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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 12 4298-4302
Copyright © 1998 by The Endocrine Society

Original Studies

Changes in Bone Mass and Bone Biomarkers of Cynomolgus Monkeys during Pregnancy and Lactation1

Cynthia J. Lees, Christopher P. Jerome2, Thomas C. Register and Cathy S. Carlson

Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Address all correspondence and requests for reprints to: Cynthia J. Lees, D.V.M., Ph.D., Comparative Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1040.


   Abstract
Top
 Abstract
Introduction
 Experimental animals
 Materials and Methods
 Results
 Discussion
 References
 
A substantial amount of calcium is transferred from the mother to the fetus and infant during pregnancy and lactation. Involvement of the skeleton in meeting this demand should be reflected in changes in bone mass and turnover. The purpose of the study was to determine the effects of pregnancy, lactation, and recovery on the skeleton in 43 young (prepeak bone mass) female monkeys. Whole body (WBBMC) and lumbar vertebrae 2–4 bone mineral content were determined by dual x-ray absorptiometry at baseline and 1, 4, and 10 months postpartum. Alkaline phosphatase, bone Gla protein, and urinary cross-links were measured at baseline, during the third trimester, and 1, 4, and 10 months postpartum. Compared to nonpregnant, nonlactating monkeys, pregnant monkeys had similar rates of bone mass gain (nonpregnant, nonlactating WBBMC, 25 ± 9 mg/day; pregnant WBBMC, 20 ± 14 mg/day). Compared to pregnant monkeys, lactating females had increased bone turnover, as indicated by elevated bone biomarker levels (lactating alkaline phosphatase, 259 ± 20 IU/L) and decreased bone mass (lactating WBBMC, -99 ± 21 mg/day). Densitometry showed that bone mass gain in the lactating monkeys did not compensate for lactational loss by 10 months postpartum (WBBMC, 6.95 ± 9 mg/day). This lack of recovery may have been due to the fact that serum estrogen concentrations were just beginning to return to baseline at 10 months postpartum. In conclusion, the cynomolgus monkey skeleton responds similarly to that of women during pregnancy and lactation. Recovery from lactational bone loss is not complete by 10 months postpartum.


   Introduction
Top
 Abstract
 Introduction
Experimental animals
 Materials and Methods
 Results
 Discussion
 References
 
THE BODY of an adult woman contains approximately 1200 g calcium. Almost all (99%) of the calcium is contained within the skeleton, with only 1% dissolved in body fluids. Pregnancy and lactation place great demands on this maternal calcium supply. During gestation, the fetus accrues nearly 30 g calcium (1). During 6 months of lactation, another 60 g calcium are transferred to the offspring (2). The combined effect of pregnancy and lactation, therefore, is to transfer an amount of calcium equivalent to 7.5% of the maternal calcium stores to the infant.

Cynomolgus monkeys (Macaca fascicularis) are similar to women in reproductive physiology and skeletal structure. These animals have 28-day menstrual cycles, with estrogen and progesterone levels and patterns similar to those of women (3). During pregnancy (gestation period of 5 months), the estrogen/progesterone pattern in cynomolgus monkeys continues to be similar to that of women, with extremely elevated levels of estrogen during pregnancy and abrupt decreases in estrogen and progesterone immediately postpartum (4). These monkeys also have lactational amenorrhea, which lasts for 4–6 months postpartum (5). The infants acquire approximately 7.5–10 g calcium during pregnancy and lactation, which equals approximately 5.0–6.6% of the maternal calcium stores. The effects of pregnancy and lactation on bone in these animals, however, have not been examined previously.

The hypotheses for this study were: 1) pregnancy is a hyperestrogenic state during which maternal bone mass is maintained despite the fetal calcium requirement for bone mineralization; 2) lactation is a hypoestrogenic state during which maternal bone mass decreases commensurate with the infant’s demand for calcium; and 3) recovery of bone mass after lactation is associated with a return to normal serum estrogen concentrations. The aims of this study were to determine the longitudinal effects of pregnancy and lactation on 1) bone mass as measured by densitometry measurements, 2) serum and urine markers of bone turnover, and 3) serum estrogen concentrations.


   Experimental animals
Top
 Abstract
 Introduction
 Experimental animals
Materials and Methods
 Results
 Discussion
 References
 
A total of 43 female cynomolgus monkeys, 4–9 yr of age (approximately equivalent to 15 to 27 yr of age in women), were available from our breeding colony for this study. The female monkeys were housed in social groups of 5–8 with 1 male and were fed a semipurified diet made at our facility that contained 2.5 IU vitamin D3/g diet, 5.91 mg calcium/g diet, and 5.03 mg phosphorus/g diet (calcium/phosporus ratio = 1.17). The monkeys, therefore, received between 825-1120 mg calcium/day during pregnancy and lactation.

Baseline data were collected for whole body bone mineral content (WBBMC; grams), lumbar vertebrae 2–4 bone mineral content (L24BMC; grams), and serum levels of alkaline phosphatase (ALP; international units per L), bone Gla protein (BGP; nanograms per mL), estradiol (picograms per mL), serum calcium (milligrams per dL), and the urinary pyridiniums pyridinoline (PYR; nanomoles of PYR per mmol creatinine) and deoxypyridinoline (DPYR; nanomoles of DPYR per mmol creatinine). Each animal was palpated rectally to estimate uterine size to determine pregnancy status (6). Monkeys found to be pregnant at initial examination were excluded from the study (n = 9). Nonpregnant monkeys were subjected to palpation for pregnancy detection and serum and urine collection every 2 months and to bone densitometry every 6 months. Once pregnancy was detected, biomarkers were determined during the third trimester (16 ± 2 weeks) and 1, 4, and 10 months postpartum. Bone densitometry also was performed at 1, 4, and 10 months postpartum. Eleven nonpregnant, nonlactating females were scanned 6 months apart. The monkeys were sedated for all procedures. Ketamine hydrochloride (20 mg/kg) was used during blood and urine collections and pregnancy palpation. Acepromazine maleate (0.05 mg/kg) was added to ketamine for bone densitometry.

The rationale for selecting these time points was as follows. 1) Densitometry could be performed only after 1 month postpartum, as that is the earliest time point that the infants could be separated from the mother without endangering the health of the neonate. Densitometry could not be performed during pregnancy because of 1) unwanted exposure of the fetus to radiation, and 2) the fact that fetal bone mineral density (BMD) would be included in the maternal measurement. Data from the 1 month postpartum point were compared to baseline data to provide information on bone mass changes during pregnancy. 2) Peak lactation occurs between 3–4 months, and weaning occurs shortly thereafter; therefore, the 4 month postpartum time point would provide information about lactational effects. 3) The monkeys in this breeding colony have an average 10-month birth-conception interval (7); therefore, we anticipated that any lactationally induced bone loss would be replaced by 10 months postpartum.

Thirty-four of the 43 females gave birth during this study. Four of these females lost their offspring in the first month and were removed from the study. Of the remaining 30 monkeys, complete datasets were compiled from 20 females before the breeding colony was disbanded. We were allowed to scan 16 of the 20 infants (4 females and 12 males) at 2, 4, and 6 months of age to follow their whole body bone mass accumulation. Because of space limitations, the average time the offspring stayed with their mothers was 10 months instead of the planned 4 months.

All animal manipulations were performed under the guidelines of state and federal laws, the U.S. DHHS, and our institutional animal care and use committee.


   Materials and Methods
Top
 Abstract
 Introduction
 Experimental animals
 Materials and Methods
Results
 Discussion
 References
 
Serum and urine biochemistry analyses

Serum total ALP, calcium, and urinary creatinine levels were determined using a COBAS FARA chemistry analyzer (Roche Diagnostics, Nutley, NJ). Serum was stored at -70 C until completion of the study. BGP and total estradiol levels were determined by RIA at the Comparative Endocrinology Laboratory at Yerkes Regional Primate Center (Atlanta, GA) using commercially available kits [BGP, Diagnostic Systems Laboratories (Webster, TX); estradiol, Diagnostic Products Corp. (Los Angeles, CA)]. Modifications used to measure estradiol concentrations have been described by Wilson et al. (8).

Urine was collected via urinary catheterization. If the bladder was empty at the time of collection, a pan specimen was collected. Portions of these urine samples were assayed immediately for creatinine levels (milligrams per dL) and specific gravity (grams per mL), and the remainder was frozen at -20 C until assayed for cross-links. Total urinary pyridiniums (PYR and DPYR) were measured using a modified high performance liquid chromatography method previously described by Jerome et al. (9).

BMC

Whole body BMC and L2–4BMC were measured using a dual energy x-ray absorptiometer (Norland XR26 DEXA, Fort Atkinson, WI). The method, accuracy, and precision for this technique in macaques were described by Jayo et al. (10).

To allow comparison between the rate of bone loss in the mother vs. the rate of bone gain in infants, rates of changes in WBBMC and L24BMC were used for analysis and were calculated in the following manner: nonpregnant, nonlactating BMC rate = (BMC 2 - BMC 1)/6 months, pregnant BMC rate = (1 month postpartum BMC - baseline BMC)/number of days between scans, lactation BMC rate = (4 months postpartum BMC - 1 month postpartum BMC)/number of days between scans, and recovery BMC rate = (10 months postpartum BMC - 4 months postpartum BMC)/number of days between scans. The average time between baseline scans and conception was 53 days. Rates of change in BMC were calculated for the offspring using a similar formula.

Statistical analyses

Repeated measures ANOVA was used to analyze bone biomarkers and estradiol levels. When overall P values were significant, matched pair t tests were performed to examine individual pair differences (baseline vs. third trimester, 1, 4, or 10 months postpartum; third trimester, vs. 1 month postpartum; 1 vs. 4 months postpartum; and 4 vs. 10 months postpartum). The rates of change in WBBMC and L24BMC were analyzed by ANOVA using separate t tests for pairwise comparisons. All data are presented as the mean ± SE.


   Results
Top
 Abstract
 Introduction
 Experimental animals
 Materials and Methods
 Results
Discussion
 References
 
Bone densitometry

The results for bone mineral content are shown in Fig. 1Go (WBBMC) and Fig. 2Go (L2–4BMC). The nonpregnant, nonlactating females group gained BMC throughout the experiment (WBBMC, +25.12 ± 9.03 mg/day; L24BMC, +1.037 ± 0.264 mg/day). Pregnant monkeys were not significantly different from nonpregnant monkeys in rate of gain in WBBMC (+21.03 ± 113.71 mg/day) and had a slightly, but not significantly, lower rate of gain in L24BMC (+0.381 ± 0.317 mg/day). Lactation, however, caused a significant decrease in bone mass accumulation (WBBMC, -98.99 ± 21.34 mg/day; L24BMC, -1.109 ± 0.457 mg/day). Between 4–10 months postpartum, the rates of change in WBBMC and L24BMC increased to levels comparable to those in nonpregnant females. The rate of gain in WBBMC of the infants rose from +77.76 ± 7.17 mg/day (2–4 months) to +114.92 ± 9.0 mg/day (4–6 months; Fig. 3Go). Therefore, the rate of gain in WBBMC of the infants was very close to the rate of loss in maternal WBBMC during lactation.



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  		Figure 1. Rate of change in WBBMC (milligrams per day) in nonpregnant (n = 11), pregnant (n = 19), lactating (n = 27), and recovering (n = 22) monkeys. The data shown are the group mean ± SE. Nonpregnant vs. lactating, pregnant vs. lactating, and lactating vs. recovery, P < 0.001.

 


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  		Figure 2. Rate of change in L2–4BMC (milligrams per day) in nonpregnant (n = 11), pregnant (n = 19), lactating (n = 27), and recovering (n = 22) monkeys. The data shown are the group mean ± SE. Nonpregnant vs. lactating P < 0.01; pregnant vs. lactating, P < 0.1; lactating vs. recovery, P < 0.05.

 


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  		Figure 3. WBBMC for 16 infants, presented as the rate of gain in milligrams per day (group mean ± SE).

 
Serum and urine chemistries

BGP concentrations were slightly decreased during pregnancy, were elevated by 1 month postpartum, and remained elevated at 10 months postpartum compared to baseline levels (Table 1Go). ALP levels showed a similar pattern (Table 1Go). Calcium levels were low during pregnancy, but returned to baseline levels by 1 month postpartum (Table 1Go). PYR and DPYR did not change during pregnancy, increased at 1 month postpartum, and returned to baseline levels by 10 months postpartum (Table 1Go). Estradiol levels were extremely elevated during pregnancy, fell below baseline levels by 1 month postpartum, and returned to baseline levels by 10 months postpartum (Table 1Go).


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  		Table 1. BGP, ALP, estradiol, serum calcium, PYR, and DPYR levels during pregnancy, lactation, and weaning (mean ± SE, (n) = number of samples analyzed).

 

   Discussion
Top
 Abstract
 Introduction
 Experimental animals
 Materials and Methods
 Results
 Discussion
References
 
The purpose of this study was to examine the effects of pregnancy and lactation on bone in cynomolgus monkeys and to determine whether serum estrogen concentrations correspond to changes in bone turnover. To accomplish these objectives, bone changes during pregnancy, lactation, and recovery were evaluated with bone biomarkers and bone densitometry.

The results indicate that the cynomolgus monkey skeleton did not serve as the primary source of calcium for the developing fetus under the conditions of our study, as the rates of change in BMC for the whole monkey and lumbar vertebrae 2–4 in pregnant monkeys were not different from those in nonpregnant females. ALP and BGP levels in pregnant monkeys were below baseline levels, and there were no significant changes in pyridinium levels. These findings indicate that the skeleton of pregnant monkeys was experiencing a turnover rate that was similar to or slightly depressed compared to nonpregnant animals. The suppressed turnover rate was probably due at least in part to the fact that serum estradiol concentrations were elevated.

In contrast, lactational demand for calcium in cynomolgus monkeys was met by mobilizing calcium from the skeleton. There was a high rate of loss in bone mass between 1–4 months postpartum. This loss was even more severe when one considers that these monkeys should have been gaining bone, as they had not yet reached peak bone mass (11). All bone biomarkers (ALP, BGP, PYR/creatinine, and DPYR/creatinine) were elevated during lactation, indicating that there was increased bone turnover. Estradiol concentrations decreased below baseline levels and were low until 10 months postpartum.

In the present study, the maternal skeletons did not return to baseline bone mass by 10 months postpartum. Although there was a positive rate of gain in bone mass between 4–10 months postpartum, it was not large enough to offset the loss that had occurred during the first 4 months of lactation. The L24BMC showed a more pronounced increase than the WMBMC, indicating that the spine, which contains a high proportion of cancellous bone, recovered from lactational loss more rapidly than the skeleton as a whole, which is predominantly composed of cortical bone. ALP and BGP levels were elevated 10 months postpartum compared to baseline levels, indicating that the bone turnover rate in the lactating monkeys remained elevated. In a study similar to ours, Hiyaoka et al. found that BMC and BMD decreased during lactation and did not return to baseline levels by 10 months postpartum in African green monkeys (13).

The cynomolgus monkey response to pregnancy and lactation demands for calcium is similar to that in women. In women, ALP rises during late pregnancy due to placental production of ALP, plateaus by 4 months postpartum, and gradually tapers to baseline levels by 6 months postweaning (14). The ALP levels in cynomolgus monkeys follow a similar pattern, but are decreased during pregnancy because these animals do not produce the placental ALP isoenzyme (15). Therefore, ALP serves as a better bone biomarker during pregnancy in the macaque than in women. In cynomolgus monkeys, BGP levels follow the same pattern as ALP. BGP levels in women are reported to remain in the normal range during pregnancy (16, 17, 18), but rise significantly during lactation (14) and do not return to baseline values until 18 months postpartum.

Very few studies have examined markers for bone resorption in pregnant and lactating women. One that examined urinary pyridiniums showed that PYR levels sharply increased at 1 month postpartum and then rapidly declined to early pregnancy levels. DPYR levels remained elevated until 3 months postpartum before decreasing (19). Another paper that examined N-telopeptides also showed a rapid peak by 4 months postpartum, with an abrupt return to baseline levels by 6 months postpartum (16). These biomarker data indicate similar patterns in responses of human and nonhuman primates to lactational demands. After a rapid increase in bone resorption occurring shortly after lactation begins, there is a decrease to baseline levels by 3–4 months postpartum. The initial period of rapid resorption could provide calcium for the increased demand placed on the body by lactation.

In women, most studies indicate that pregnancy has little effect on skeletal mass (20, 21), similar to what we observed in monkeys. Lactation, however, causes a temporary decrease in bone mass in women, which is restored by 6 months postweaning (22). Cynomolgus monkeys experience a substantial bone loss during lactation, and recovery does not occur within 10 months of delivery.

As far as we are aware, there are no published data comparing the BMC changes in human mothers and their infants during the lactation period. In the cynomolgus monkey, the loss seen during lactation (99 mg/day) is reflected in the gains seen in the offspring (78 mg/day between 2–4 months of age). These findings support calcium metabolic studies that indicate that the skeleton serves as the primary source of calcium during lactation (23).

Another interesting similarity between monkeys and women during pregnancy and lactation is the inability of high calcium diets to prevent a decrease in skeletal mass. The monkeys were fed approximately 160 mg calcium/kg BW, roughly 8 times the recommended intake for women. Yet even with this seemingly excessive amount of dietary calcium, the lactating monkeys lost bone. Similarly, the bone mass of Gambian women who received calcium supplementation of up to 714 mg/day was not significantly different from that of nonsupplemented women (24). These data suggest that some underlying mechanism, possibly decreased estrogen concentrations, causes the skeleton, rather than dietary sources, to serve as one of the main calcium resources during lactation.

Regulation of bone metabolism during pregnancy and lactation is not fully understood. High estrogen levels correspond to bone conservation (pregnancy), and low estrogen levels correspond to bone loss (lactation). However, PTH-related peptide (PTHrP) levels also fluctuate during pregnancy and lactation. Sowers et al. found that the relationship between PTHrP and BMD was independent of breastfeeding status, return of menses, or PRL, estradiol, and PTH levels (25). However, Dobnig et al. found no significant correlation between PTHrP levels and PRL, BGP, or BMD and suggested that PTHrP did not modulate the lactation-induced increase in bone turnover (26). Clearly, more research is needed to understand the regulation of bone metabolism during pregnancy and lactation.

In conclusion, the skeletal response of cynomolgus monkeys to pregnancy and lactation is similar to that seen in women. In this study, unlike in women, the bone loss caused by lactation in monkeys was not restored within 10 months postpartum. The skeleton acts as the main source of calcium during lactation; however, the mechanisms controlling calcium metabolism during lactation are not fully understood. We hypothesize that estrogen concentrations play a significant role in this process, although other factors not examined in the present study may also be important. Because of the similarities between the cynomolgus macaques and women, these monkeys would serve as a good model to further explore the regulation of calcium metabolism during pregnancy and lactation.


   Acknowledgments
 
The authors thank Jean Gardin and Sam Rankin for technical assistance, and Ms. Karen Klein for editorial assistance.


   Footnotes
 
1 This work was supported in part by a grant from National Center for Research Resources (T32-RR-07009). Back

2 Current address: SkeleTech, Inc., Kirkland, Washington 98034. Back

Received February 19, 1997.

Revised May 20, 1997.

Revised December 30, 1997.

Accepted September 8, 1998.


   References
Top
 Abstract
 Introduction
 Experimental animals
 Materials and Methods
 Results
 Discussion
 References
 

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