Calcium and Bone Metabolism During Pregnancy and Lactation

Journal of Mammary Gland Biology and Neoplasia, Vol. 10, No. 2, April 2005 ( C© 2005)DOI: 10.1007/s10911-005-5394-0

Calcium and Bone Metabolism DuringPregnancy and Lactation

Christopher S. Kovacs1

Pregnancy and lactation both place significant demands on the mother to provide sufficientcalcium (among other minerals and nutrients) to the fetus and neonate. Despite facing similardemands for calcium during pregnancy and lactation, the maternal adaptations differ signif-icantly between these two reproductive periods. Women lose 300 to 400 mg of calcium dailythrough breast milk, and this calcium demand is met by a 5–10% loss of skeletal mineral con-tent during 6 months of exclusive lactation. Most importantly, the lost mineral is fully restoredwithin a few months of weaning, such that women who have breastfed do not have a long-term deficit in skeletal mineral content. This article will review our present understanding ofthe adaptations in mineral metabolism that occur during pregnancy and lactation, and will fo-cus on recent evidence that the breast itself plays a central role in regulating the adaptationsduring lactation.

KEY WORDS: pregnancy; lactation; calcium metabolism; bone metabolism; osteoporosis.

Mineral metabolism in the mother must adapt tothe demand created by the fetus and placenta, whichtogether draw calcium and other minerals from themother in order to mineralize the developing fetalskeleton. Similarly, mineral metabolism must adaptin the lactating woman in order to supply sufficientcalcium to the milk. Potential adaptations includeincreased intake of mineral, increased efficiencyof intestinal absorption of mineral, mobilizationof mineral from the skeleton, and increased renalconservation of mineral. Despite a similar mag-nitude of calcium demand presented to pregnantand lactating women, the adjustments made in eachof these reproductive periods differ significantly(Fig. 1). These hormone-mediated adjustments nor-mally satisfy the needs of the fetus and infant withshort-term depletions of maternal skeletal calciumcontent, but without long-term consequences to thematernal skeleton. However, in states of maternalmalnutrition and vitamin D deficiency, the depletion

1 Faculty of Medicine - Endocrinology, Health Sciences Centre,Memorial University of Newfoundland, St. John’s, Newfound-land, A1B 3V6, Canada; e-mail: ckovacs@mun.ca.

of skeletal mineral content may be proportionatelymore severe, and may in turn be accompanied byincreased skeletal fragility.

This article will review our present understand-ing of the adaptations that occur during pregnancyand lactation, making use of animal data to fill inthe gaps where human data are unavailable. Due torestrictions on the length of the reference list, thereader is also referred to several other comprehen-sive reviews on the subject (1–3).

PREGNANCY

The developing fetal skeleton accretes about30 g of calcium by term, about 80% of it during thethird trimester. This demand for calcium is largelymet by a doubling of maternal intestinal calcium

Abbreviations used: CT, calcitonin; DPA, single photon absorp-tiometry; DXA, dual X-ray absorptiometry; FSH, follicle stim-ulating hormone; GFR, glomerular filtration rate; GnRH, go-nadotropin releasing hormone; LH, luteinizing hormone; PTH,parathyroid hormone; PTHrP, parathyroid hormone-relatedprotein; SPA, single photon absorptiometry.

1051083-3021/05/0400-0105/0 C© 2005 Springer Science+Business Media, Inc.

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Fig. 1. Schematic illustration contrasting calcium homeostasis in human preg-nancy and lactation, as compared to normal. The thickness of arrows indicates arelative increase or decrease with respect to the normal and non-pregnant state.Adapted with permission from ref. (1), c©1997 The Endocrine Society.

absorption, mediated by 1,25-dihydroxyvitamin Dand possibly other factors.

Mineral Ions and Calcitropic Hormones

Normal pregnancy results in altered levels of cal-cium and the calcitropic hormones, as schematicallydepicted in Fig. 2 (1). The ionized calcium (the phys-iologically important fraction of calcium) remainsconstant throughout pregnancy. In contrast, the to-tal serum calcium (which is the sum of the ionized,complexed and albumin-bound fractions of calciumin the circulation) falls in pregnancy due to a fallin the serum albumin. In clinical practice, the totalserum calcium is more commonly measured than theionized calcium. The commonly observed decreasein total serum calcium should not be mistaken forevidence of “physiological hyperparathyroidism ofpregnancy,” an erroneous concept that has persistedin some modern texts (4,5). The fall in total serumcalcium is an unimportant artifact of an unphysiolog-ical measurement; the ionized calcium is the relevantmeasurement and should always be assayed if there isany doubt about the true value of the serum calciumduring pregnancy (or at any time). Serum phospho-rus levels are also normal during pregnancy.

As observed by longitudinal measurementsduring pregnancy with modern 2-site immuno-radiometric assays, serum parathyroid hormone

(PTH) falls to the low-normal range (i.e., 10–30%of the mean non-pregnant value) during the firsttrimester, and then increases steadily to the mid-normal range by term (6–10). Therefore, as judged bythe serum PTH level, the parathyroids are modestlysuppressed beginning early in the first trimester, andreturn to apparently normal function by the end ofpregnancy. First-generation PTH assays in the 1970sand 80s were insensitive and measured multiple bi-ologically inactive fragments of PTH; a few studieswith these assays had detected higher levels of PTHduring pregnancy in humans. Those early studies ofPTH in pregnancy, combined with the observationthat total serum calcium falls during pregnancy, rein-forced the erroneous concept that secondary hyper-parathyroidism occurs during pregnancy. Modern as-says have made it very clear that in well-nourishedwomen, the ionized calcium is normal throughoutpregnancy, and that PTH is suppressed during earlypregnancy. In contrast, there is evidence that PTHmay increase above normal in late pregnancy inwomen from Malay who have very low intakes ofcalcium (11).

Total 1,25-dihydroxyvitamin D levels doubleearly in pregnancy and maintain this increaseuntil term; free 1,25-dihydroxyvitamin D levels areincreased from the third trimester and possibly ear-lier. The rise in 1,25-dihydroxyvitamin D may belargely independent of changes in PTH, since PTH

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Fig. 2. Schematic illustration of the longitudinal changes incalcium, phosphorus, and calcitropic hormone levels in thecirculation during pregnancy and lactation. Normal adult rangesare indicated by the shaded areas. The progression in PTHrPlevels has been depicted by a dashed line to reflect that the datais less complete; the implied comparison of PTHrP levels in latepregnancy and lactation are uncertain extrapolations because noreports followed patients serially. In both situations PTHrP levelsare elevated. Adapted with permission from ref. (1), c©1997 TheEndocrine Society.

levels are typically decreasing at the time of theincrease in 1,25-dihydroxyvitamin D. The maternalkidneys likely account for most, if not all, of therise in 1,25-dihydroxyvitamin D during pregnancy,although the decidua, placenta and fetal kidneys maycontribute a small amount. The relative contribution

of the maternal kidneys is based on several lines ofevidence [reviewed in (1)], including the report of ananephric woman on hemodialysis who had low 1,25-dihydroxyvitamin D levels before and during a preg-nancy (12). The renal 1α−hydroxylase may be up-regulated in response to factors such as PTH-relatedprotein (PTHrP), estradiol, prolactin, and placentallactogen.

Serum calcitonin levels are also increased dur-ing pregnancy, with the C-cells of the thyroid, breastand placenta possibly contributing to the circulatinglevel of calcitonin. It has been postulated that cal-citonin protects the maternal skeleton from exces-sive resorption of calcium, but this hypothesis re-mains unproved. No human studies have addressedthe question, while recent studies in genetically en-gineered mice demonstrated that absence of calci-tonin does not impair the ability of mice to increaseskeletal mineral content during pregnancy (13).

PTH-related protein (PTHrP) levels are in-creased during pregnancy, as determined by assaysthat detect PTHrP fragments encompassing aminoacids 1–86. Since PTHrP is produced by many tissuesin the fetus and mother (including the placenta,amnion, decidua, umbilical cord, fetal parathyroids,and breast), it is not clear which source(s) contributeto the rise detected in the maternal circulation.PTHrP may contribute to the elevations in 1,25-dihydroxyvitamin D and suppression of PTH thatare noted during pregnancy. PTHrP may have otherroles during pregnancy, such as regulating placentalcalcium transport in the fetus (1,14). Also, PTHrPmay have a role in protecting the maternal skeletonduring pregnancy, since the carboxyl-terminal por-tion of PTHrP (“osteostatin”) has been shown toinhibit osteoclastic bone resorption (15).

Pregnancy induces significant changes in the lev-els of other hormones, including the sex steroids, pro-lactin, placental lactogen, and IGF-1. Each of thesemay have direct or indirect effects on calcium andbone metabolism during pregnancy, but these issueshave been largely unexplored.

Intestinal Absorption of Calcium

Several clinical studies have demonstrated thatintestinal absorption of calcium is doubled duringpregnancy from as early as 12 weeks of gestation(the earliest time-point studied); this change appearsto be a major maternal adaptation to meet the fe-tal need for calcium. This increase may be largely

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the result of a 1,25-dihydroxyvitamin D-mediatedincrease in intestinal calbindin9K-D and other pro-teins; based on evidence from limited animal stud-ies, prolactin and placental lactogen (and possiblyother factors) may also mediate part of the in-crease in intestinal calcium absorption. The increasedabsorption of calcium early in pregnancy may al-low the maternal skeleton to store calcium in ad-vance of the peak fetal demands that occur later inpregnancy.

Renal Handling of Calcium

The 24-h urine calcium excretion is increased asearly as the 12th week of gestation (the earliest time-point studied), and the amounted excreted may ex-ceed the normal range. Since fasting urine calciumvalues are normal or low, the increase in 24-h urinecalcium likely reflects the increased intestinal ab-sorption of calcium (absorptive hypercalciuria). Theelevated calcitonin levels of pregnancy might alsopromote renal calcium excretion.

Skeletal Calcium Metabolism

Animal models indicate that histomorphomet-ric parameters of bone turnover are increased duringpregnancy, which could be interpreted to mean thatmineral is mobilized from the maternal skeleton tocontribute to the fetal skeleton (16). However, serialmeasurements of bone mineral density by dual X-rayabsorptiometry (DXA) in several strains of normalmice have demonstrated that the bone mineral con-tent increases by 5–10% during pregnancy (13,17),and thus the increased bone turnover of pregnancymight (at least in rodents) reflect an anabolic or boneformative state, as opposed to a net bone resorptivestate. As noted below in the lactation section, a netloss of bone mineral content occurs during lactationin humans and rodents. An increase in bone mineralcontent during pregnancy might serve to protect thematernal skeleton against excessive demineralizationand fragility during lactation.

Comparable histomorphometric data are notavailable for human pregnancy. In one study (18),15 women who electively terminated a pregnancyin the 1st trimester (8–10 weeks) had bone biopsyevidence of increased bone resorption, includingincreased resorption surface, increased numbers ofresorption cavities, and decreased osteoid. Thesefindings were not present in biopsies obtained

from non-pregnant controls, or in biopsies ob-tained at term from 13 women who had electiveC-sections.

Most human studies of skeletal calciummetabolism in pregnancy have examined changes in“bone markers,” that is, serum indices that reflectbone formation, and serum or urine indices thatreflect bone resorption. These studies have beenfraught with a number of confounding variablesthat cloud the interpretation of the results, includ-ing lack of pre-pregnancy baseline values; effectsof hemodilution in pregnancy on serum markers;increased glomerular filtration rate (GFR) and renalclearance; altered creatinine excretion; placental,uterine and fetal contribution to the markers; degra-dation and clearance by the placenta; and lack ofdiurnally timed or fasted specimens. Given theselimitations, many studies have reported that urinarymarkers of bone resorption (24-h collection) areincreased from early to mid-pregnancy (including de-oxypyridinoline, pyridinoline, and hydroxyproline).Conversely, serum markers of bone formation (gen-erally not corrected for hemodilution or increasedGFR) are often decreased from pre-pregnancy ornon-pregnant values in early or mid-pregnancy,rising to normal or above before term (includingosteocalcin, procollagen I carboxypeptides and bonespecific alkaline phosphatase). It is conceivablethat the bone formation markers are artifactuallylowered by normal hemodilution and increased renalclearance of pregnancy, obscuring any real increasein the level of the markers. One study adjustedfor the confounding effects of hemodilution andaltered GFR, and demonstrated that osteocalcinproduction was not reduced in pregnancy (19). Totalalkaline phosphatase rises early in pregnancy duelargely to contributions from the placental fraction;it is not a useful marker of bone formation inpregnancy.

Based on the scant bone biopsy data, andthe measurements of bone markers (with afore-mentioned confounding factors), one may cau-tiously conclude that bone turnover is increasedin human pregnancy, from as early as the 10 thweek of gestation. There is comparatively littlematernal-fetal calcium transfer occurring at thisstage of pregnancy, as compared to the peakrate of calcium transfer in the third trimester.One might have anticipated that markers of boneturnover would increase particularly in the thirdtrimester; however, no further increase is seen at thattime.

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Changes in skeletal calcium content during preg-nancy would ideally be assessed by sequential bonedensity measurements in each woman; however, dueto concerns about fetal radiation exposure, few suchstudies have been done. Those studies used the oldertechniques of single photon absorptiometry (SPA)of the wrist and dual-photon absorptiometry (DPA)of the spine and hip, with abdominal shielding inplace to protect the fetus. Such studies were con-founded by changes in body composition and weightduring normal pregnancy that can lead to artifac-tual changes in bone density. Using these outdatedtechniques (SPA/DPA), no significant change wasobserved in cortical or trabecular bone density dur-ing pregnancy (1). No studies have used the moderntechnique of DXA sequentially during pregnancy.Instead, numerous recent studies have utilized DXAbefore conception (range 1–8 months prior, but notalways stated) and after delivery (range 1–6 weekspostpartum) (19–25). Most studies involved 16 orfewer subjects. One study found no change in lum-bar spine bone density measurements obtained pre-conception and within 1–2 weeks post-delivery (21),whereas the other studies reported decreases of 4–5% in lumbar spine bone density with the postpar-tum measurement taken between 1–6 weeks post-delivery. The puerperium is associated with bonedensity losses of 1–3% per month in women wholactate (see lactation section, below), and thus itis important that the postpartum measurement bedone as soon as possible after delivery. Finally, ul-trasound measurements of the os calcis have beenperformed in longitudinal studies during pregnancy,and such studies have shown a progressive decreasein indices thought to correlate with bone mineraldensity (26). Thus, although the longitudinal stud-ies with SPA/DPA suggested no change in trabec-ular or cortical bone density during pregnancy, thesubsequent evidence from pre-conception and post-delivery DXA measurements and sequential periph-eral ultrasound measurements suggest that there maybe a small net loss of maternal bone mineral contentduring normal human pregnancy. None of the afore-mentioned studies can address the question whetherskeletal calcium content is increased early in preg-nancy in advance of the third trimester, as has beenobserved in normal mice. Further studies, with largernumbers of patients, will be needed to clarify the ex-tent of bone loss during pregnancy.

It seems certain that any acute changes in bonemetabolism during pregnancy do not normally causelong-term changes in skeletal calcium content or

strength. Numerous studies of osteoporotic or os-teopenic women have failed to find a significant as-sociation of parity with bone density or fracture risk(1,27). Although many of these studies could not sep-arate out the effects of parity from those of lactation,it may be reasonable to conclude that if parity has anyeffect on bone density or fracture risk, it must be onlya very modest effect. A more recent study of twinsindicated that there may be a small protective effectof parity and lactation on maintaining bone mineralcontent (28).

Osteoporosis in Pregnancy

Occasionally, women experience fragility frac-tures and are noted to have low bone mineral densityduring or shortly after pregnancy. Most will not havehad a prior bone mineral density measurement, andthus the possibility that low bone density was presentprior to pregnancy cannot be excluded. It is conceiv-able that the weight of the gravid uterus may precip-itate vertebral compression fractures in women withlow bone density. Some women may experience ex-cessive resorption of calcium from the skeleton dueto changes in mineral metabolism induced by preg-nancy, or due to other factors such as low dietarycalcium intake and vitamin D insufficiency. Further-more, the apparently increased rate of bone turnoverin pregnancy may contribute to fracture risk, be-cause a high rate of bone turnover is an indepen-dent risk factor for fragility fractures outside of preg-nancy. Therefore, fragility fractures in pregnancyor the puerperium may be a consequence of pre-existing low bone density, loss of bone mineral con-tent during pregnancy, and increased bone turnover,among other possible factors. Additional changesin mineral metabolism occur during lactation whichmay further increase fracture risk in some women(see below).

Focal, transient osteoporosis of the hip is a rare,self-limited form of pregnancy-associated osteoporo-sis. It is not a manifestation of altered calcitropichormone levels or mineral balance during pregnancy,but rather might be a consequence of local factors. Itis included herein for the sake of completeness andto emphasize that it is not, as its name implies, a dis-order of mineral metabolism. The theories proposedto explain the condition include femoral venousstasis due to the gravid uterus, reflex sympatheticdystrophy, ischemia, trauma, viral infections, mar-row hypertrophy, immobilization, and fetal pressureon the obturator nerve. These patients present with

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unilateral or bilateral hip pain, limp and/or hipfracture in the third trimester. There is objectiveevidence of reduced bone density of the symptomaticfemoral head and neck which has been shown byMRI to be the consequence of increased watercontent of the femoral head and the marrow cavity;a joint effusion may also be present. The symptomsand the radiological appearance usually resolvewithin 2–6 months post-partum.

Primary Hyperparathyroidism

Although probably a rare condition (there areno data available on its prevalence), primary hyper-parathyroidism in pregnancy has been associated inthe literature with an alarming rate of adverse out-comes in the fetus and neonate, including a 30%rate of spontaneous abortion or stillbirth, a 50%rate of tetany, and a 25% rate of neonatal death(1). The adverse postnatal outcomes are thought toresult from suppression of the fetal and neonatalparathyroid glands; this suppression may occasion-ally be prolonged after birth for months. MaternalPTH does not cross the placenta; the suppression offetal parathyroids may be a consequence of increasedflux of calcium across the placenta to the fetus, aidedby the maternal hypercalcemia. To prevent these ad-verse outcomes, surgical correction of primary hyper-parathyroidism during the second trimester has beenalmost universally recommended (29). Several caseseries have found elective surgery to be well toler-ated, and to dramatically reduce the rate of adverseevents when compared to the earlier cases reportedin the literature. However, many of the women inthose early cases had a relatively severe form of pri-mary hyperparathyroidism that is not often seen to-day (symptomatic, with nephrocalcinosis and renalinsufficiency). Recent case reports suggest that themilder, asymptomatic form of primary hyperparathy-roidism commonly seen today may have similar risksof adverse maternal, fetal or neonatal outcomes; con-sequently, parathyroidectomy continues to be man-dated during pregnancy whenever the condition isidentified (30–33).

Familial Hypocalciuric Hypercalcemia

Although familial hypocalciuric hypercalcemia(FHH) has not been reported to adversely affectthe mother during pregnancy, the maternal hypercal-cemia can cause fetal and neonatal parathyroid sup-pression with subsequent tetany (34).

Hypoparathyroidism andPseudohypoparathyroidism

During pregnancy, hypoparathyroid womenhave been found to have a rise in serum calcium,fewer hypocalcemic symptoms, and to require lesssupplemental calcium (1). This is consistent with alimited role for PTH in the pregnant woman, andsuggests that an increase in 1,25-dihydroxyvitamin Dand/or increased intestinal calcium absorption willoccur in the absence of PTH. However, it is clearfrom other case reports (1) that some pregnant hy-poparathyroid women required increased calcitriolreplacement in order to avoid worsening hypocal-cemia. In some reports, it was not clear whether theartifact of low total serum calcium was being treated,as opposed to a physiologically relevant (and symp-tomatic) low ionized calcium. It is clearly importantto maintain a normal ionized calcium level in preg-nant women, since maternal hypocalcemia has beenassociated with the development of intrauterine fetalhyperparathyroidism and fetal death. Late in preg-nancy, hypercalcemia may occur in hypoparathyroidwomen unless the calcitriol dosage is substantially re-duced or discontinued. This effect appears to be me-diated by increasing levels of PTHrP in the maternalcirculation in late pregnancy, an effect that becomesmore pronounced during lactation (see below).

In limited case reports of pseudohypoparathy-roidism (an inherited condition manifest by resis-tance to PTH), pregnancy has been noted to normal-ize the serum calcium level, reduce the PTH level byhalf, and increase the 1,25-dihydroxyvitamin D level2- to 3-fold (35). The presence of PTHrP cannot ex-plain the improvements because such patients are re-sistant to the actions of both PTH and PTHrP. Themechanism by which pseudohypoparathyroidism isimproved in pregnancy remains unclear, but it maybe a post-receptor effect.

Vitamin D Deficiency

Vitamin D insufficiency and deficiency have notbeen sufficiently studied in humans to understandwhat levels of supplementation are necessary or ideal(36), but adequate vitamin D supplementation of themother should be maintained throughout pregnancy.The evidence cited above has established how in-testinal calcium absorption is normally doubled dur-ing pregnancy to meet the fetal demand for min-eral and maintain maternal calcium homeostasis; inthe absence of that vitamin D-dependent effect on

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intestinal calcium transfer, one can anticipate thatthe mother would have difficulty maintaining themineral supply without compromising her skeletonand perhaps the fetus as well. However, there is apaucity of clinical data on the effects of pregnancyon mineral metabolism in women who are vitaminD deficient. Clearly chronic maternal hypocalcemiaof any cause is potentially detrimental to human fe-tuses. Evidence from animal models of vitamin D de-ficiency and absence of the vitamin D receptor in-dicates that the mothers have impaired fertility andsmaller gestational litter sizes; the fetuses are alsosmaller but have normal serum calcium and fullymineralized skeletons (37–40). The animal modelsindicate that the mother may suffer the brunt ofthe effects of severe hypocalcemia in late pregnancy,including tetany, seizures, cardiac arrhythmias, anddeath (37,41). In both humans and in animals, vita-min D deficiency and absence of the vitamin D recep-tor can lead to very profound effects in the neonate,including rickets and craniotabes (see below onLactation).

Low Calcium Intake

Intuitively, limited maternal intake of calciumand other minerals may adversely affect fetal skele-tal development, or perhaps lead to severe lossesof maternal bone mineral content during pregnancy.Most of the studies cited in this review have in-volved women who were well nourished, and whomay also have been taking a calcium supplement dur-ing pregnancy. Limited information is available fromwomen who customarily had low (<300 mg/day) di-etary intakes of calcium, with discrepant results as towhether or not calcium supplementation altered thematernal bone density response during pregnancy,or the neonatal bone density at birth (3). More re-cently, a short crossover trial of 1.2 g calcium sup-plementation daily (10 days on supplement, 10 dayson placebo) in Mexican women during pregnancydemonstrated that a bone resorption marker wassuppressed in the third trimester by the addition ofa calcium supplement. Thus, there is at least short-term evidence that bone turnover in the mother canbe suppressed by supplemental calcium intake. Also,a double-blind study of 2 g calcium supplementationduring pregnancy in 256 women demonstrated thatthe neonatal bone mineral content was improved inthe infants of calcium-supplemented mothers whowere in the lowest quintile of calcium intake versus

the infants of mothers in the same quintile that tooka placebo (42). There was no benefit of calcium sup-plementation to infants whose mothers were in thehigher quintiles of dietary calcium intake. Thus, thereis limited evidence that low calcium intake might ad-versely affect fetal development, and it remains espe-cially prudent to recommend calcium supplementa-tion during pregnancy to women known to have lowdietary intake of calcium.

LACTATION

About 280 to 400 mg of calcium is lost throughbreast milk daily, with losses as great as 1000 mgcalcium or more in women who are nursing twins.A temporary demineralization of the skeleton ap-pears to be the main mechanism by which lactat-ing humans meet these calcium requirements. Thisdemineralization does not appear to be mediated byPTH or 1,25-dihydroxyvitamin D. Instead, it is medi-ated by PTHrP released from the breast tissue, com-bined with the effects of low estrogen levels on boneturnover.

Mineral Ions and Calcitropic Hormones

The normal lactational changes in maternal cal-cium, phosphorus, and calcitropic hormone levels areschematically depicted in Fig. 2 (1). The mean ion-ized calcium level of exclusively lactating womenis increased, although it remains within the normalrange. Serum phosphorus levels are also higher dur-ing lactation, and the level may exceed the normalrange. The serum phosphorus is likely increased dueto accelerated skeletal resorption combined with re-duced renal phosphorus excretion.

Intact PTH, as determined by a 2-site IRMAassay, has been found to be reduced 50% or morein lactating women during the first several months.It rises to normal at weaning, but may rise abovenormal post-weaning. In contrast to the high 1,25-dihydroxyvitamin D levels of pregnancy, maternalfree and bound 1,25-dihydroxyvitamin D levels fallto normal within days of parturition and remain therethroughout lactation.

PTHrP levels are significantly higher in lactatingwomen and mice than in non-lactating controls, asmeasured by 2-site IRMA assays. The source ofPTHrP appears be the breast or mammary tissue,since PTHrP has been detected in milk at concentra-tions exceeding 10,000 times the level found in the

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blood of patients with hypercalcemia of malignancyor normal human controls. A small rise in thematernal level of PTHrP can be demonstrated aftersuckling (43). Furthermore, blood levels of PTHrPare reduced in lactating mice that had the PTHrPgene ablated only from breast tissue, as compared tonormal lactating mice (44). PTHrP appears to playseveral roles within the breast, as indicated by studiesin animals that suggest that PTHrP may regulatemammary development and blood flow. The calciumreceptor is expressed in mammary tissue during lac-tation, where it regulates PTHrP production as wellas the calcium and water content of the milk (Fig. 3)(45). It is also expressed in the developing and virginmammary tissue, but not in mammary tissue duringpregnancy.

It has become clear that PTHrP plays a key roleduring lactation in regulating the demineralizationof the skeleton. In response to suckling (43) and sig-

Fig. 3. The role of the calcium receptor in the breast. The calciumreceptor (represented schematically) is expressed in the breastduring lactation, wherein it has several key functions as elucidatedfrom recent studies in mice (45). The calcium receptor monitorsthe systemic concentration of calcium to control PTHrP synthe-sis and, thereby, the supply of calcium to the breast. An increasein systemic calcium or administration of a calcimimetic inhibitedPTHrP expression, whereas a decrease in systemic calcium stim-ulated PTHrP expression. The calcium receptor also directly reg-ulates the calcium and fluid composition of milk. Administrationof calcium or a calcimimetic stimulated the transport of calciuminto the breast, and the administration of a calcimimetic also en-hanced the entry of water into the milk, thereby making it lessviscous.

naling from the calcium sensing receptor expressedby lactating mammary tissue (Fig. 3) (45), PTHrPreaches the maternal circulation from mammarytissue and stimulates resorption of calcium fromthe maternal skeleton, renal tubular reabsorptionof calcium, and (indirectly) suppression of PTH(Fig. 4). In a sense, the breast becomes an accessoryparathyroid gland during lactation, but the “hyper-parathyroidism” of lactation is increased secretionof PTHrP and not PTH. The strongest evidence insupport of this model comes from the study of micein which the PTHrP gene was ablated at the onsetof lactation but only within mammary tissue (44).The lactational decrease in bone mineral contentwas significantly blunted in the absence of mammarygland production of PTHrP. Other evidence forthe central role of PTHrP in lactation comes fromhumans, in that PTHrP levels correlate negativelywith PTH levels and positively with the ionizedcalcium levels of lactating women (43,46), and thathigher PTHrP levels correlate with greater lossesof bone mineral density during lactation in humans(47). Furthermore, observations in aparathyroidwomen provide evidence of the impact of PTHrP incalcium homeostasis during lactation (see below).

Calcitonin levels are elevated in the first 6 weeksof lactation. Recent studies in mice lacking the genethat encodes calcitonin indicate that calcitonin maymodulate the rate of skeletal resorption duringlactation. Calcitonin-null mice lost more than 50% ofskeletal mineral content during 3 weeks of lactation,approximately twice that of normal littermate sisters(13). The calcitonin-depleted mice still regained allof the lost mineral content after weaning, whichindicates that although calcitonin is needed in theshort-term to prevent severe losses of mineral con-tent and potential skeletal fragility, calcitonin is notrequired in the long-term because the skeletal lossesof mineral are restored anyway.

Intestinal Absorption of Calcium

Intestinal calcium absorption decreases tothe non-pregnant rate from the increased rate ofpregnancy. This corresponds to the fall in 1,25-dihydroxyvitamin D levels to normal.

Renal Handling of Calcium

In humans, the GFR falls during lactation, andthe renal excretion of calcium is typically reduced to

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Fig. 4. The role of the breast in controlling skeletal demineralization duringlactation. Suckling induces release of prolactin. Suckling and prolactin bothinhibit the hypothalamic GnRH pulse center, which in turn suppresses thegonadotropins (LH, FSH), leading to low levels of the ovarian sex steroids(estradiol and progesterone). PTHrP production and release from the breastis controlled by several factors, including suckling, prolactin, and the calciumreceptor. PTHrP enters the bloodstream and combines with systemically lowestradiol levels to markedly upregulate bone resorption. Increased bone re-sorption releases calcium and phosphate into the blood stream, which thenreaches the breast ducts and is actively pumped into the breast milk. PTHrPalso passes into the milk at high concentrations, but whether PTHrP plays arole in regulating calcium physiology of the neonate is unknown. Calcitonin(CT) modulates the skeletal responsiveness, as demonstrated by a doublingof mineral losses from the skeleton in mice that lack the gene that encodescalcitonin.

very low levels. This observation suggests that thetubular reabsorption of calcium must be increased inorder to account for reduced calcium excretion in thesetting of increased serum calcium.

Skeletal Calcium Metabolism

Histomorphometric data from animals con-sistently show increased bone turnover duringlactation, and losses of 30% of bone mineral areachieved during 2–3 weeks of normal lactation inthe rat [reviewed in (1)] while a similar amount islost in the lactating mouse within 21 days (17). Theloss is greatest in trabecular bone of rats and mice.

Comparative histomorphometric data are lacking forhumans, and in place of that, serum markers of boneformation, and urinary markers of bone resorptionhave been assessed in numerous cross-sectional andprospective studies of lactation. Some of the con-founding factors discussed with respect to pregnancyapply to the use of these markers in lactating women.During lactation, GFR is reduced and the intravas-cular volume is more contracted. Urinary markersof bone resorption (24-h collection) have beenreported to be elevated 2–3 fold during lactationand to be higher than the levels attained in the thirdtrimester. Serum markers of bone formation (notadjusted for hemoconcentration or reduced GFR)are generally high during lactation, and increased

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over the levels attained during the third trimester.Total alkaline phosphatase falls immediately post-partum due to loss of the placental fraction, but maystill remain above normal due to the elevation inthe bone-specific fraction. Despite the confoundingvariables, these findings suggest that bone turnoveris significantly increased during lactation.

In women, serial measurements of bone densityduring lactation (by SPA, DPA or DXA) have showna fall of 3 to 10.0% in bone mineral content aftertwo to 6 months of lactation at trabecular sites (lum-bar spine, hip, femur and distal radius), with smallerlosses at cortical sites (1,27). The peak rate of loss is1–3% per month, far exceeding the rate of 1–3% peryear that can occur in women with postmenopausalosteoporosis who are considered to be losing bonerapidly. Loss of bone mineral from the maternalskeleton appears to be a normal consequence of lac-tation and may not be preventable by raising thecalcium intake above the recommended dietary al-lowance. Several recent studies have demonstratedthat calcium supplementation does not significantlyreduce the amount of bone lost during lactation (48–51). The lactational decrease in bone mineral den-sity correlates with the amount of calcium lost in thebreast milk (52).

The mechanisms controlling the rapid loss ofskeletal calcium content are not well understood.The reduced estrogen levels of lactation are clearlyimportant, but are unlikely to be the sole expla-

nation. To estimate the effects of estrogen defi-ciency during lactation, it is worth noting the al-terations in calcium and bone metabolism that oc-cur in reproductive-age women who have estrogendeficiency induced by GnRH agonist therapy forendometriosis and other conditions. Six months ofacute estrogen deficiency induced by GnRH agonisttherapy leads to 1–4% losses in trabecular (but notcortical) bone density, increased urinary calcium ex-cretion and suppression of 1,25-dihydroxyvitamin Dand PTH levels (1). During lactation, women are notas estrogen deficient but lose more bone mineral den-sity (at both trabecular and cortical sites), have nor-mal (as opposed to low) 1,25-dihydroxyvitamin Dlevels, and have reduced (as opposed to increased)urinary calcium excretion. The difference betweenisolated estrogen deficiency and lactation may be dueto the effects of other factors (such as PTHrP) thatadd to the effects of estrogen withdrawal in lactation(Fig. 5). The relative influences of estrogen deficiencyand PTHrP have been partly determined in normalmice, in which it has been demonstrated that treat-ment with pharmacological doses of estrogen bluntedbut did not abolish the normal demineralization thatoccurs during lactation (53).

The bone density losses of lactation are substan-tially reversed during weaning at a rate of 0.5 to 2%per month (1,27,50). The mechanism for this restora-tion of bone density is uncertain and largely unex-plored; there is preliminary evidence from animal

Fig. 5. The roles of estrogen deficiency and PTHrP. Acute estrogen deficiency (e.g., GnRH analog therapy) increases skeletal resorptionand raises the blood calcium; in turn, PTH is suppressed and renal calcium losses are increased. During lactation, the combined effectsof PTHrP (secreted by the breast) and estrogen deficiency increase skeletal resorption, reduce renal calcium losses, and raise the bloodcalcium, but calcium is directed into breast milk. Reprinted with permission from ref. (1), c©1997 The Endocrine Society.

Calcium and Bone Metabolism During Pregnancy and Lactation 115

models to suggest that PTH, 1,25-dihydroxyvitaminD, calcitonin, and estrogen may not be requiredfor the regain to be achieved. In the long-term,the consequences of lactation-induced depletion ofbone mineral appear clinically unimportant. The vastmajority of epidemiologic studies of pre- and post-menopausal women have found no adverse effect ofa history of lactation on peak bone mass, bone den-sity, or hip fracture risk.

Osteoporosis of Lactation

Rarely, a woman will suffer a fragility fractureduring lactation, and osteoporotic readings will beconfirmed by DXA. Like osteoporosis in pregnancy,this may represent a coincidental, unrelated disease;the woman may have had low bone density prior toconception. Alternatively, some cases might repre-sent an exacerbation of the normal degree of skeletaldemineralization that occurs during lactation. Forexample, excessive PTHrP release from the lactatingbreast into the maternal circulation might cause ex-cessive bone resorption, osteoporosis, and fractures.PTHrP levels were high in one case of lactationalosteoporosis, and were found to remain elevated formonths after weaning (54). Some cases of lactationalosteoporosis might represent the human equivalentof calcitonin deficiency, based on the evidence fromthe murine model that absence of calcitonin exacer-bates the normal losses of mineral during lactation.Future cases of lactational osteoporosis should bemore extensively assessed to determine whetherPTHrP excess or calcitonin deficiency are to blame.

Hypoparathyroidism andPseudohypoparathyroidism

Calcitriol requirements of hypoparathyroidwomen fall early in the postpartum period, especiallyif a woman breastfeeds, and hypercalcemia mayoccur if the calcitriol dosage is not substantiallyreduced (55). As observed in one seminal case, thisis consistent with PTHrP reaching the maternal cir-culation in amounts sufficient to allow stimulation of1,25-dihydroxyvitamin D synthesis, and maintenanceof normal (or slightly increased) maternal serumcalcium (56).

The effect of lactation on pseudohypoparathy-roidism has been less well documented. Sincethese patients are likely resistant to the renal ac-tions of PTHrP, and the placental sources of 1,25-

dihydroxyvitamin D are lost at parturition, thecalcitriol requirements might well increase and mayrequire further adjustments during lactation.

Vitamin D Deficiency

Skeletal demineralization occurs during lacta-tion due to PTHrP-stimulated bone resorption andthe low estradiol levels, and it appears that vitamin Dsufficiency may not be required to maintain lactation.Even in women with very low calcium intakes, thesame amount of mineral was lost from the skeletonas compared to women who had supplementedcalcium intakes, and the breast milk calcium contentwas unaffected by calcium intake or vitamin D status(57–59). Conversely, since high calcium intakes donot affect the degree of skeletal demineralizationthat occurs during lactation (48–51), it is unlikelythat increasing vitamin D supplementation abovenormal would affect skeletal demineralization either.Whether vitamin D deficiency affects the abilityto restore the skeleton after weaning has not beenexamined.

It remains prudent to advise vitamin D supple-mentation for the mother during lactation for herown long-term skeletal health. Supplementation ofthe mother will indirectly lead to higher levels ofvitamin D in the nursing infant, although higherdoses than normal are required due to the low pen-etrance of vitamin D into breast milk (36). Con-sequently, breast fed babies of vitamin D deficientmothers should directly receive vitamin D supple-ments to avoid nutritional rickets. Evidence fromanimal models suggests that lactation can provoketetany and sudden death in mothers that are vitaminD deficient, perhaps because the lactational drain ofmineral overwhelms the mother’s ability to maintaina normal ionized calcium level. However, such ex-treme outcomes have not been reported for vitaminD deficient women who lactate.

IMPLICATIONS

The studies of pregnant women suggest that thefetal calcium demand is met in large part by intesti-nal calcium absorption, which more than doublesfrom early in pregnancy. The studies of biochemicalmarkers of bone turnover, DXA and ultrasoundare not conclusive, but are compatible with thepossibility that the maternal skeleton contributescalcium to the developing fetus. In comparison,

116 Kovacs

the studies in lactating women suggest that skeletalcalcium resorption is a dominant mechanism bywhich calcium is supplied to the breast milk, whilerenal calcium conservation is also apparent. Theseobservations indicate that the maternal adaptationsto pregnancy and lactation have evolved differentlyover time, such that dietary calcium absorptiondominates in pregnancy, whereas the temporaryborrowing of calcium from the skeleton dominatesduring lactation. Lactation programs an obligatoryskeletal calcium loss irrespective of maternal calciumintake, but the calcium is completely restored to theskeleton after weaning. The rapidity of calcium lossand regain by the skeleton of the lactating womanare through mechanisms that are at best, only partlyunderstood. A full elucidation of the mechanismsof bone loss and restoration in the lactating womanmight lead to the development of novel approachesto the treatment of osteoporosis and other metabolicbone diseases. Finally, while it is apparent that somewomen will experience fragility fractures as a conse-quence of pregnancy or lactation, the vast majorityof women can be reassured that the changes incalcium and bone metabolism during pregnancy andlactation are normal, healthy, and without adverseconsequences in the long-term.

ACKNOWLEDGMENTS

The author acknowledges his previous and cur-rent graduate students whose work has been citedin this review, including Janine Woodrow, Char-lene Noseworthy, Kerri Buckle, Christopher Sharpe,Mandy Woodland, and Kirsten McDonald. Researchin the author’s laboratory has been funded by theCanadian Institutes of Health Research (operatinggrants and New Investigator Award), the JanewayResearch Foundation, and the Medical ResearchFoundation of Memorial University of Newfound-land.

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