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INTRODUCTION

During gestation the average fetus requires about 30 g of calcium to mineralize its skeleton and maintain normal physiological processes. The suckling neonate requires more than this amount in breast milk during six months of exclusive lactation. Although pregnant and lactating women face a comparable demand in the amount of calcium that must be provided, the adaptations during each of these reproductive periods are quite different (Figure 1). Although providing extra calcium to the offspring could conceivably jeopardize the ability of the other to maintain calcium homeostasis and skeletal mineralization, as this review will make clear, pregnancy and lactation normally do not cause any adverse long-term consequences to the maternal skeleton. Detailed references on this subject are also available in several comprehensive reviews(1-5).

CALCIUM PHYSIOLOGY DURING PREGNANCY

Calcium provided from the maternal decidua aids in fertilization of the egg and implantation of the blastocyst; from that point onward the rate of transfer from mother to offspring increases substantially. About 80% of the calcium present in the fetal skeleton at the end of gestation crossed the placenta during the third trimester and is mostly derived from dietary absorption of calcium during pregnancy. Intestinal calcium absorption doubles during pregnancy, driven by 1,25-dihydroxyvitamin D (calcitriol or 1,25-D) and other factors, and this appears to be the main adaptation through which women meet the calcium demands of pregnancy.

Mineral Ions

There are several characteristic changes in maternal serum chemistries and calciotropic hormones during pregnancy (Figure 2) which can easily be mistaken as indicating the presence of disorder of calcium and bone metabolism, especially since it is not common for clinicians to order calcium and the calciotropic hormone levels during pregnancy (1). It should be well appreciated that the serum albumin and hemoglobin fall during pregnancy due to hemodilution; the albumin remains low until parturition. Less well appreciated is that the fall in albumin causes the total serum calcium to fall to levels normally associated with symptomatic hypocalcemia. The total calcium includes albumin-bound, bicarbonate-and-citrate-complexed, and ionized or free fractions of calcium. The ionized calcium, the physiologically important fraction, remains constant during pregnancy and this confirms that the fall in total calcium is but an artifact that can be ignored. Calculating the albumin-corrected total calcium or measuring the ionized calcium should resolve any uncertainty as to whether hypocalcemia is present or not in a pregnant woman. Serum phosphate and magnesium levels remain normal during pregnancy.

Parathyroid Hormone

Parathyroid hormone (PTH) was first measured with assays that reported high circulating levels during pregnancy; the finding of a low total serum calcium and an apparently elevated PTH led to the concept of “physiological secondary hyperparathyroidism in pregnancy.” This erroneous concept persists in some textbooks even today. Those early-generation PTH assays measured many biologically inactive fragments of PTH. When measured with 2-site “intact” assays or the more recent “bio-intact” PTH assays, PTH falls during pregnancy to the low-normal range (i.e. 0-30% of the mean non-pregnant value) during the first trimester, and may increase back to the mid-normal range by term. Most of these recent studies of PTH during pregnancy have examined women from North America and Europe who also consumed calcium-replete (often calcium-supplemented) diets. In contrast, in women from Asia and Gambia who have very low dietary calcium intakes, the PTH level did not suppress during pregnancy and in some cases it increased significantly.

Vitamin D Metabolites

25-hydroxyvitamin D or calcifediol (25-D) readily crosses the rodent hemochorial placenta (6)and probably crosses hemochorial human placentas just as easily because cord blood 25-D levels generally range from 75% to near 100% of the maternal value (7, 8). A common concern is that the placenta and fetus will deplete maternal 25-D stores, but this does not appear to be the case. Even in severely vitamin D deficient women there was either no change or at most a nonsignificant decline in maternal 25-D levels during pregnancy (4, 9, 10).

Total 1,25-D levels double early in pregnancy and stay elevated until parturition whereas free 1,25-D levels have only been reported to be increased in the third trimester. There are several unusual aspects about this situation. PTH is normally the main stimulator of the renal 1α-hydroxylase; consequently elevated 1,25-D values mandate high PTH levels. One exception to this is the ectopic expression of an autonomously functioning 1α-hydroxylase by such conditions as sarcoidosis and other granulomatous diseases. Another exception is pregnancy because the rise in 1,25-D occurs when PTH levels are typically falling or low. Evidence from animal models suggests that it is not PTH but other factors such as PTH-related protein (PTHrP), estradiol, prolactin and placental lactogen which drive the 1α-hydroxylase (1). The placenta expresses the 1α-hydroxylase and it is often assumed that autonomous placental production of 1,25-D explains why the maternal 1,25-D level doubles; other sources such as maternal decidua and the fetus itself could conceivably contribute. However, it appears that any contributions of placenta and other extra-renal sources to the maternal 1,25-D level are trivial. Animal studies indicate that the maternal renal 1α-hydroxylase is markedly upregulated during pregnancy (11, 12), and clinical studies have shown that anephric women on dialysis have very low circulating 1,25-D levels during pregnancy (1, 13).

Calcitonin

Serum calcitonin levels are increased during pregnancy and may derive from maternal thyroid, breast, decidua, and placenta. Whether calcitonin plays an important role in the physiological responses to the calcium demands of pregnancy is unknown. Calcitonin has been proposed to protect the maternal skeleton against excessive resorption during times of increased calcium demand. There are no clinical studies which have addressed this question; since multiple tissues express calcitonin during pregnancy, it would require study of women who lack the gene for calcitonin or the calcitonin receptor. Such studies in mice which lack the gene for calcitonin showed no impairment of calcium homeostasis or skeletal mineralization during pregnancy (14).

PTHrP

PTHrP levels are increased during the third trimester but whether this occurs earlier in pregnancy has not been systematically studied. The assays used in these studies detected PTHrP peptides encompassing amino acids 1-86, but PTHrP is a prohormone that produces multiple N-terminal, mid-molecule, and C-terminal peptides which differ in their biological activities and specificities; none of these peptides have been systematically measured during pregnancy. PTHrP is produced by many tissues in the fetus and mother and it is unknown which source(s) account for the rise in PTHrP 1-86 detected in the maternal circulation. Whether circulating PTHrP has a role in maternal physiology during pregnancy is unclear, but its rise may stimulate the renal 1α-hydroxylase and contribute to the increase in 1,25-D and, indirectly, the suppression of PTH. However, PTHrP is not as potent as PTH to stimulate the 1α-hydroxylase (15, 16)and so its contribution to the rise in 1,25-D during pregnancy is in doubt. A carboxyl-terminal form of PTHrP (so-called “osteostatin”) has been shown to inhibit osteoclastic bone resorption in vitro, and thus the notion arises that PTHrP may play a role in protecting the maternal skeleton from excessive resorption during pregnancy (17). Animal studies have shown that PTHrP has other roles during gestation such as regulating placental calcium transport in the fetus (1, 18).

Other Hormones

This section has focused on changes in static levels of minerals and the known calciotropic hormones; there are no studies testing hormonal reserves or response to challenges such as hypocalcemia. Pregnancy induces significant changes in other hormones known to affect calcium and bone metabolism, including sex steroids, prolactin, placental lactogen, and IGF-1. Each of these – and possibly other hormones not normally associated with calcium and bone metabolism – may have direct or indirect effects on calcium homeostasis during pregnancy. However, this aspect of the physiology of pregnancy has been largely unexplored.

Intestinal Calcium Absorption

Intestinal absorption of calcium doubles as early as 12 weeks of pregnancy and appears to be the major maternal adaptation to meet the fetal need for calcium. Common dogma is that the doubling in 1,25-D levels is responsible for this by stimulating an increase in intestinal calbindin_9k-D, TRPV6, Ca²⁺-ATPase, and other proteins; however, intestinal calcium absorption doubles in the first trimester, well before the rise in free 1,25-D levels during the third trimester. Animal studies have indicated that placental lactogen, prolactin, and other factors may stimulate intestinal calcium absorption (1)and that 1,25-D or the vitamin D receptor are not required (19). The peak fetal demand for calcium does not occur until the third trimester and so it is unclear why intestinal calcium absorption should be upregulated in the first trimester. It may allow the maternal skeleton to store calcium in advance of the peak fetal demands that occur later in pregnancy; some studies in rodents have shown this to be the case with the bone mineral content rising significantly before term (14).

Renal Handling of Calcium

The doubling of intestinal calcium absorption in the first trimester means that the extra calcium must be deposited passed to the fetus, deposited in the maternal skeleton, or excreted in the urine. Renal calcium excretion is increased as early as the 12th week of gestation and 24 hour urine values (corrected for creatinine excretion) can exceed the normal range. Conversely, fasting urine calcium values are normal or low, confirming that the hypercalciuria is a consequence of the enhanced intestinal calcium absorption. Pregnancy is recognized as a risk factor for kidney stones and the absorptive hypercalciuria of pregnancy is one reason for this. Pharmacological doses of calcitonin promote renal calcium excretion but whether the physiologically elevated levels of calcitonin during pregnancy promote renal calcium excretion is unknown.

Skeletal Calcium Metabolism and Bone Density/Bone Marker Changes

As mentioned earlier, some studies in rodents indicate that bone mineral content increases during pregnancy, and other studies have shown that histomorphometric parameters of bone turnover are increased at this time. Systematic studies of bone histomorphometry from pregnant women have not been done. However, one study of 15 women who electively terminated a pregnancy at 8-10 weeks found bone biopsy evidence of increased bone resorption, including increased resorption surface and increased numbers of resorption cavities (20). These findings were not present in biopsies obtained from 13 women at term, or in the non-pregnant controls. This study bears repeating but it does suggest that early pregnancy induces skeletal resorption.

Bone turnover markers – by-products of bone formation and resorption that can be measured in the serum or urine – have been systematically studied during pregnancy. In the non-pregnant adult with osteoporosis these bone markers are fraught with significant intra- and inter-individual variability which limit their utility on an individual basis. There are additional problems with the use of bone markers during pregnancy, including lack of pre-pregnancy baseline values; hemodilution; increased GFR; altered creatinine excretion; placental, uterine and fetal contributions; degradation and clearance by the placenta; and lack of diurnally timed or fasted specimens. Bone resorption has most often been assessed using urinary markers (deoxypyridinoline, pyridinoline, and hydroxyproline) and the consistent finding is that bone resorption appears increased from early or mid-pregnancy. Conversely, bone formation has been assessed by serum markers (osteocalcin, procollagen I carboxypeptides and bone specific alkaline phosphatase) that were generally not corrected for hemodilution or increased GFR. These bone formation markers appear decreased in early or mid-pregnancy from pre-pregnancy or non-pregnant values and rise to normal or above before term. The lack of correction for hemodilution and increased GFR means that the apparent decline in bone formation markers may actually occur despite no change or even an increase in bone formation. It should be noted that total alkaline phosphatase rises early in pregnancy due to the placental fraction and is not a useful marker of bone formation during pregnancy.

Overall, the scant bone biopsy data and the results of bone turnover markers suggest that bone resorption is increased from as early as the 10^thweek of pregnancy whereas bone formation may be suppressed (if the bone formation marker results are correct) or normal (if the bone formation markers are artifactually suppressed due to the aforementioned confounding factors). Notably there is little maternal-fetal calcium transfer occurring in the first trimester, nor is there a marked increased in turnover markers during the third trimester when maternal-fetal calcium transfer is at a peak. These findings may simply underscore that the maternal skeleton makes a minimal contribution to calcium homeostasis during pregnancy whereas the upregulation of intestinal calcium absorption is the main mechanism.

Another way of assessing whether the maternal skeleton contributes to calcium regulation during pregnancy is to measure bone mineral content or density. A few sequential areal bone density (aBMD) studies have been done using older techniques (single and/or dual-photon absorptiometry, i.e., SPA and DPA), and none with newer techniques (DXA or qCT) due to concerns about fetal radiation exposure. Studies of aBMD are known to be confounded by changes in body composition, weight and skeletal volumes, and all three of these factors change during normal pregnancy. The longitudinal studies used SPA or DPA and found no significant change in cortical or trabecular aBMD during pregnancy (1). Most recent studies examined 16 or fewer subjects with DXA prior to planned pregnancy (range 1-8 months prior, but not always stated) and after delivery (range 1-6 weeks postpartum) [studies reviewed in detail in (2)]. One study found no change in lumbar spine aBMD measurements obtained pre-conception and within 1-2 weeks post-delivery, whereas the other studies reported 4-5% decreases in lumbar aBMD with the postpartum measurement taken between 1-6 weeks post-delivery. Whether these small changes in aBMD are real or artifactual due to changes in body composition, volume, and weight is unknown. Since the puerperium is associated with bone density losses of 1-3% per month (see lactation section, below), it is also possible that obtaining the second measurement 2 to 6 weeks after delivery contributed to the bone loss documented in some of these studies.

Ultrasound measurements of the os calcis have been examined in other longitudinal studies which reported a progressive decrease in indices thought to correlate with volumetric BMD (1, 2). Whether these observed changes in the os calcis accurately indicate a true decrease in volumetric BMD or losses of BMD in the spine or hip is not known.

Overall, the existing studies have insufficient power to allow a firm conclusion as to whether any bone loss occurs during pregnancy. In the long term pregnancy does not cause impair skeletal strength or density. Most epidemiological studies of osteoporotic and osteopenic women have failed to find a significant association of parity with bone density or fracture risk (1, 21).

DISORDERS OF CALCIUM AND BONE METABOLISM DURING PREGNANCY

Osteoporosis in Pregnancy

The occasional woman will present with a fragility fracture during the third trimester or puerperium, and low bone mineral density may be confirmed by DXA (22-25). In such cases it is not possible to exclude the possibility that low bone density or skeletal fragility preceded pregnancy. In favor of a genetic predisposition is the report that among 35 women who presented with pregnancy associated osteoporosis, there was a high prevalence of a higher than expected prevalence of fractures in their mothers (26). It is conceivable that pregnancy may induce significant skeletal losses in some women and, thereby, predispose to fracture. The normal pregnancy-induced changes in mineral metabolism may cause excessive resorption of the skeleton in selected cases, and that other factors such as low dietary calcium intake and vitamin D insufficiency may contribute to skeletal losses. A high rate of bone turnover is an independent risk factor for fragility fractures outside of pregnancy, and so the apparently increased bone resorption observed during pregnancy may increase fracture risk. In favor of pregnancy inducing fragility through excess skeletal losses is an observational study of 13 women with pregnancy-associated osteoporosis who were followed for up to eight years. Since the bone mineral density at the spine and hip increased significantly during follow-up in these women, the investigators concluded that a large part of the bone loss must have been related to the pregnancy itself (23). Taken together, fragility fractures in pregnancy or the puerperium may result from the combination of abnormal skeletal microarchitecture prior to pregnancy and increased bone resorption during pregnancy.

Osteoporosis in pregnancy usually presents in a first pregnancy at age 27-28 and there is no increased risk with higher parity (23-25). About 60% of patients present with lower thoracic or lumbar pain that may be quite debilitating due to vertebral collapse (23-25). Most cases show normal serum chemistries and calciotropic hormone levels, but in a few, secondary causes of bone loss could be identified including anorexia nervosa, hyperparathyroidism, osteogenesis imperfecta, and corticosteroid or heparin therapy (24-26). Bone biopsies have confirmed osteoporosis and the absence of osteomalacia, while bone density Z-score is often lower than expected (23-25). The pain resolves spontaneously over several weeks in most cases while the bone density improves following pregnancy. Fractures tend not to recur in subsequent pregnancies. Thus, although myriad treatments (bisphosphonates, estrogen, testosterone, calcitonin, teriparatide, etc.) have been used in individual cases of pregnancy-associated osteoporosis, the tendency for this condition to remit on its own makes pharmacological treatment unjustified except for the severest cases.

A distinct condition is focal, transient osteoporosis of the hip. This rare, self-limited, and probably not a manifestation of altered calciotropic hormone levels or mineral balance during pregnancy. Instead, it may be a consequence of local factors. These patients present with unilateral or bilateral hip pain, limp and/or hip fracture in the third trimester or puerperium (27-29). Radiographs and DXA indicate reduced bone density of the symptomatic femoral head and neck while MRI demonstrates this to be due to increased water content of the femoral head and the marrow cavity; a joint effusion may also be present. The differential diagnosis of this condition includes inflammatory joint disorders, avascular necrosis of the hip, bone marrow edema, and reflex sympathetic dystrophy. It is a self-limiting condition with both symptoms and radiological appearance resolving within two to six months post-partum; conservative measures including bed rest are all that is required during the symptomatic phase. It does tend to recur in about 40% of cases, unlike osteoporosis involving the spine.

Primary Hyperparathyroidism

This is probably a rare condition but there are no firm data available on its prevalence. Two case series indicated that parathyroidectomies were done during pregnancy in about 1% of all cases (30, 31). The diagnosis will be obscured by the normal pregnancy-induced changes that lower the total serum calcium and suppress PTH; finding the ionized calcium to be increased and the PTH to be detectable should indicate primary hyperparathyroidism in most cases.

Primary hyperparathyroidism during pregnancy has been reported to cause a variety of symptoms that are not specific to hypercalcemia and cannot be distinguished from those occurring in normal pregnancy (nausea, vomiting, renal colic, malaise, muscle aches and pains, etc.). Conversely the literature associates primary hyperparathyroidism with an alarming rate of adverse outcomes in the fetus and neonate, including a 10-30% rate for each of spontaneous abortion, stillbirth, and perinatal death, and 30-50% incidence of neonatal tetany (31-35). These high rates were reported in older literature; more recent case series suggest that the rates of stillbirth and neonatal death are each about 2%, while neonatal tetany occurred in 15% (32). The adverse postnatal outcomes are thought to result from suppression of the fetal and neonatal parathyroid glands; this suppression may be prolonged after birth for 3-5 months (32)and in some cases it has been permanent (32, 34, 36).

To prevent these adverse outcomes, surgical correction of primary hyperparathyroidism during the second trimester has been almost universally recommended. Several case series have found elective surgery to be well tolerated, and to dramatically reduce the rate of adverse events when compared to the earlier cases reported in the literature. In a series of 109 mothers with hyperparathyroidism during pregnancy who were treated medically (N=70) or surgically (N=39), there was a 53% incidence of neonatal complications and 16% incidence of neonatal deaths among medically treated mothers, as opposed to a 12.5% neonatal complications and 2.5% neonatal deaths in mothers underwent parathyroidectomy (31). Choosing the second trimester allows organogenesis to be complete in the fetus and to avoid the poorer surgical outcomes and risk of preterm birth associated with surgery during the third-trimester (32, 35, 37, 38).

Many women in the earliest published cases had a relatively severe form of primary hyperparathyroidism that is not often seen today (symptomatic, with nephrocalcinosis and renal insufficiency). While mild, asymptomatic primary hyperparathyroidism during pregnancy has been followed conservatively with successful outcomes, complications continue to occur, so that, in the absence of definitive data, surgery during the second trimester remains the most common recommendation(39). Milder cases diagnosed during the third trimester may be observed until delivery, although rapid worsening of the hypercalcemia remains a concern.

There are no definitive medical management guidelines for hyperparathyroidism during pregnancy apart from ensuring adequate hydration and correction of electrolyte abnormalities (39). Pharmacologic agents to treat hypercalcemia have not been adequately studied in pregnancy. Calcitonin does not cross the placenta and has been used safely (39). Oral phosphate has also been used but is limited by diarrhea, hypokalemia, and risk of soft tissue calcifications. Bisphosphonates and mithramycin are contra-indicated because of their adverse effects on fetal development. High-dose magnesium has been proposed as a therapeutic alternative which should decreases serum PTH and calcium levels by activating the calcium sensing-receptor, but it has not been adequately studied for this purpose (40, 41). The calcium receptor agonist cinacalcet, which is used to suppress PTH and calcium in nonpregnant subjects with primary or secondary hyperparathyroidism and parathyroid carcinoma, has also been tried in pregnancy in a few cases (42). However, since the calcium receptor regulates fetal-placental calcium transfer (43)the possibility of adverse effects of cinacalcet on the fetus and neonate remain a concern.

In any case that was followed medically, parathyroidectomy is recommended to be done postpartum.

Familial Hypocalciuric Hypercalcemia

Inactivating mutations in the calcium-sensing receptor cause this autosomal dominant condition which presents with hypercalcemia and hypocalciuria (44). Pregnancy in women with familial hypocalciuric hypocalcemia may be uneventful for the mother, but the maternal hypercalcemia has caused fetal and neonatal parathyroid suppression with subsequent tetany (45, 46).

Hypoparathyroidism

Hypoparathyroidism during pregnancy usually presents as a pre-existing condition that the clinician is challenged to manage. The natural history of hypoparathyroidism during pregnancy is confusing due to conflicting case reports in the literature [reviewed in (1)]. Early in pregnancy, some hypoparathyroid women have fewer hypocalcemic symptoms and require less supplemental calcium. This is consistent with a limited role for PTH in the pregnant woman, and suggests that an increase in 1,25-D and/or increased intestinal calcium absorption occurs in the absence of PTH. However, other case reports clearly indicate that some pregnant hypoparathyroid women required increased calcitriol replacement in order to avoid worsening hypocalcemia. Adding to the confusion is that in some case reports, it appears that the normal, artifactual decrease in total serum calcium during pregnancy was the parameter that led to treatment with increased calcium and calcitriol supplementation; fewer cases report that dose increments in calcitriol and calcium were made because of maternal symptoms of hypocalcemia or tetany. It is not possible to know in advance who will improve and who will worsen during pregnancy; the task is to maintain the albumin-corrected serum calcium or ionized calcium in the normal range. Maternal hypocalcemia due to hypoparathyroidism must be avoided because it has been associated with intrauterine fetal hyperparathyroidism and fetal death. Conversely, overtreatment must be avoided because maternal hypercalcemia is associated with the fetal and neonatal complications described above under Primary Hyperparathyroidism. Calcitriol and 1α-calcidiol are recommended due to their shorter half lives, lower risk of toxicity, and the clinical experience with these agents.

Late in pregnancy, hypercalcemia may occur in hypoparathyroid women unless the calcitriol dosage is substantially reduced or discontinued. This effect appears to be mediated by the increasing levels of PTHrP in the maternal circulation in late pregnancy.

Pseudohypoparathyroidism

Pseudohypoparathyroidism is a genetic disorder causing resistance to PTH and manifest by hypocalcemia, hypophosphatemia, and high PTH levels. In two case reports of pseudohypoparathyroidism during pregnancy, the serum calcium normalized, PTH reduced by half, and 1,25-D increased 2- to 3-fold (47). The mechanism by which these changes occur despite pseudohypoparathyroidism remains unclear.

Vitamin D Deficiency and Insufficiency

There are no comprehensive studies of the effects of vitamin D deficiency or insufficiency on human pregnancy, but the available data from small clinical trials of vitamin D supplementation, observational studies, and case reports suggest that, consistent with animal studies, vitamin D insufficiency and deficiency is not associated with any worsening of maternal calcium homeostasis (this topic is reviewed in detail in (4)). Maternal hypocalcemia is milder with vitamin D deficiency due to the effects of secondary hyperparathyroidism to increase skeletal resorption and renal calcium reabsorption. Consequently, hypocalcemia due to vitamin D deficiency has not been clearly associated with the same adverse fetal outcomes that maternal hypoparathyroidism causes. The fetal effects of vitamin D deficiency, inability to form calcitriol, and absence of the vitamin D receptor have been examined across several animal species and all have indicated that the fetus will have a normal serum calcium and fully mineralized skeleton at term reviewed in detail in (4)). Neonatal hypocalcemia and rickets can occur in infants born of mothers with severe vitamin D deficiency, but it is in the weeks to months after birth as intestinal calcium absorption becomes more dependent on calcitriol.

Currently there is much interest in epidemiological studies that have associated third-trimester measurements of 25-hydroxyvitamin D, or estimated vitamin D intakes during pregnancy or the first year after birth, with extraskeletal benefits in the mother (reduced bacterial vaginosis, pre-eclampsia, pre-term delivery) or in the offspring (lower incidence of type 1 diabetes, greater skeletal mineralization, etc.). Presently there are no randomized trials of vitamin D supplementation which have examined these outcomes, although the results of two trials are awaited in which supplemented women received 4,000 or 2,000 IU of vitamin D in one study, and 4,000, 2,000, or 400 IU of vitamin D in another. It is anticipated that these studies may demonstrate maternal benefits of vitamin D supplementation but the follow-up will not be long enough to determine whether any neonatal or childhood benefits are seen.

Low Calcium Intake

Through the doubling of intestinal calcium absorption during pregnancy women have the ability to adapt to wide ranges of calcium intakes and still meet the fetal demand for calcium. It is conceivable that extremely low maternal calcium intakes could impair maternal calcium homeostasis and fetal mineral accretion, but there is scant clinical data examining this possibility (48). Among women with low dietary calcium intake, there are differing results as to whether or not calcium supplementation during pregnancy improved maternal or neonatal bone density (49). There is short term evidence that bone turnover markers were reduced when 1.2 gm of supplemental calcium was given for 20 days to 31 Mexican woman at 25-30 weeks of gestation; their mean dietary calcium intake was 1 gm (50). In a double-blind study conducted in 256 pregnant women, 2 gm of calcium supplementation improved bone mineral content only in the infants of supplemented mothers who were in the lowest quintile of calcium intake (51).

Overall the physiological changes in calcium and bone metabolism that usually occur during pregnancy and lactation are likely to be sufficient for fetal bone growth and breast-milk production in women with reasonably sufficient calcium intake (52). However, the inclusion of calcium supplementation for pregnant women with low calcium intake can be defended by the links between low calcium intake and both preeclampsia and hypertension in the offspring (48). Clinical trials have also demonstrated the supplemental calcium will reduce the risk of preeclampsia in women with low dietary calcium intakes, but not in those with adequate intake.

CALCIUM PHYSIOLOGY DURING LACTATION

As lactation begins the mother is faced with another demand for calcium in order to make milk. The typical daily losses of calcium in breast milk have been estimated to range from 280 to 400 mg, although daily losses as great as 1000 mg calcium have been reported when nursing twins (1). Although women meet the calcium demands of pregnancy by upregulating intestinal calcium absorption and calcitriol, during lactation a different adaptation occurs. A temporary demineralization of the maternal skeleton appears to be the main mechanism by which lactating women meet these calcium requirements. This demineralization does not appear to be mediated by PTH or 1,25-D, but may be mediated by high PTHrP and low estradiol levels.

Mineral Ions

The albumin-corrected serum calcium and ionized calcium are both normal during lactation, but longitudinal studies have shown that both are increased over the non-pregnant values. Serum phosphate levels are also higher and may exceed the normal range. Since reabsorption of phosphate by the kidneys appears to be increased, the increased serum phosphate levels may, therefore, reflect the combined effects of increased flux of phosphate into the blood from diet and from skeletal resorption in the setting of decreased renal phosphate excretion.

Parathyroid Hormone

PTH, as measured by 2-site “intact” assays, may be zero to 50% of the normal value during the first several months of lactation. It rises to normal by the time of weaning and in a couple of case series was found to rise above normal post-weaning. Mice lacking the gene that encodes parathyroid hormone have hypocalcemia and hyperphosphatemia, and are prone to sudden death due to hypocalcemia, but otherwise lactate normally (53).

Vitamin D Metabolites

As with pregnancy, a common concern is that the placenta and fetus will deplete maternal 25-D stores, but this does not appear to be the case. In observational studies and in the placebo arms of several clinical trials, even in severely vitamin D deficient women there was either no change or at most a nonsignificant decline in maternal 25-D levels during lactation (4). Calcitriol levels were twice normal during pregnancy but free and bound 1,25-D levels fall to normal within days of parturition and remain there. Animal studies show that severely vitamin D deficient rodents and mice lacking the vitamin D receptor are able to lactate and provide normal milk (4, 19).

Calcitonin

Calcitonin levels fall to normal sometime after the first six weeks postpartum. Mice lacking the calcitonin gene lose twice the normal amount of bone mineral content during lactation, which indicates that physiological levels of calcitonin may protect the maternal skeleton from excessive resorption during this time period (14). Whether calcitonin plays a similar role in human physiology is unknown.

PTHrP

PTHrP levels are significantly higher in lactating women than in non-pregnant controls. The source of PTHrP appears to be the breast, which secretes PTHrP into breast milk at concentrations exceeding 10,000 times the level found in the blood of patients with hypercalcemia of malignancy or in normal human controls. Further, lactating mice with the PTHrP gene ablated only from mammary tissue have lower blood levels of PTHrP than control lactating mice (54). PTHrP has an intimate association with breast tissue: studies in animals suggest that it regulates mammary development and blood flow, the calcium and water content of milk, and it is commonly expressed by breast cancers. As described below, during lactation PTHrP reaches the maternal circulation from the lactating breast and causes resorption of calcium from the maternal skeleton, renal tubular reabsorption of calcium, and (indirectly) suppression of PTH. In support of this hypothesis, deletion of the PTHrP gene from mammary tissue at the onset of lactation resulted in more modest losses of bone mineral content during lactation in mice (54). In humans, PTHrP correlates with the amount of bone mineral density lost, negatively with PTH, and positively with the ionized calcium of lactating women (55-57). Furthermore, clinical observations in aparathyroid women provide corroborative evidence of the physiological importance of PTHrP during lactational calcium homeostasis (see Hypoparathyroidism, below).

Intestinal Absorption of Calcium

Although intestinal calcium absorption was upregulated during pregnancy, it quickly decreases post-partum to the non-pregnant rate. This corresponds to the fall in 1,25-D levels to normal.

Renal Handling of Calcium

Renal excretion of calcium is typically reduced to about 50 mg per 24 hours or lower, and the glomerular filtration rate is also decreased. These findings suggests that the tubular reabsorption of calcium must be increased, perhaps by the actions of PTHrP.

Skeletal Calcium Metabolism and Bone Density/Bone Marker Changes

Histomorphometric data from lactating animals have consistently shown increased bone turnover, and losses of 35% or more of bone mineral are achieved during 2-3 weeks of normal lactation in the rat [reviewed in (1)]. There are no histomorphometric data from lactating women; instead, biochemical markers of bone formation and resorption have been assessed in numerous cross-sectional and prospective studies. Confounding factors discussed earlier for pregnancy need to be considered when assessing bone turnover markers in lactating women; in particular, the glomerular filtration rate is reduced and the intravascular volume is contracted. Urinary markers of bone resorption (24-hr collection) are elevated 2-3 fold during lactation and are higher than the levels attained in the third trimester. Serum markers of bone formation (not adjusted for hemoconcentration or reduced GFR) are generally high during lactation, and increased over the levels attained during the third trimester. The most marked increase is in the bone resorption markers, suggesting that bone turnover becomes uncoupled with bone resorption markedly exceeding bone formation. Total alkaline phosphatase falls immediately postpartum due to loss of the placental fraction, but may still remain above normal due to elevation of the bone-specific fraction. Overall, these bone marker results are compatible with significant increased bone resorption during lactation.

Serial measurements of aBMD during lactation (by SPA, DPA or DXA) have shown that bone mineral content falls 3 to 10.0% after two to six months of lactation at trabecular sites (lumbar spine, hip, femur and distal radius), with smaller losses at cortical sites and whole body (1, 21). These aBMD changes are in accord with studies in rats, mice, and primates in which the skeletal resorption has been shown to occur largely at trabecular surfaces and to a lesser degree in cortical bone. The loss occurs at a peak rate of 1-3% per month, far exceeding the 1-3% per year that can occur in postmenopausal women who are considered to be losing bone rapidly. This bone resorption is an obligate consequence of lactation and cannot be prevented by increasing the calcium intake. Several randomized trials and other studies have shown that calcium supplementation does not significantly reduce the amount of bone lost during lactation (58-61). Not surprisingly, the lactational decrease in bone mineral density correlates with the amount of calcium lost in the breast milk (62).

The skeletal losses are due in part to the low estradiol levels during lactation which stimulate osteoclast number and activity. However, low estradiol is not the sole cause of the accelerated bone resorption or other changes in calcium homeostasis that occur during lactation. It is worth noting what happens to reproductive-age women who have marked estrogen deficiency induced by GnRH agonist therapy in order to treat endometriosis or severe acne. Six months of GnRH-induced estrogen deficiency caused 1-4% losses in trabecular (but not cortical) aBMD, increased urinary calcium excretion, and suppression of 1,25-D and PTH (Figure 3) [reviewed in (1)]. In contrast, during lactation women are not as estrogen deficient but lose more aBMD (at both trabecular and cortical sites), have normal (as opposed to low) 1,25-D levels, and have reduced (as opposed to increased) urinary calcium excretion (Figure 3). The difference between isolated GnRH-induced estrogen deficiency and lactation appears to be explained by PTHrP. It stimulates osteoclast-mediated bone resorption and stimulates renal calcium reabsorption; by so doing, it complement the effects of low estradiol during lactation. Stimulated in part by suckling and high prolactin levels, the PTHrP and estrogen deficiency combine to cause marked skeletal resorption during lactation (Figure 4).

The lactational bone density losses are substantially and completely reversed during six to twelve months following weaning (1, 21, 59). This corresponds to a gain in bone density of 0.5 to 2% per month in the woman who has weaned her infant. The mechanism for this restoration of bone density is unknown, but studies in mice have shown that it is not dependent upon calcitriol, calcitonin, parathyroid hormone, or parathyroid hormone-related protein (14, 19, 53, 63); nor is it fully explained by restoration of estradiol levels to normal [unpublished data]. In the long-term, lactation-induced depletion of bone mineral appear clinically unimportant. The vast majority of epidemiologic studies of pre- and postmenopausal women have found no adverse effect of a history of lactation on peak bone mass, bone density, or hip fracture risk (1, 2, 21).

DISORDERS OF CALCIUM AND BONE METABOLISM DURING LACTATION

Osteoporosis of Lactation

On occasion a woman will suffer one or more fragility fractures during lactation, and osteoporotic bone density will be found by DXA. As with osteoporosis in pregnancy, this may represent a coincidental, unrelated disease; the woman may have had low bone density and abnormal skeletal microarchitecture prior to pregnancy. Alternatively, it is likely that some cases represent an exacerbation of the normal degree of skeletal demineralization that occurs during lactation, and a continuum from the changes in bone density and bone turnover that occurred during pregnancy. It may be somewhat artificial, therefore, to separate “osteoporosis of lactation” from “osteoporosis of pregnancy.” But since lactation normally causes increased bone resorption whereas pregnancy does not, it seems more likely that lactation could cause a subset of women to develop low bone density and fractures. For example, excessive PTHrP release from the lactating breast into the maternal circulation could conceivably cause excessive bone resorption, osteoporosis, and fractures. PTHrP levels were high in one case of lactational osteoporosis, and were found to remain elevated for months after weaning (64).

The diagnostic and treatment considerations described above for osteoporosis of pregnancy also apply to women who are lactating.

Primary Hyperparathyroidism

When surgical correctional of primary hyperparathyroidism is not possible or advisable during pregnancy it is normally carried out in the postpartum interval. If a woman with untreated primary hyperparathyroidism chooses to lactate the serum calcium should be monitored closely for significant worsening due to the effects of secretion of PTHrP from the breast (see Hypoparathyroidism, below.)

Hypoparathyroidism

The lactating breast produces PTHrP at high levels, and some of this escapes into the maternal circulation to stimulate bone resorption and raise the serum calcium level slightly. In women who lack parathyroid glands, the release of PTHrP into the circulation during lactation can temporarily restore calcium and bone homeostasis to normal. Levels of calcitriol and calcium supplementation required for treatment of hypoparathyroid women fall early and markedly after the onset of lactation, and hypercalcemia can occur if the calcitriol dosage and calcium intake is not substantially reduced (65-68). This decreased need for calcium and calcitriol occurs at a time when circulating PTHrP levels are high in the maternal circulation (65, 68, 69). As observed in one case, this is consistent with PTHrP reaching the maternal circulation in amounts sufficient to allow stimulation of 1,25-D synthesis, and maintenance of normal (or slightly increased) maternal serum calcium (69).

Management of hypoparathyroidism during lactation requires monitoring the albumin-corrected calcium or ionized calcium, reducing or stopping the calcitriol and calcium as indicated, and planning to reinstitute them in escalating doses as lactation wanes.

Pseudohypoparathyroidism

The management of pseudohypoparathyroidism has been less well documented. Since these patients are likely resistant to the renal actions of PTHrP, and the placental sources of 1,25-D are lost at parturition, the calcitriol requirements might well increase and may require further adjustments during lactation. Conversely, these patients do not have skeletal resistance to PTH, and so it is possible that calcium and calcitriol requirements may decrease secondary to enhanced skeletal resorption caused by the combined effects of high PTH levels, PTHrP release from the breast, and lactation-induced estrogen deficiency. Thus, women with pseudohypoparathyroidism might lose morebone density than normal during lactation, but this has not been studied.

Vitamin D Deficiency and Insufficiency

The available data from small clinical trials, observational studies and case reports indicate that lactation proceeds normally regardless of vitamin D status, and breast milk calcium content is unaffected by vitamin D deficiency or supplementation in doses as high as 6,400 IU per day given to the mother (topic reviewed in detail in (70)). This is likely because maternal calcium homeostasis is dominated by skeletal resorption induced by estrogen deficiency and PTHrP. It is the neonate who will suffer the consequences of being born of a vitamin D deficient mother and especially if exclusively breast fed, since both vitamin D and 25-hyroxyvitamin D penetrate poorly into breast milk.

Whether vitamin D deficiency impairs the ability of the maternal skeleton to recover post-weaning has not been examined in any clinical study. However, studies in mice lacking the vitamin D receptor indicate that these mice are able to fully remineralize their skeletons after lactation (19).

Low Calcium Intake

The calcium content of milk appears to be largely derived from skeletal resorption during lactation, a process that cannot be suppressed by consuming greater amounts of supplemental calcium. It shouldn’t be surprising, therefore, that low calcium intake does not impair breast milk quality, nor does it accentuate maternal bone loss (52). Even in women with very low calcium intakes, the same amount of mineral was lost during lactation from the skeleton as compared to women who had supplemented calcium intakes, and the breast milk calcium content was unaffected by calcium intake or vitamin D status (71-73). Conversely, since high calcium intakes do not affect the degree of skeletal demineralization that occurs during lactation (58-61), it is unlikely that increasing calcium supplementation well above normal would affect skeletal demineralization either. There is a lingering concern that adolescents mothers with low calcium intakes may not achieve normal peak bone mass as a consequence of lactation-induced bone loss. In fact there is some evidence that the adolescent skeleton recovers fully from lactation (74), but it remains reasonable to give a calcium supplement to adolescents who lactate in order to ensure that the needs of adolescent growth are met and that peak bone mass is achieved (52, 74).

IMPLICATIONS

During pregnancy and lactation, novel regulatory systems specific to these settings complement the usual regulators of calcium homeostasis. Intestinal calcium absorption more than doubles from early in pregnancy in order to meet the fetal demand for calcium. In comparison, skeletal calcium resorption is a dominant mechanism by which calcium is supplied to the breast milk, while renal calcium conservation is also apparent. While calcium supplementation during pregnancy will enable the mother to absorb more calcium, it is clear from clinical trials and observational studies that calcium supplements have little or no impact on the amount of bone lost during lactation.

The skeleton recovers promptly from lactation to achieve the pre-pregnancy bone mass through mechanisms that remain unclear. The transient loss of bone mass during lactation can compromise skeletal strength and lead to fragility fractures in some women. But the vast majority of women can be assured that the changes in calcium and bone metabolism during pregnancy and lactation are normal, healthy, and without adverse consequences in the long-term.