epithelial cells wherein it plays a sorption to be achieved during lactation. Intestinal calcium
supportive role in regulating the calcium content of milk, absorption has not been measured in lactating Vdr null and
largely by stimulating systemic bone resorption and renal
On the other hand, although reducing either the dietary 2. Human data
intake of calcium or skeletal resorption during lactation will
cause maternal hypocalcemia, neither manipulation re- Multiple studies have demonstrated that intestinal calcium
duces the calcium content of milk. It is only when both are absorption is normal (equivalent to nonpregnant values)
reduced, such as a calcium-restricted diet in mice also during lactation, reduced from the doubled rate that occurs
treated with OPG to block bone resorption, that more pro- during pregnancy (324, 372, 453, 467 469, 764, 873).
found maternal hypocalcemia and reduced milk calcium This fall in the rate coincides with calcitriol also declining to
content result (see also sect. IVE). These findings indicate normal (sect. IVA) and supports that calcitriol contributes
that the rodent balances input from both skeletal resorption to the increased efficiency of calcium absorption during
and increased intestinal absorption of calcium, and that pregnancy.
either route of delivery can make up for the other during
lactation. It is only when both are impaired that systemic Even when lactating and control women were randomized
hypocalcemia and reduced milk calcium content will result. to receive 1 g calcium or placebo to take daily, no difference
in fractional absorption of calcium was evident across the
As with studies in pregnancy, factors other than calcitriol groups (453). A small increase in intestinal calcium absorp-
may stimulate intestinal calcium absorption during lacta- tion occurs in women whose menses have resumed while
they are still lactating (453), which supports a role for This relative hypocalciuria is consistently accompanied by
higher estradiol levels boosting calcium absorption. phosphaturia in mice (330, 477, 478, 580, 994), which is
likely a demonstration of the physiological actions of
Women often increase dietary or supplemental intake of PTHrP to conserve calcium and excrete phosphorus. A
calcium while breastfeeding, and this will increase the total suckling-induced phosphaturia attributable to PTHrP has
amount of calcium absorbed, even though the efficiency of also been demonstrated in rats, goats, cows, and sheep (56,
absorption is not altered (453). However, randomized trials 226, 907, 1003).
and cohort studies have found that this increases urine cal-
cium excretion without affecting milk calcium or the In rats, the persistence of elevated PTH during lactation (see
amount of bone resorbed during lactation (206, 452, 484, sect. IVA2) likely complements the actions of PTHrP to
723, 729, 730) (see sects. IVE and VI). conserve calcium and excrete phosphorus.
maximum for phosphorus suggests the presence of an anti- fivefold physiological levels of estradiol (37, 115, 956). But
phosphaturic factor (or low FGF23) despite the increased osteoclast-mediated bone resorption is not the only mecha-
urine phosphorus excretion. nism by which bone is resorbed to release calcium during
lactation. More recent histomorphometric and electron mi-
croscopy assessments have shown that osteocytic osteolysis
E. Increased Skeletal Resorption and also occurs during lactation, in both trabecular and cortical
Osteocytic Osteolysis During Lactation bone (904, 998). Because cortical bone makes up more than
90% of the skeleton, there is the potential for substantial
1. Animal data mineral to be mobilized through osteocytic osteolysis.
Multiple lines of evidence have demonstrated that the ma- Visible enlargement of osteocyte lacunae in certain human
ternal skeleton is significantly resorbed during lactation to pathological states was first described by Rigal and Vignal
provide calcium and other minerals to milk. Osteoclast- in 1881 (763). This was reaffirmed by von Recklinghaus-
mediated bone resorption is upregulated to resorb mainly ens observations in 1910 (962), who proposed that osteo-
trabecular bone and endocortical surfaces, while osteocytic cytes digest their surrounding bone matrix when stressed by
FIGURE 5. Osteocytic osteolysis and osteoclast-mediated bone resorption. A: quiescent bone with an
osteocyte surrounded by its lacuna and canaliculi (gray halo and tentacles). B: lactation with an osteoclast
resorbing bone (resorption pit) while an osteocyte resorbs mineral from its lacuna and pericanalicular spaces
(surrounding white regions). C: post-weaning phase, during which osteoblasts restore bone in areas previously
resorbed by osteoclasts (hatched resorption pit), and osteocytes remineralize their lacuna and pericanalicular
of the ash, and radiological assessment of mineral content while a peripheral QCT (pQCT) study found that lactation
by DXA. Lactating rats and mice normally resorb 25 increased tibial mid-shaft cortical width, area, periosteal cir-
35% of bone mineral, primarily from trabecular-rich verte- cumference, and cross-sectional moment of inertia in frontal,
brae, to a lesser extent from trabecular bone of the femora sagittal, and torsional planes (772). The latter two studies
and tibiae, and much less from purely cortical bone (34, 35, suggest that the weight-bearing limbs have a compensatory
101, 176, 271, 296, 320, 330, 337, 392, 408, 477, 478, improvement in bone volumes and strength during lactation
486, 518, 580, 628, 629, 708, 740, 772, 920, 972, 991, that may offset the potential loss of strength induced by re-
994). Ewes resorb bone preferentially from the vertebrae sorption of trabecular microarchitecture.
and pelvis, resulting in reduced ash weight, while the limbs
and digits are relatively spared (69). The African green That resorption of bone during lactation is needed to sup-
monkey, which may resemble the human condition more port milk production has been confirmed by finding that a
closely, loses 20% of bone mineral density of the lumbar low-calcium diet initiated at delivery causes greater skeletal
spine during 20 wk of lactation (393). The greater losses of losses that can exceed 43% of trabecular bone mineral con-
mineral content from trabecular bone demonstrate the abil- tent in rats and mice (37, 271, 320, 350, 355, 708, 991).
ity of osteoclasts to resorb mineral from bone that has the Furthermore, nursing larger numbers of pups, which means
greatest surface area. The proportionately smaller losses of increased milk production, causes greater resorption of
mineral from cortical bone may be due to osteocytic oste- bone in rats (320, 708). Bone strength assessments have
olysis. demonstrated that a low-calcium diet or nursing more pups
each leads to weaker bone at the end of lactation compared
In rats and mice, the material properties of bone are ad- with a normal-calcium diet or fewer pups (708). MicroCT
versely impacted by the resorption of bone during lactation. studies have confirmed that calcium restriction results in
The strength, stiffness, and toughness of vertebrae, tibiae, greater reductions in bone volumes, trabecular number and
and femora are reduced while ductility is increased (489, thickness, and tissue density (37). In ewes, a low-calcium
518, 580, 708, 709, 947). diet exacerbates the decline in ash weight (69). Treating
lactating rats with a bisphosphonate causes maternal hy-
MicroCT measurements of the lumbar vertebrae of lactat- pocalcemia that is not seen in control rats (115), confirming
ing mice have revealed 30 50% reductions in trabecular that skeletal resorption of mineral is required to maintain
bone volumes, 20% lower trabecular thickness, trabecular maternal serum calcium in the setting of milk production.
perforations, reductions in tissue density, and progression However, this effect was not seen in one study of lactating
to more rodlike than platelike structures (34, 35, 566). The mice (956).
tibiae and femora show similar changes in trabecular bone,
while cortical bone displays reductions in cortical thickness, Conversely, a high-calcium diet may blunt but not prevent
cross-sectional area, and tissue mineral density, and an in- bone loss during lactation, confirming that it is hormonally
crease in cortical porosity and endosteal perimeter (35, 101, programmed independent of maternal serum calcium or
566, 580). However, another microCT study from the same dietary calcium intake. When lactating rats were studied on
investigators found no significant change in cortical parame- diets ranging from 1.2 to 0.3% calcium, there was no
ters in the femora except for an increase in tissue density (34), change in resorption of skeletal calcium (271, 318),
whereas when lactating mice were studied on a 2 versus 1% histomorphometric evidence of increased osteoclast num-
calcium diet there was definite blunting of mineral content ber and activity, and reduced osteoblast parameters (194,
loss (478). In lactating ewes, a high-calcium diet also 992, 994) (see sect. VH).
blunted the decline in ash weight (69). Bone loss was com-
pletely blocked with OPG treatment in mice, but even then Collectively these data show that PTH, calcitriol, VDR, low
milk production remained normal, likely from upregulated or high estradiol, and adrenal hormones are not needed for
intestinal calcium absorption (37). It took the combined the normal mobilization of skeletal calcium during lacta-
effects of OPG treatment and a 0.01% calcium diet to dis- tion, but loss of calcitonin can lead to more severe losses of
rupt lactation, resulting in maternal hypocalcemia and bone mass during lactation. Since ovariectomy in lactating
deaths in 41% of the mothers by day 12 of lactation (37). rodents does not increase the amount of bone lost, this
implies that estradiol is already low in lactating rodents or
The classic calciotropic hormones do not appear to be re- that low estradiol is not a relevant stimulus for bone loss
quired for increased osteoclast-mediated bone resorption during lactation. The comparatively slow bone loss after
and osteocytic osteolysis to occur during lactation. Parathy- ovariectomy alone indicates that low estradiol cannot ac-
roidectomy in rats did not blunt the lactational fall in skel- count for the rapidity and extent of bone loss that occurs
The mechanism that leads to the failure to resorb bone is above normal due to the increased bone-specific fraction
unknown. It may be due to altered energy metabolism or (769, 1002). These values confirm that bone turnover is
some interaction with PTHrP, which was not measured. significantly increased during lactation in women.
Finally, increased weight bearing has been theorized to re- One of the earliest longitudinal studies to assess skeletal
duce skeletal losses during lactation. This was assessed by changes during lactation used a 241Am source and found
DXA and pQCT at multiple skeletal sites in rats forced to that the femoral shaft BMC declined 2.2% over the first 100
stand erect to reach their food and water from time of days of lactation (40). Since that time, multiple longitudinal
mating through the end of pregnancy, and then switched to studies (observational studies and clinical trials) have been
cages of normal height, compared with rats housed in cages carried using SPA, DPA, or DXA. A consistent decline in
of normal height (772). Skeletal losses in the lumbar spine, BMD or BMC has been reported, with mean values ranging
femora, tibiae, and whole body were unaffected by in- from 3 to 10.0% after 3 6 mo of lactation. The greatest
creased weight-bearing, except for a borderline statistically
(510%) losses occur in the lumbar spine, with more mod-
significant and very small relative improvement in mineral-
est (0 5%) losses at less-trabecular-rich sites (hip, femur
ization and strength parameters of the tibial diaphysis
and distal radius), and the smallest (0 2%) changes at
increase, which may be an artifact from trabecularization of terventional studies have shown that the lumbar spine and
cortical bone (84, 109). hip are preferentially resorbed during lactation such that
taking a 1 g calcium supplement in addition to usual intake
Peripheral ultrasound is not a useful technique to assess will not reduce the amount of bone lost. One study com-
bone loss during lactation. Although DXA and HR-pQCT pared 1,800 to 800 mg calcium intake daily and the lumbar
have confirmed that bone mass declines significantly during spine declined 4% over 6 mo of lactation with no differ-
lactation, ultrasound of the os calcis or midtibial shaft ence between the groups (452). A second compared with
showed no changes (533, 917, 1015). 2,400 to 1,200 mg calcium daily, and the lumbar spine,
radius, and ulna declined 6% in both groups (206). A
Few studies have looked at lactating adolescents. A 15% third study compared 1,400 to 300 mg calcium, and the
decrease in radial BMC over 16 wk of lactation was found intervention caused an increase in urinary calcium excre-
in teenaged mothers whose calcium intake was below the tion but neither group lost radial BMD or experienced a
recommended amount, whereas lactating adults showed no change in markers of bone resorption during up to 18 mo of
change in radial BMC; the lumbar spine was not assessed lactation (the spine was not assessed) (729, 730). A fourth
(166, 167). A follow-up study of lactating adolescents also used a 1 g supplement but did not measure dietary
The studies in adolescents indicate that a higher calcium Intervening to correct calcium intake in women who habit-
intake prevents bone resorption in the radius during lacta- ually consume low calcium may be detrimental. A random-
tion, a site that normally shows proportionately little re- ized intervention administered 1,500 mg calcium or pla-
sorption during lactation. Several blinded, randomized in- cebo during pregnancy but not postpartum to Gambian
women with habitual intakes of 350 mg calcium. There tinued to decline in women who breastfed for an extended
was no effect on bone density at any skeletal site at the end period after their menses resumed (301, 857).
of pregnancy, but during 12 mo of lactation, the women
who had received the calcium supplement during pregnancy It is difficult to analyze the independent effects of low estra-
more than doubled their losses in BMD of the lumbar spine, diol on bone turnover during lactation. More intense lacta-
total hip, and distal radius and had greater increases in bone tion causes more breast milk output and bone loss, but
turnover markers (439). A followup study showed that more intense lactation is also associated with lower estra-
these effects persisted long term, including through a sub- diol and prolonged amenorrhea. The impact of isolated low
sequent pregnancy and lactation cycle (441). These results estradiol is that it causes 12% annual losses of BMD in
suggest that Gambian women are beneficially adapted to recently menopausal women (331), but the older ages of
their low calcium intakes, while use of a calcium supple- these women may not reflect what happens to reproductive
ment during pregnancy disrupts this adaptation to create an age women with low estradiol.
adverse response when the supplement is subsequently
withheld during lactation. In this context the effects of GnRH analog-induced estra-
diol deficiency in reproductive-age women are illuminat-
Table 3. Comparison of the effects of 6 months of lactation versus 6 months of GnRH agonist therapy
Lactation GnRH Agonist
PTHrP reduces bone turnover and loss, while mammary- totrophs and reduce the release of prolactin, which in
specific ablation of the calcium receptor leads to mark- turn would lessen ovarian suppression and inhibit pro-
edly increased mammary expression of PTHrP, higher duction of PTHrP. A conditional deletion of calcitonin
systemic PTHrP levels, increased bone turnover, and from mammary tissue is needed to determine its role
greater net bone loss (591, 953). Suckling induces pro- during lactation.
duction and release of PTHrP, whereas milk stasis causes
the entire process to shut down. Additional players in the cross-talk among breast, brain,
and bone include oxytocin and calcitonin, and there may
Lactating mammary epithelial cells also produce high be others. In addition to its critical role in stimulating
concentrations of calcitonin, which may act locally to
milk ejection, oxytocin may affect the differentiation and
reduce the calcium content of milk or inhibit PTHrP, as
suggested by Ctcgrp null mice (see sect. VH). Calcitonin function of osteoblasts and osteoclasts. Serotonin may
also has systemic actions to suppress osteoclast-mediated stimulate the production of PTHrP and have other di-
bone resorption and osteocytic osteolysis in bone. Fur- rect and indirect effects on bone metabolism during
thermore, calcitonin may inhibit the pituitary lac- lactation.
G. Bone Formation and Skeletal Recovery creased bone formation rate. Bone volumes, trabecular
Post-Weaning thickness, and mineral content are recovered within 2 4 wk
of weaning in the mouse and 4 8 wk of weaning in the rat
1. Animal data (107, 194, 628, 947). Detailed histomorphometric assess-
ment of vertebrae and cortical bone of femora at 8 wk after
After the pups are weaned, the maternal skeleton undergoes weaning in rats showed that bone formation rates and min-
a rapid phase of remineralization. Bone turnover continues eralizing surfaces on trabecular, periosteal, and endosteal
to be increased over nonpregnant values, but it is now un- surfaces had declined to age-matched nulliparous values,
coupled in the opposite direction from lactation, favoring while bone mass, cortical thickness, and cortical area had
net bone gain. increased to virgin values (947).
When weaning is forced by the sudden removal of pups Microradiographs, scanning electron microscopy, and mi-
before the natural end of lactation, within 24 48 h there is croCT have been used to assess recovery of microarchitec-
widespread apoptosis of osteoclasts that prompts a fall in ture, which have revealed normalization at some sites, and
osteoclast number and activity below prepregnant values, a permanent alterations at others. The vertebrae fully recover
Histomorphometry has revealed increased osteoid seams The rapidity and relative completeness of this post-weaning
covering 50 70% of bone surfaces, while dynamic histo- phase of bone recovery has prompted numerous ap-
morphometry has shown widely spaced tetracycline labels proaches to try to identify the factors that stimulate bone
(107, 194, 628, 947). The combination of increased osteoid formation and post-weaning recovery. Severely vitamin D-
surface and widened seams corresponds to a markedly in- deficient rats improve bone mass and architecture after lac-
tation, appearing to regain the amount that was lost during Women also undergo a substantial increase in bone mass
lactation (628); however, an earlier study from the same and mineralization after weaning, evidently reversing the
investigators suggested that there was no recovery of ash losses that transiently occur during lactation. There are no
weight or calcium content (362). Vdr null mice and histomorphometric studies or direct tests of bone strength
Cyp27b1 null mice display osteomalacia and reduced bone in women, as there are in the rodent models. Instead, skel-
mass before pregnancy, but after lactation they upregulate etal recovery after lactation has largely been determined by
longitudinal assessment of bone mass and mineralization
bone formation markers and increase BMC substantially to
during lactation and post-weaning by DXA at the total
values 40 50% higher than prior to pregnancy (296, 330).
body, lumbar spine, and hip. More recently, changes in
Pth null mice have low bone turnover prior to pregnancy,
microarchitecture by HR-pQCT have been assessed at pe-
but upregulate bone formation markers normally during
ripheral sites. Many dozens of studies have examined the
post-weaning, and increase BMC after lactation to values
effect that lactation has on predicting future risk of low
20% higher than prepregnancy (478). Ctcgrp null mice lose
bone density, osteoporosis, or fracture.
55% of skeletal mineral content during lactation but fully
regain it post-weaning (194, 992, 994). Osteoblast-specific Analysis of women who inadvertently ingested isotopes
ablation of Pthrp results in an osteoporotic phenotype in while living near the Techa River in Russia revealed that
adult mice, but these obPthrp null mice lactate normally women who were pregnant and lactated during the time of
and have full recovery of bone mass afterward (477). Col- exposure had a greater content of 90Sr in the maternal skel-
lectively these studies indicate that PTH, osteoblast-derived eton years after the exposure, compared with women living
PTHrP, vitamin D, VDR, calcitriol, and calcitonin are not in the region who were pregnant prior to the exposure or
required full remineralization of the maternal skeleton to be had never been pregnant (923). This result is compatible
achieved after lactation (194, 296, 477, 478, 992, 994). with increased uptake of isotope into the maternal skeleton
during post-weaning recovery.
Adequate calcium is required, since a low-calcium diet pre-
vented skeletal recovery in rats, whereas normalizing the The available DXA data suggest that lactational loss of
diet 3 wk later allowed normal recovery to occur (355). An bone density is completely reversed by 12 mo after weaning
increased rate of mineral absorption is evidently not re- in most women (140, 168, 206, 379, 403 405, 412, 452,
quired since both intestinal calcium and phosphorus ab- 457, 470, 484, 505, 532, 572, 635, 705, 723, 729, 764,
sorption are normal during post-weaning recovery in rats 856, 857, 860, 1009), whereas recovery has been incom-
(93, 360). The marked increase in bone mass of Vdr nulls plete at some skeletal sites when assessed at 6 mo or less
and Cyp27b1 nulls (296, 330) may imply that intestinal after weaning the baby (9, 123, 124, 168, 403 405, 457,
calcium absorption is increased, since these mice have a 484, 532, 633, 635, 1009). A small longitudinal study of 22
reduced, rachitic bone structure on the same diet when non- women found a marked loss of 8% in the distal radius that
was still reduced 5% by 12 mo after weaning (609), which lactation. These changes reversed by 6 mo after lactation
suggests that the radius is slower to recover BMD. Note that ceased, during which no changes were seen in the controls
these studies report the mean responses of a cohort; the (537).
response of individual women will vary, such that some
women may not return to baseline after lactation, while If a permanent reduction in BMD or skeletal strength were
others may end up with a BMD even higher than prior to to occur from lactation, then lactation should be a strong
pregnancy. Recovery is fast enough that women who risk factor for low BMD or fracture in women of all ages.
breastfeed for 6 mo or more and have a second pregnancy However, over five dozen epidemiologic studies of pre-,
within 18 mo do not have reduced BMD of the spine or hip peri-, and postmenopausal women have found a neutral
at the end of the second pregnancy (534, 860). effect (16, 38, 63, 158, 203, 214, 215, 290, 292, 299, 341,
356, 368, 379, 383, 397, 444, 445, 448, 463, 481, 506,
A study from China took a different approach of doing a 509, 541, 547, 611, 619, 625, 636, 648, 683, 700, 761,
baseline BMD reading in 40 women with habitually low 828, 845, 846, 861, 864, 865, 869, 879, 934, 935, 944,
calcium intakes, who had either stopped lactating or were 951, 969, 1020) or a protective effect (25, 27, 71, 83, 144,
still lactating but had recovered their menses. They were 169, 212, 244, 279, 327, 365, 416, 421, 482, 507, 700,
for example, low calcium intake or vitamin D deficiency done in women, the fact that more than five dozen epide-
may impair skeletal recovery post-lactation. miological studies found that lactation confers a neutral or
protective effect against low BMD and fragility suggests
Recovery of estradiol to normal during post-weaning likely that recovery is effectively complete, without long-term ad-
facilitates skeletal recovery but cannot explain it fully. Es- verse effects on bone strength. Some data are compatible
tradiol suppresses bone formation and resorption when ad- with the possibility that weight-bearing exercise and in-
ministered as replacement therapy in peri- and postmeno- creased calcium intake during post-weaning may contribute
pausal women (305, 750); it is not a potent stimulator of to an even greater BMD being achieved.
bone formation. Moreover, when reproductive-age women
experience temporary estradiol deficiency induced by The question arises as to whether or not the skeletal losses
GnRH analog treatment, they lose a small amount of BMD invoked by lactation and the recovery post-weaning are the
and (unlike after lactation) most do not restore it afterwards same in a first compared with a second or third reproductive
(288, 415, 640, 657, 684, 696, 758, 762, 781, 891, 942). cycle, or in younger versus older mothers. In areas where
Earlier resumption of menses has correlated with an earlier the trabecular microarchitecture is not completely restored,
apparent increase in bone mass after lactation (484, 764), such as the tibia or femur, there may be less resorption of
677, 687). These fractures can be quite debilitating. The 143, 178, 263, 438, 475, 671, 677, 685, 799, 885, 897),
literature is confusing because many cases are described as strontium ranelate (897, 1016), and teriparatide (98, 178,
pregnancy-associated osteoporosis despite the fractures 377, 527, 544, 885) to treat osteoporosis diagnosed during
occurring several months into lactation. pregnancy or lactation. In each of these uncontrolled cases,
the achieved BMD increase was assumed to be due to phar-
In some breastfeeding women, the physiological bone re- macological therapy, but remained within the expected
sorption induced by PTHrP and low estradiol may be a range of increase that can occur spontaneously during post-
sufficient explanation for reduced skeletal strength that pre- weaning recovery.
disposes to fragility fractures. As noted earlier, in some
individuals the lumbar spine BMD has been shown to drop 3. Summary
from normal to osteoporotic values during otherwise nor-
Fragility fractures of the spine and other sites rarely occur
mal lactation. In some instances release of PTHrP by the
during lactation and may result from the normal physiolog-
breasts may be more exuberant than normal, leading to
ical resorption of the skeleton during lactation, combined
more marked resorption of bone. Three such breastfeeding
with effects of low bone mass or skeletal fragility that pre-
women presented with hypercalcemia, increased PTHrP, ceded pregnancy, and skeletal resorption that may have
As noted earlier, individual case reports have described use Primary hyperparathyroidism can worsen significantly
of nasal calcitonin (263, 687, 885), bisphosphonates (43, postpartum, with variable effects in women who breast-
feed. The clinician should be alert to this and consider dard 1% calcium diet, normalize serum calcium and phos-
whether parathyroidectomy or medical therapy might be phorus, and experience a normal loss of BMC at whole
needed during the postpartum interval. body, lumbar spine, and hindlimb (478). After weaning,
they fully regain the mineral content lost during lactation,
reach a BMC that is 10 15% higher than the prepregnancy
C. Familial Hypocalciuric Hypercalcemia baseline value, and redevelop hypocalcemia and hyper-
phosphatemia. They are somewhat more prone to anesthet-
1. Animal data ic-related deaths associated with serial DXA readings (133).
A 2% calcium diet blunted the lactational decline in BMC
Casr/ mice have life-long hypercalcemia and hypocalci- but did not reduce the post-lactation gain in BMC (478).
uria and mimic the human condition of FHH (394). They Overall, the studies in Pth null mice indicate that loss of
lactate normally, and their pups grow at the expected rate. PTH has no significant effect on lactational or post-weaning
However, mammary tissue shows twofold increased PTHrP mineral homeostasis. Calcitriol, PTHrP, and intestinal cal-
expression while milk has twice the normal content of
cium absorption have not been measured in lactating Pth
PTHrP but modestly reduced calcium content (36). These
null mice.
results imply that skeletal resorption increases to com-
calcium being 50% of normal (295). This confirms that monitoring the serum calcium and the anticipated require-
achieving a normal calcium content in milk does not require ment for the doses of calcium and calcitriol to be decreased
PTH. Based on studies in mice, systemic hypocalcemia may (148, 161, 790, 796, 811, 837, 1008). In some women
cause increased milk PTHrP content (36, 952). calcium and calcitriol both need to be stopped, whereas in
other women reduced doses may be all that is required.
Weight gain of the pups was normal when lactating, para-
thyroidectomized rats consumed a 2% calcium diet (395), The reason for the improvement in mineral and skeletal
whereas weight gain was modestly reduced as early as 24 h homeostasis is that PTHrP, released from lactating breast
after parathyroidectomy when the mothers consumed 1 or tissue, stimulates bone turnover, renal tubular calcium con-
0.4% calcium diets (295, 569). This reduced weight gain servation, and production of calcitriol by the kidneys (148,
was not seen in pups nursed by Pth null mice compared with 607, 837). Calcitriol does not increase above normal, and
WT mice; the ash weight and calcium content were no dif- this may be because in some studies PTHrP appears less
ferent at the end of 3 wk of lactation (133). Since the cal- potent than PTH in activating the PTH/PTHrP receptor and
cium content of milk is normal in parathyroidectomized stimulating Cyp27b1 (308, 413, 414, 494, 988). Another
rats, other factor(s) must be contributing to reduced weight potential reason is that the hormonal milieu of lactation,
involved a woman who developed hypercalcemia with sup- In longitudinal studies wherein Vdr null mice were raised on
pressed PTH during two successive lactation episodes a standard 1% calcium diet to allow them to develop rick-
(179). The hypercalcemia resolved and PTH rose to normal ets, but switched to a 2% calcium diet prior mating to
with weaning each time; no measurements of PTHrP were maximize fertility, Vdr null mice increased BMC by 55%
done. A fifth and much older case from 1981 (prior to the during pregnancy, and lactated normally, losing a normal
discovery of PTHrP) also involved lactational hypercalce- amount of BMC compared with their WT sisters on the
mia with low PTH; a bone biopsy revealed active skeletal same diet (296). Serum calcium and phosphorus remained
resorption suggestive of hyperparathyroidism (847). The normal throughout lactation and post-weaning. Within 14
hypercalcemia resolved after weaning, and the authors cor- days after weaning, the Vdr null mice restored all that had
rectly deduced that the breasts must be producing a PTH- been lost to achieve a BMC that was 50% higher than their
like hormone. prepregnant baseline but equal to the WT value. Histomor-
phometry during late pregnancy compared with prepreg-
These cases emphasize the extreme of women developing
nancy showed that the pregnancy-related increase in BMC
symptomatic hypercalcemia during lactation. This appears
was largely attributable to mineralization of osteoid (296).
to be uncommon; however, some cases may go undiagnosed
The subsequent increase in BMC after weaning implies that
Vitamin D-deficient mice from the CD1 background, kept compared with the 1.21.7.% calcium diet (360). Both
on a 1.2% calcium diet, had normal serum calcium and studies indicate that the normal rate of intestinal mineral
ionized calcium but lower serum phosphorus during lacta- absorption in virgin rats is sufficient to facilitate skeletal
tion (19). Their pups grew at the same rate as pups from recovery during post-weaning (93, 360).
vitamin D-replete mice (19). Milk from these mice showed
normal nutritional and calcium content, but there was a In one study, vitamin D-deficient rats produced only 20%
15% lower lactose content (19). Conversely, vitamin D-de- of the volume of milk of vitamin D-replete rats, as deter-
ficient mice in the Swiss background had mild (20% lower) mined by injecting the rats with oxytocin and then manually
hypocalcemia and normal phosphorus (79). Analysis of expressing the milk. The nutritional content of the milk was
milk from these mice, and from vitamin D-deficient rats, normal to enhanced, since it contained more protein, cal-
showed reduced protein content; the calcium content was cium, phosphorus, but somewhat less carbohydrate than
not measured (79). normal milk (119). Pups of vitamin D-deficient rats had
modestly reduced weight gain, but this was corrected by
Severely vitamin D-deficient rats have also been studied giving the mothers fewer pups to nurse, confirming that the
during lactation and post-weaning skeletal recovery. On mother may be producing milk of insufficient quantity to
the randomized trials measured only the achieved 25OHD boosted by the lactose content of milk, which increases
level as the outcome of interest (13, 60, 402, 780, 788, 965). passive, paracellular absorption of calcium (479, 480).
Therefore, a 25OHD level of 100 nM is far above the value
Milk normally contains little vitamin D or 25OHD, at which intestinal calcium absorption maximizes, and is
30 40 IU/liter in total, while calcitriol is usually very low unlikely to confer any additional benefit on intestinal cal-
to undetectable (400, 410, 515, 545, 587, 748, 872, 939). cium absorption or bone metabolism in the neonate or in-
Consequently, maternal 25OHD should not decline signif- fant.
icantly as a consequence of milk production, and this has
been confirmed by multiple studies (156, 157, 165167, Moreover, in areas where severe vitamin D deficiency rick-
470, 505, 558, 764, 805, 862, 871). Moreover, this means ets is endemic, it has been effectively treated with breast
that breast milk is normally not a good source of vitamin D milk as the only form of nutrition in mothers who received
for the neonate or infant. These facts are often disbelieved 150,000 IU vitamin D every 3 mo, or 1,800 IU/day (902,
because marketed milk and other dairy products in the 903). These babies and their mothers were protected from
United States and Canada contain 10 times the concen- sun exposure and had negligible vitamin D in the diet, so a
tration of vitamin D, i.e., 400 IU/liter or 100 IU/standard maternal supplement was the main source. Starting
783), which likely contributes to maternal hypocalcemia needs. Since milk normally contains little vitamin D or
and low breast milk calcium content. 25OHD, a theoretical benefit of high-dose vitamin D sup-
plementation is that all of a babys nutrition could then
The effect of vitamin D deficiency or insufficiency has not come from breast milk, rather than requiring that breast-fed
been explicitly examined during the recovery phase from babies alone be stigmatized to receive vitamin D supple-
lactation. This is when calcitriol may be especially impor- ments. Further study is needed of the effectiveness, safety,
tant to ensure adequate delivery of mineral to the rebuilding and adherence to this route of delivery compared with giv-
skeleton. One study suggested that the FokI polymorphism ing vitamin D supplements directly to the baby. The high
in Chinese women interacted with calcium intake to deter- doses used in some of these studies are not needed if the
mine the magnitude of BMD increase 1 yr after lactation neonatal goal is a 25OHD level of only 50 nM, as the
ended or menses resumed, but the study was too small (40 Institute of Medicine and pediatric societies have suggested
subjects) to make generalizations to larger populations and (430).
other ethnicities, or to know if it confirms an effect of cal-
citriol to directly or indirectly regulate skeletal recovery. H. Calcitonin Deficiency
The animal data indicate that resorption of bone and milk These results were refuted by a later study that used a larger
calcium content may be unaffected by extremes of vitamin sample size of rats, and confirmed that serum thyroxin and
D physiology, including absence of VDR, calcitriol, and calcium were no different between thyroidectomized and
vitamin D. Post-weaning recovery of bone mass also occurs sham-operated rats during lactation. Both groups resorbed
despite absence of VDR, calcitriol, and vitamin D, although bone, but there was no difference between them in femoral
data from vitamin D-deficient rats are inconsistent. ash weight or calcium content at the end of lactation (392).
Clinical data are largely similar, suggesting that maternal Similar experiments were carried out in lactating, thyroid-
vitamin D stores are not adversely impacted by lactation, ectomized, thyroxin-replaced goats but without confirma-
that milk calcium content is unaffected by extremes of se- tion of thyroid or parathyroid status. The thyroidectomized
vere vitamin D deficiency and excess, and that lactational goats lost 9% more ash weight and calcium from metatar-
bone loss is likely also unaffected. Given the prevalence of sals and metacarpals compared with sham-operated ani-
insufficient to low levels of 25OHD in the normal popula- mals (55). The sample size was quite small, consisting of
tion, the epidemiological studies also suggest that post- only five thyroidectomized and four intact goats.
weaning recovery of bone mass is also likely not impaired.
Overall, there is no clear evidence that the requirement for None of these studies in rats or goats examined the trabec-
vitamin D increases during lactation to meet maternal ular bone of the spine, which is the site that loses the most
mineral during lactation. Moreover, extrathyroidal sources sorption during lactation, but it remains to be determined
of calcitonin synthesis were not appreciated when these how much of calcitonins actions are at the level of oste-
models were created; lactating mammary tissue is a potent oclasts, mammary epithelial cells, and pituitary lactotrophs
source of calcitonin, and there is additional expression in (994). Moreover, the model is confounded by loss of
the pituitary. CGRP-, which may contribute to the phenotype of altered
mineral and skeletal homeostasis. A mouse model in which
The postulated physiological role of calcitonin to protect CGRP- only was deleted, apparently leaving calcitonin
the maternal skeleton during lactation was reexamined in expression intact, resulted in osteopenia and reduced bone
Ctcgrp null mice, which lack calcitonin and calcitonin gene- formation (801). These mice have not been studied during
related peptide-, but retain calcitonin gene-related pep- lactation. A mouse model with selective deletion of calci-
tide- (394). This global calcitonin deficiency resulted in tonin has not been created. It would be especially informa-
lactating Ctcgrp null mice losing double the BMC as their tive to selectively delete calcitonin from mammary epithe-
WT sisters from whole body, lumbar spine, and hindlimb, lial cells at the onset of lactation.
with the losses reaching 55% of lumbar spine BMC (994).
Treatment with calcitonin through 3 wk of lactation pre- Calcitonin acts on the calcitonin receptor, which is ex-
Ctcgrp nulls leads to effects that loss of CTR cannot repro- since the skeleton recovers fully from these extreme losses of
duce. Since the breast appears to be a key controller of the bone. Conditional deletion of CTR did not fully reproduce
skeletal response to lactation, as explained in section IVF, if the effects of loss of calcitonin and CGRP-. No human
CTR is not ablated in mammary tissue or if calcitonins studies have tested whether calcitonin deficiency causes ex-
actions within mammary tissue are not mediated by CTR, cess bone loss during lactation, but it may contribute to
then that could explain the more modest phenotype of the some of the extreme cases of lactational bone loss and frac-
conditional Ctr knockout during lactation. tures that have been reported in the literature.
calcium excretion. These data from randomized clinical tri- idea that skeletal resorption is responsible for the increase in
als and cohort studies indicate that it does not matter how serum phosphorus that normally occurs during lactation.
much calcium is consumed during lactation because mater- However, despite normalization of serum phosphorus, the
nal skeletal resorption is hormonally programmed to sup- phosphorus content in expressed milk was 50% of normal
ply needed calcium. There is no evidence that women re- in two cases, whereas the calcium content was modestly
quire a higher intake of calcium during lactation compared reduced in one but normal in the other (447, 745). Oral
with nonpregnant women. phosphorus supplementation normalized the milk compo-
sition (447). In both cases, the babies inherited XLH and
No studies have examined calcium requirements during subsequently became hypophosphatemic with skeletal evi-
post-weaning, which may be the more critical time for ad- dence of rickets, which was likely due to the combined
equate calcium intake. However, a study of adolescents effects of the mutation and the low phosphorus content of
recovering from lactation found that there was a substantial milk (447, 745). This contrasts with apparently normal
increment in bone mass despite a habitual intake of 500 milk phosphorus content in the mouse model.
mg calcium/day (78). Randomization to a 1 g calcium sup-
plement conferred a small benefit in bone mass gain during There are no data from lactating women with hyperphos-
search & Development Corporation of Newfoundland and 19. Allen JC. Effect of vitamin D deficiency on mouse mammary gland and milk. J Nutr
114: 42 49, 1984.
Labrador Grant 5404.1145.102.
20. Allen JC, Keller RP, Archer P, Neville MC. Studies in human lactation: milk compo-
sition and daily secretion rates of macronutrients in the first year of lactation. Am J
DISCLOSURES Clin Nutr 54: 69 80, 1991.
21. Allen WM, Sansom BF. Parturient paresis (milk fever) and hypocalcemia (cows,
No conflicts of interest, financial or otherwise, are declared ewes, and goats). In: Current Veterinary Therapy: Food Animal Practice 2, edited by
by the author. Howard JL. Philadelphia, PA: Saunders, 1986, p. 311320.
22. Alles N, Soysa NS, Hayashi J, Khan M, Shimoda A, Shimokawa H, Ritzeler O, Akiyoshi
K, Aoki K, Ohya K. Suppression of NF-kappaB increases bone formation and ame-
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