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. Author manuscript; available in PMC: 2025 Sep 3.
Published in final edited form as: Ecotoxicol Environ Saf. 2025 Jul 22;302:118698. doi: 10.1016/j.ecoenv.2025.118698

Women’s bone health trajectories from pregnancy to postpartum: Associations with bone-seeking metal exposure mixtures during pregnancy

Sandra India-Aldana a,*, Hachem Saddiki a, Marcela Tamayo-Ortiz b, Katerina Margetaki c, Damaskini Valvi a, Julio Landero a, Lauren Petrick a, Adriana Mercado-García d, Andrea Baccarelli e, Martha María Téllez-Rojo d, Robert Wright a, Elena Colicino a
PMCID: PMC12404151  NIHMSID: NIHMS2104488  PMID: 40700966

Abstract

Exposure to metals can impact bone health in women during sensitive periods. However, the longitudinal effect of exposure to a metal mixture on bone strength trajectories during peri-pregnancy is unknown. Our study included pregnant women from the PROGRESS cohort with metal exposures and bone strength z-scores of the radius (n = 329) and proximal phalanx (n = 270). Bone strength z-scores were assessed using quantitative ultrasound during the 3rd trimester, and 1 and 6 months postpartum. We then averaged levels of bone-seeking metals in blood (Pb, Mn) and urine (Cd, Ba, Al) assessed during pregnancy. Metals were jointly linked as a single exposure mixture with prospective bone strength z-scores using Bayesian Varying Coefficient Kernel Machine Regression. We observed that a quartile increase in Al levels was positively associated with radius z-scores at 3rd trimester of pregnancy [β = 0.10 (95 % CI: 0.02, 0.18)], while a quartile increase in Cd levels was negatively associated with radius z-score trajectories from the 3rd trimester across postpartum [β = −0.30 (95 % CI: −0.49, −0.11)]. We also observed several negative associations between Mn [β = −0.10 (95 % CI: −0.18, −0.03)], Pb [β = −0.09 (95 % CI: −0.16, −0.02)], or Al [β = −0.12 (95 % CI: −0.21, −0.03)] with phalanx z-score levels at pregnancy, but that did not persist throughout the postpartum trajectory. Stratified models indicated potential differential effects in mothers carrying a male fetus compared to mothers carrying a female fetus. Our study findings indicate overall deleterious effects from metals on bone strength in pregnancy and at postpartum.

Keywords: Bone strength, Pregnancy, Postpartum, Metals, Mixtures

1. Introduction

Poor bone health is a major public health concern affecting more than 500 million people worldwide (Cummings and Melton, 2002; Hunter et al., 2020). Poor bone health is often more prominent with aging and consists of bone weakness triggering higher risk of fractures. Signs of weak bones can be monitored through bone strength, a composite measure of bone mineral density, geometry, architecture, and elasticity (Vahle et al., 2015). Poor bone health left untreated can develop into osteoporosis, a condition that even when treated cannot restore optimal bone health and increases the risk for osteoporotic fractures (van Oostwaard, 2018), disability (Darbà et al., 2015), depression (Kashfi et al., 2022), and premature mortality (Leboime et al., 2010). Throughout the past three decades, there has been a substantial rise in the global burden of disability-adjusted life years (DALYs) and deaths related to low bone mineral density (BMD) and its associated osteoporotic fractures with an average year loss of nearly half a million deaths and 16 million DALYs number attributable to poor bone health to date (Shen et al., 2022). Women are particularly affected by poor bone health due to fluctuations in hormones (estrogens) during the menopause transition, resulting in women ages 50 and over with four times the prevalence in osteoporosis than age-matched men, worldwide (Zhang et al., 2024).

Emerging evidence suggests that bone-seeking environmental contaminants like ubiquitous trace metals can be deleterious to bone health by increasing the risk for osteoporosis, osteomalacia, osteoarthritis, and bone degeneration (Rodríguez and Mandalunis, 2018; Zhang et al., 2020b). Potential toxicological mechanisms driving the deleterious associations exerted by bone-seeking metals include decreased mineralization in bone (Olchowik et al., 2014) or inhibition of mineralization and osteoblast differentiation (Li et al., 2011; Yang et al., 2016), and increased osteoclast activity (Chen et al., 2013a, 2013b; Zhang et al., 2020a), increased calcium and phosphorus excretion, influence on vitamin D cycles (Akesson et al., 2006; Kazantzis, 2004), or oxidative stress and generation of reactive oxygen species (Flora et al., 2012; Rodríguez and Mandalunis, 2018). Emerging experimental evidence in animals (Li et al., 2011; Rodriguez et al., 1990) and epidemiological studies (Chen et al., 2014; Cui et al., 2022; Li et al., 2020a; Lu et al., 2021) indicate that several bone-seeking heavy metals and metalloids can increase the risk for poor bone strength. For instance, putative pathways for heavy metals like cadmium impeding processes of bone formation include decrease expression of markers for osteoblastic differentiation and enzymes involved in the bone mineralization, such as osteocalcin and alkaline phosphatase, respectively (Brzóska and Moniuszko-Jakoniuk, 2005). However, there is paucity of studies taking into consideration concurrent exposure to multiple bone-seeking metals when examining associations with bone strength, especially considering repeated bone strength measures. Further, no studies have investigated the role of multiple simultaneous exposures (let alone bone-seeking metal exposures) during pregnancy on bone strength trajectories.

In women of childbearing age, pregnancy can act as a potential sensitive window for bone health. The maternal skeletal system accelerates its remodeling rate towards the end of pregnancy (Kalkwarf and Specker, 2002) to meet the nutritional and mineral demands of the fetus and the newborn. During this active remodeling phase, bone metabolic activity as well as maternal bone uptake of circulating bone-seeking metals is accelerated compared to other life stages (Baroncelli, 2008a; Hans and Baim, 2017; Hans et al., 2022; Osorio-Yáñez et al., 2021; Ott, 2016). There are several studies showing an increase on bone turnover during pregnancy, resulting in a subsequent release of lead and/or heavy metals from human bone tissue into the bloodstream (Gulson et al., 1997, 2003; Riess and Halm, 2007). Similarly, mobilization of heavy metals from bone tissue during the postnatal period is also significant (Gulson et al., 1998). For this reason, pregnancy and postpartum may constitute an exposure period of susceptibility, which can translate into a later increased risk for poor bone health. Furthermore, BMD is considered a gold-standard clinical indicator for life-course bone health as it describes the amount of mineral mass in the bone tissue evolving over time (Farr and Khosla, 2015; Office of the Surgeon, 2004). Although BMD provides key information about mineral content across the life-span, it is not commonly assessed during pregnancy (Farr and Khosla, 2015; Ott, 2016; Small, 2005). Alternatively, bone strength can be safely measured in women during pregnancy (Hans and Baim, 2017; Hans et al., 2022) because it is an ultrasound-based bone measure. Bone strength offers insight into the bone’s ability to endure stress and resist fractures (Baroncelli, 2008a; Hans and Baim, 2017; Hans et al., 2022; Ott, 2016) and it can be safely measured with no radiation in women during pregnancy (Hans and Baim, 2017; Hans et al., 2022), when bone metabolic activity and calcium turnover have accelerated rates (Baroncelli, 2008a; Hans and Baim, 2017; Hans et al., 2022; Ott, 2016).

Our team previously identified an association between individual exposures to lead and cadmium with loss of bone strength during pregnancy (Osorio-Yáñez et al., 2021), as well as an association between air pollution (particulate matter below 2.5 microns in diameter) and changes in bone strength in mothers longitudinally (Wu et al., 2020). For the first time and using state-of-the-art statistical methods, we leverage mothers from the prospective Programming Research in Obesity, Growth, and Environment and Social Stress (PROGRESS) cohort to examine whether an exposure mixture of bone-seeking metals can deleteriously alter immediate bone strength measures during pregnancy and their trajectories six months postpartum.

2. Methods

2.1. The PROGRESS cohort

The Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study is an ongoing cohort that enrolled 948 mother-children pairs between 2007 and 2011 that were followed for over a decade (Braun et al., 2014). Healthy pregnant women, affiliated with the Mexican Social Security Institute (Instituto Mexicano del Seguro Social or IMSS), were recruited during the 2nd trimester of pregnancy (12–20 gestational weeks). Any pregnant woman, ≥ 18 years old and living in Mexico City, with no intention of changing address location for at least three years, was eligible for enrollment. Medical exclusion criteria included history of infertility, heart or renal diseases, diabetes, psychosis or use of anti-epilepsy drugs, use of steroids, consumption of one or more alcoholic drinks per day, or drug addiction. Information on socio-demographic (i.e. age at parturition, socio-economic status [SES] (Carrasco, 2002; India Aldana et al., 2024), pre-pregnancy body mass index [BMI](Thomas et al., 2019)), lifestyle (i.e. breastfeeding, second-hand smoking during pregnancy), and environmental factors was collected through validated questionnaires, along with biological samples during pregnancy and later examinations. Health outcomes during follow-up were measured in mothers using standardized protocols. All participants enrolled in the study provided signed consent in Spanish; mothers provided written informed consent at each follow-up visit. This study was approved by the Institutional Review Boards of the Icahn School of Medicine at Mount Sinai and the National Institute of Public Health in Mexico (Instituto Nacional de Salud Pública).

2.2. Bone strength assessment

Bone strength measures in PROGRESS mothers have been previously described in detail (Wu et al., 2020). Briefly, quantitative ultrasound is a non-invasive method of estimating bone strength in the peripheral skeleton (Baroncelli, 2008b). Ultrasound measures included in this study were administered by a trained nurse during three study visits: third trimester or 27–36 weeks of gestation, 1 month, and 6 months postpartum. We used a Sunlight Omnisense 7000 bone sonometer (BeamMed, Plantation, FL, USA). The velocity of the ultrasound transmission reflects a combination of bone density, architecture, and elasticity, and it is an important predictor of fracture risk (Olszynski et al., 2013). For all visits, the ultrasound scans were obtained for the radius and the proximal phalanx of the middle finger in the non-dominant arm, which reflect predominantly the trabecular and cortical bone compartment, respectively. The speed-of-sound (SOS) measurements were converted into z-scores using a machine-provided standard population that was age-specific, sex-specific, and ethnicity-race-specific.

2.3. Laboratory metal measurements

Exposure biomarker analysis of toxic bone-seeking metals was performed at the Lautenberg Laboratory at Mount Sinai. Bone-seeking metals that were consistently shown to be deleterious in vitro, in vivo, and in bone health epidemiological studies (and available in PROGRESS) were included in this study: aluminum (Al) (Cumming and Klineberg, 1994; Li et al., 2011; Rodriguez et al., 1990), barium (Ba) (Tang et al., 2023), manganese (Mn) (Li et al., 2020a; Liu et al., 2023; Wang et al., 2022), lead (Pb) (Chen et al., 2014; Cui et al., 2022; Lu et al., 2021; Wang et al., 2019; Wong et al., 2015), and cadmium (Cd) (Chen et al., 2014; Engström et al., 2011, 2012; Lei et al., 2024; Lu et al., 2021; Rignell-Hydbom et al., 2009; Wallin et al., 2016; Xie et al., 2023). Metals were assessed in mothers’ urine (Al, Ba, Cd) and blood (Mn, Pb) (Politis et al., 2022) during the 2nd and 3rd trimesters of pregnancy. Our analysis focuses on elements assessed in the gold-standard exposure biomarker matrices (e.g., blood for Mn, Pb; urine for Al, Ba, Cd). Samples were collected in trace element free tubes, briefly refrigerated at 2–6 °C, and subsequently frozen at −20 °C until analyzed. Digested blood samples and acidified diluted urine were analyzed using external calibration using the Agilent 8800 ICP Triple Quad in MS/MS mode and QA/QC procedures were performed. When metal concentrations were below the limit of detection (LOD), we replaced concentrations with a value of LOD/√2 (Barr et al., 2006). For metals measured in urine, we used specific gravity (SG) to account for urine dilution implementing the following formula separately for each trimester concentration (2nd and 3rd trimester): Corrected Value = Original Value × (SGmedian–1)/(SG–1) where SGmedian = 1.016 (Colicino et al., 2021; Green et al., 2020). Specific gravity was measured on a digital handheld refractometer (AR200, Reichert Technologies, Buffalo, NY). Metal concentrations for each biomarker of exposure from each trimester of pregnancy were averaged (2nd and 3rd trimesters) as a proxy of exposure throughout pregnancy.

2.4. Statistical analyses

We restricted our analyses to women with bone strength measures across all three time points (3rd trimester, 1 month, and 6 months postpartum). The resulting sample size selected for inclusion were 329 women with complete data on radius bone strength (Table S1) and 270 women with complete data on phalanx bone strength (Table S2). Characteristic distributions between PROGRESS overall cohort and our subsets were similar (Tables S1-S2). To assess the association between the overall bone-seeking metal mixture during pregnancy and bone strength at baseline (3rd trimester of pregnancy) and bone strength trajectories up to the ~6 month postpartum visit, we implemented the Bayesian Varying Coefficient Kernel Machine Regression (BVCKMR), a hierarchical model that estimates how exposure mixtures at a given time point are associated with health outcome trajectories accommodating for repeated endpoints, as previously described (Liu et al., 2018). Briefly, this approach was developed to capture exposure-response relationships with multiple exposures, while accounting for potential non-linear exposure-response associations and/or non-additive effects among chemical exposures. A major advantage of the longitudinal BVCKMR regression is its ability to estimate both baseline (3rd trimester pregnancy) and longitudinal changes (perinatal trajectory from 3rd trimester to 6 month postpartum), thus easing the interpretation of the result estimates. The model enables a more accurate characterization of the complex relationships between toxic metal exposure and longitudinal bone health outcomes. Prior to BVCKMR modeling, we ranked exposures using the empirical cumulative distribution function, and age-centered to the baseline age at the 3rd trimester. All longitudinal BVCKMR models were iterated 20,000 times (with a 10,000 of burn-in) and were adjusted for age at the 3rd trimester, SES (low, middle/higher) (Myong et al., 2012; Wang and Dixon, 2006), pre-pregnancy BMI (continuous) (Hou et al., 2020; Vári et al., 2023), breastfeeding (as a dummy variable: never breastfeed/attempted/started but did not sustain, non-exclusive at 1 month, exclusive at 1 month) (Salari and Abdollahi, 2014), and second-hand smoking during pregnancy (exposed, not exposed) (Holmberg et al., 2011) (Figure S1). We also examined stratified analyses by fetal sex (mothers carrying a male vs female fetus), given the potential sex-divergent health effects influenced by shifting hormone concentrations throughout pregnancy (Clifton, 2010). All analyses were conducted in R version 4.3.

3. Results

Women enrolled in PROGRESS were slightly overweight prior to pregnancy with a mean (SD) BMI of 26.5 (4.1) kg/m2 and were on average (SD) 29 years old (5.4) at enrollment (Table 1). About half of the women had lower socio-economic status (~50 %) and most were not exposed to passive (second-hand) smoke during pregnancy (62 %), and breastfed (either exclusively or not exclusively) by the 1st month of postpartum (90 %). About half of the mothers carried a male offspring (>52 %). Radius z-scores were relatively lower than phalanx z-scores throughout the whole follow-up period (Table 1). In addition, while z-scores for radius overall decrease over time slightly, phalanx z-scores increase from pregnancy to one month postpartum and then plateaued until 6 months after pregnancy.

Table 1.

Participant Characteristics.a

Variable PROGRESS with Radius
(Trabecular Bone) Data
N = 329		 PROGRESS with Phalanx
(Cortical Bone) Data
N = 270
Age at 3 T Pregnancy (Years) 28.5 (5.36) [20.0, 42.4] 28.6 (5.42) [20.0, 41.7]
Pre-pregnancy BMI (in kg/m2) 26.5 (4.10) [18.4, 43.5] 26.5 (4.14) [18.4, 43.5]
AMAI SES Index
Middle/Higher 158 (48.0 %) 135 (50.0 %)
Low 171 (52.0 %) 135 (50.0 %)
Second Hand Smoking(SHS) during Pregnancy
Not Exposed to SHS 205 (62.3 %) 168 (62.2 %)
Exposed to SHS 124 (37.7 %) 102 (37.8 %)
Breastfeeding by Month 1
No Breastfeeding Ever 33 (10.0 %) 27 (10.0 %)
Breastfeeding 1 m not Exclusive 189 (57.4 %) 149 (55.2 %)
Breastfeeding 1 m Exclusive 107 (32.5 %) 94 (34.8 %)
Fetal Sex
Male 172 (52.3 %) 146 (54.1 %)
Female 157 (47.7 %) 124 (45.9 %)
Metal Exposures b
Cd in urine (μg/L) 0.28 (0.24) [0.04, 1.83] 0.29 (0.23) [0.04, 1.63]
Pb in blood (μg/L) 38.4 (25.0) [8.02, 150] 38.6 (25.0) [8.02, 150]
Mn in blood (μg/L) 17.5 (5.95) [4.69, 53.3] 17.5 (6.04) [4.69, 53.3]
Al in urine (μg/L) 53.6 (89.3) [12.2, 1168] 51.1 (87.7) [13.8, 1167]
Ba in urine (μg/L) 5.47 (4.99) [0.19, 51.8] 5.40 (5.20) [0.19, 51.8]
Bone Strength Z-scores
3rd Trimester −1.05 (1.04) [−3.53, 4.09] −0.49 (1.12) [−3.62, 3.34]
1 m. Postpartum −1.03 (1.00) [−3.51, 3.67] −0.41 (1.11) [−2.86, 3.01]
6 m. Postpartum −1.07 (1.00) [−3.80, 1.90] −0.43 (1.13) [−3.34, 3.19]
Speed of Sound (SOS) Raw Bone Strength Values (m/s)
3rd Trimester 4027 (104.8) [3782, 4562] 3948 (163.5) [3492, 4531]
1 m. Postpartum 4031 (100.6) [3781, 4514] 3961 (161.3) [3599, 4482]
6 m. Postpartum 4028 (100.8) [3766, 4347] 3959 (164.7) [3537, 4469]
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a

Participant characteristics [Mean (SD) [Range]; n (%)].

b

Average of 2nd and 3rd trimester values, after limit of detection (LOD) imputation and specific gravity (SG) correction whenever applicable.

Using the BVCKMR model, we estimated the association of the metals on bone strength z-scores both at baseline (during the 3rd trimester of pregnancy) and over time (trajectories from the 3rd trimester of pregnancy until 6 months after delivery). Relative importance of each metal was quantified by the difference in the estimated main effect of a single metal at higher exposure (75th percentile) relative to lower exposure levels (50th percentile), holding all other metals constant at median exposures (50th percentile). We observed that a quartile increase in Al levels was positively associated with radius z-scores at baseline [β = 0.10 (95 % CI: 0.02, 0.18)] (Fig. 1; Table S3), while a quartile increase in Cd levels was negatively associated with radius z-scores across the perinatal trajectory (from the 3rd trimester of pregnancy until 6 months after delivery) [β = −0.30 (95 % CI: −0.49, −0.11)] (Fig. 1; Table S3). In addition, we observed negative associations between Mn [β = −0.10 (95 % CI: −0.18, −0.03)], Pb [β = −0.09 (95 % CI: −0.16, −0.02)], and Al [β = −0.12 (95 % CI: −0.21, −0.03)] with phalanx z-score levels at baseline (Fig. 2; Table S4).

Fig. 1.

Fig. 1.

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Associations between exposure to a bone-seeking metal mixture during pregnancy and baseline (left plot) and trajectory (right plot) of radius z-scores in PROGRESS mothers (n = 329) estimated using covariate-adjusted Bayesian Varying Coefficient Kernel Machine Regression (BVCKMR). BVCKMR estimates are represented by squares and 95 % credible intervals (CIs) are denoted by whiskers. The BVCKMR estimated the relative importance of each metal on trabecular radius bone strength at baseline (3rd trimester of pregnancy) and trabecular radius bone strength trajectory (from the 3rd trimester of pregnancy until ~6 months after delivery). We plotted the relative importance of the following metals: manganese (Mn) in blood, lead (Pb) in blood, aluminum (Al) in urine, barium (Ba) in urine, and cadmium (Cd) in urine. Relative importance is quantified by the difference in the estimated main effect of a single metal at higher exposure (75th percentile) and lower exposure (50th percentile), holding all other metals constant at median exposures.

Fig. 2.

Fig. 2.

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Associations between exposure to a bone-seeking metal mixture during pregnancy and baseline (left plot) and trajectory (right plot) of phalanx z-scores in PROGRESS mothers (n = 270) estimated using covariate-adjusted Bayesian Varying Coefficient Kernel Machine Regression (BVCKMR). BVCKMR estimates are represented by squares and 95 % credible intervals (CIs) are denoted by whiskers. The BVCKMR estimated the relative importance of each metal on cortical phalanx bone strength at baseline (3rd trimester of pregnancy) and cortical phalanx bone strength trajectory (from the 3rd trimester of pregnancy until ~6 months after delivery). We plotted the relative importance of the following metals: manganese (Mn) in blood, lead (Pb) in blood, aluminum (Al) in urine, barium (Ba) in urine, and cadmium (Cd) in urine. Relative importance is quantified by the difference in the estimated main effect of a single metal at higher exposure (75th percentile) and lower exposure (50th percentile), holding all other metals constant at median exposures.

To visualize synergistic effects, we plotted the predicted crosssection of the exposure-response surface for statistically or marginally significant metals in the mixture in relation to bone strength (Figures S2-S6). For instance, we showed the metal-radius surface for Al, at lower (50th percentile) and higher Cd (75th percentile) exposure levels, holding all other metal exposures at their median values (Figure S2). Comparing the top panel (lower Cd) to the bottom panel (higher Cd), we detect a suggested Al-Cd interaction in the association with trajectory radius strength z-scores from baseline to approximately 6 months after delivery, while at baseline slopes remained similar. We also generated metal-phalanx surface plots (Figures S4-S6), such as for Mn, at lower (50th percentile) and higher (75th percentile) Pb (Figure S4) and Al (Figure S5) exposure levels, holding all other metal exposures at their median values. We also observed potential interaction effects of Pb and Al in the association with phalanx bone strength (Figure S6). Comparing the top panel (lower Al) to the bottom panel (higher Al), we detect a suggested Pb-Al interaction with phalanx strength across the perinatal trajectory.

BVCKMR models stratified by fetal sex indicated potential divergent effects in mothers carrying a male fetus compared to mothers carrying a female fetus. This pattern was primarily observed for Cd. Although consistent significant effects were observed in stratified models (Figs. 3-4) compared to non-stratified models (Fig. 1) for Cd on negative radius z-score changes over time, we observed that at baseline mothers carrying a male fetus had a positive association between Cd and radius z-score [β = 0.14 (95 % CI: 0.05, 0.22)] (Fig. 3; Table S5) while mothers carrying a female fetus had a negative association [β = −0.15 (95 % CI: −0.25, −0.06)] (Fig. 4; Table S6). In addition, we also observed negative Mn effects [β = −0.14 (95 % CI: −0.23, −0.05)] and Ba effects [β = −0.13 (95 % CI: −0.23, −0.03)] on radius z-scores at baseline in mothers carrying males (Fig. 3; Table S5), while Al positive baseline effects [β = 0.16 (95 % CI: 0.06, 0.26)] and a suggestive Pb negative effects on radius z-score trajectories [β = −0.21 (95 % CI: −0.43, 0.01)] in mothers carrying females (Fig. 4; Table S6).

Fig. 3.

Fig. 3.

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Associations between exposure to a bone-seeking metal mixture during pregnancy and baseline (left plot) and trajectory (right plot) of radius z-scores in PROGRESS mothers carrying a male fetus (n = 172) estimated using covariate-adjusted Bayesian Varying Coefficient Kernel Machine Regression (BVCKMR). BVCKMR estimates are represented by squares and 95 % credible intervals (CIs) are denoted by whiskers. The BVCKMR estimated the relative importance of each metal on trabecular radius bone strength at baseline (3rd trimester of pregnancy) and trabecular radius bone strength trajectory (from the 3rd trimester of pregnancy until ~6 months after delivery). We plotted the relative importance of the following metals: manganese (Mn) in blood, lead (Pb) in blood, aluminum (Al) in urine, barium (Ba) in urine, and cadmium (Cd) in urine. Relative importance is quantified by the difference in the estimated main effect of a single metal at higher exposure (75th percentile) and lower exposure (50th percentile), holding all other metals constant at median exposures.

Fig. 4.

Fig. 4.

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Associations between exposure to a bone-seeking metal mixture during pregnancy and baseline (left plot) and trajectory (right plot) of radius z-scores in PROGRESS mothers carrying a female fetus (n = 157) estimated using covariate-adjusted Bayesian Varying Coefficient Kernel Machine Regression (BVCKMR). BVCKMR estimates are represented by squares and 95 % credible intervals (CIs) are denoted by whiskers. The BVCKMR estimated the relative importance of each metal on trabecular radius bone strength at baseline (3rd trimester of pregnancy) and trabecular radius bone strength trajectory (from the 3rd trimester of pregnancy until ~6 months after delivery). We plotted the relative importance of the following metals: manganese (Mn) in blood, lead (Pb) in blood, aluminum (Al) in urine, barium (Ba) in urine, and cadmium (Cd) in urine. Relative importance is quantified by the difference in the estimated main effect of a single metal at higher exposure (75th percentile) and lower exposure (50th percentile), holding all other metals constant at median exposures.

In BVCKMR phalanx models stratified by fetal sex, we also observed strong divergent effects with Cd across fetal sex groups. At baseline, we observed that mothers carrying a male fetus had a positive association between Cd and phalanx z-score [β = 0.25 (95 % CI: 0.14, 0.35)] (Fig. 5; Table S7) while mothers carrying a female fetus had a negative association [β = −0.26 (95 % CI: −0.39, −0.13)] (Fig. 6; Table S8). Notably, we also observed negative Mn effects [β = −0.26 (95 % CI: −0.37, −0.14)], Pb effects [β = −0.27 (95 % CI: −0.37, −0.16)], and Ba effects [β = −0.14 (95 % CI: −0.26, −0.03)] on phalanx z-scores at baseline in mothers carrying a male fetus (Fig. 5; Table S7). However, these associations changed in directionality in the phalanx z-score trajectory; for instance, Mn [β = 0.38 (95% CI: 0.10, 0.67)] and Pb [β = 0.33 (95% CI: 0.06, 0.60)] were positively associated with phalanx z-score trajectory.

Fig. 5.

Fig. 5.

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Associations between exposure to a bone-seeking metal mixture during pregnancy and baseline (left plot) and trajectory (right plot) of phalanx z-scores in PROGRESS mothers carrying a male fetus (n = 146) estimated using covariate-adjusted Bayesian Varying Coefficient Kernel Machine Regression (BVCKMR). BVCKMR estimates are represented by squares and 95 % credible intervals (CIs) are denoted by whiskers. The BVCKMR estimated the relative importance of each metal on cortical phalanx bone strength at baseline (3rd trimester of pregnancy) and cortical phalanx bone strength trajectory (from the 3rd trimester of pregnancy until ~6 months after delivery). We plotted the relative importance of the following metals: manganese (Mn) in blood, lead (Pb) in blood, aluminum (Al) in urine, barium (Ba) in urine, and cadmium (Cd) in urine. Relative importance is quantified by the difference in the estimated main effect of a single metal at higher exposure (75th percentile) and lower exposure (50th percentile), holding all other metals constant at median exposures.

Fig. 6.

Fig. 6.

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Associations between exposure to a bone-seeking metal mixture during pregnancy and baseline (left plot) and trajectory (right plot) of phalanx z-scores in PROGRESS mothers carrying a female fetus (n = 124) estimated using covariate-adjusted Bayesian Varying Coefficient Kernel Machine Regression (BVCKMR). BVCKMR estimates are represented by squares and 95 % credible intervals (CIs) are denoted by whiskers. The BVCKMR estimated the relative importance of each metal on cortical phalanx bone strength at baseline (3rd trimester of pregnancy) and cortical phalanx bone strength trajectory (from the 3rd trimester of pregnancy until ~6 months after delivery). We plotted the relative importance of the following metals: manganese (Mn) in blood, lead (Pb) in blood, aluminum (Al) in urine, barium (Ba) in urine, and cadmium (Cd) in urine. Relative importance is quantified by the difference in the estimated main effect of a single metal at higher exposure (75th percentile) and lower exposure (50th percentile), holding all other metals constant at median exposures.

4. Discussion

Findings from this study reveal that pregnancy exposure to a mixture of bone-seeking metals can have an overall deleterious impact on bone strength both during pregnancy and throughout the postpartum period in women of childbearing age. We also identified potential differential detrimental associations by bone compartments (trabecular vs cortical). Mn, Pb, Al, and Cd were the individual metals of the mixture that primarily drove the associations with bone strength of the radius and/or phalanx. Specifically, we observed deleterious effects induced by Mn and Pb on bone strength at baseline (pregnancy), as well as by Cd across the perinatal trajectory, while inconsistent effects (positive and negative) were found for Al on bone strength at baseline across bone compartments (trabecular vs. cortical). The metal associations observed with predominantly cortical phalanx strength (Mn, Pb, Al) had a significant negative trend only at baseline, suggestive of potential postpartum bone restoration. Similarly, results indicated a positive association between Al exposure and radius (predominantly trabecular bone) during pregnancy that failed to reach significance across the perinatal trajectory. Notably, the only significant association across the perinatal trajectory was found for Cd in relation to negative radius strength. We also found that models stratified by fetal sex particularly indicated potential divergent Cd effects at baseline (pregnancy) in mothers carrying a male fetus compared to mothers carrying a female fetus.

Different findings in the results for radius bone strength compared to the phalanx bone strength in our cohort could be due to the differential turnover rate (resorption of old bone and formation of new bone) of the bone composition, with more trabecular compartment in the radius than in the phalanx. It is known that cortical bone regions, particularly those with low porosity, may be turned over at a much slower rate than trabecular bone (Eriksen et al., 2002; Parfitt, 2002). Trabecular bone has higher surface to volume ratio and is more biological active with 26 % per year of bone remodeling compared to 3 % in cortical bone compartment (Jee, 1983a; Oftadeh et al., 2015), such as the phalanx measures (Buenzli, 2016; Jee, 1983b; Lerebours et al., 2020; Oftadeh et al., 2015; Seeman, 2013). This may also explain our lower z-score levels in the trabecular radius samples than in the cortical phalanx samples during peri-pregnancy. Furthermore, given that trabecular bone (as compared to cortical bone) has a faster remodeling rate, it also tends to have lower calcium content and is less mineralized given that older bone has higher mineralization than newly formed bone tissue (Ott, 2018). On the one hand, this is consistent with more persistent negative associations on trabecular radius strength across postpartum trajectories, where potentially newer bone sites that are lower in calcium content could be interfering resulting in a higher accumulation of metals. On the other hand, we observed that cortical phalanx bone, which tends to be more mineralized, is more affected by metals during pregnancy. Given that bone-seeking metals can compete with the adsorption of calcium in bones but may do so differentially across the period surrounding pregnancy, further studies should measure calcium concentration levels as potential mediators of these associations at different time points during and after pregnancy.

Our findings indicated overall negative effects of metals (Mn, Pb, Cd) on bone strength, particularly Cd effects on radius strength in the overall population of pregnant women. There is consistent evidence showing that heavy metal Cd individually can cast a deleterious effect on bone strength and remodeling in women (Banjabi et al., 2022; Callan et al., 2015; Dahl et al., 2014; Kim et al., 2021; Lei et al., 2024; Li et al., 2020b; Lu et al., 2021; Tagt et al., 2022; Tsai et al., 2016; Wong et al., 2015; Ximenez et al., 2021), or may interfere with bone remodeling in pregnant populations (Gulson et al., 2016; Ohta et al., 2002). Yet, most of these studies were cross-sectional. There is paucity of prospective studies examining the impact of heavy metals or bone-seeking metals on bone health in women, and prior prospective research did not examine the period of peri-pregnancy (Tagt et al., 2022). Moreover, only two studies examined co-exposure (but not mixtures) to multiple heavy metals: As, Cd, and W metals were linked to BMD loss in White women ages 50 and over from the National Health and Nutrition Examination Survey (NHANES) population (Ximenez et al., 2021), and interactions between Cd and Pb on bone health were observed in Chinese women ages 40 and over (Li et al.,2020b). In NHANES, Cd was also observed to be more deleterious to BMD loss in female minorities (Xie et al., 2023). Cd is a well-known heavy metal with prolonged half-life of nearly 30 years, promoting its accumulation in the body (Lordan and Zabetakis, 2022; Zuhra et al., 2024). Cd induces oxidative stress increasing bone disorders and osteoporosis (Zuhra et al., 2024). Moreover, in adults, more than 90 % of certain heavy metals like Pb is stored in the bones (Agency for Toxic Substances and Disease Registry (Agency for Toxic Substances and Disease Registry ATSDR,2023) and women may be at a heightened risk of heavy metal exposures not only at older ages (menopause) but also during late pregnancy and post-partum due to the higher remodeling occurring around that period. Our results are aligned also with what we previously found in the PROGRESS cohort examining heavy metals like Cd as a single exposure in analyses, which was shown to decrease bone strength during pregnancy (baseline) in PROGRESS mothers (Osorio-Yáñez et al., 2021). Our study adds on to these findings as it incorporates a combined mixture of metals and examines the potentially sensitive period of postpartum as well. Overall, our findings support the notion that pregnant women are at potentially elevated risk of trabecular bone strength loss from toxicants due to increased remodeling during the postpartum period. Meanwhile, cortical phalanx strength was deteriorated during pregnancy more prominently. Other potentially deleterious bone-seeking metals such as Ba were not observed to exert consistent deleterious effects unlike other metals examined in the mixture. This aligns with previous literature where heavy metals like Pb and Cd have been found to act more gravely on bone health.

In our study, it is of interest our divergent results particularly between the baseline pregnancy and postpartum trajectory time points, as well as analyses stratified by fetal sex. We observed more quantity of metals in our mixture to have a negative effect in bone at baseline (3rd trimester). Pregnancy, fetal sex, and breastfeeding overall can influence significantly the homeostasis of nutritional compounds and bone remodeling processes in mothers, as the body prepares to meet the demand of the fetus and growing child (Møller et al., 2013). Mineral content in the fetus (such as calcium, phosphorus, and magnesium) is heavily accumulated during the 3rd trimester of pregnancy (Ardeshirpour et al., 2006; Farias et al., 2020; Horseman and Hernandez, 2014; Kovacs, 2016; Land and Schoenau, 2008), and in fact, our study suggests that maternal bone metabolism may be susceptible to toxicants from late pregnancy exposures, although this trend was observed only in relation to phalanx. In addition, our stratified analyses by fetal sex showed more negative effects of particularly heavy metal Cd in mothers carrying a female fetus as compared to those carrying a male fetus. This is evident for Cd exposure effects on radius and phalanx bone strength at baseline (during pregnancy) comparing groups of mothers carrying a male vs female fetus. We also observed potential divergent baseline effects for Mn and Pb on phalanx strength across stratified groups, where mothers carrying instead a male experienced negative effects on phalanx strength at baseline while mothers carrying a female had marginally significant positive effects. Toxicants like bone-seeking metals can compete with nutrients (Bocca et al., 2020), ultimately affecting hormonal changes that could change bone remodeling during pregnancy (Farias et al., 2020; Mills et al., 2021; Niwczyk et al., 2023; Reese and Casey, 2015). Fetal sex may further amplify these associations although this hypothesis has not been studied in relation to bone health. Emerging studies indicate sex-specific risk of fetal exposure to metals in pregnant women, revealing metals including titanium and silver to have stronger accumulation and fetal transfer in males (Li et al., 2019). Exposure to maternal heavy metal levels generally can have more significant consequences for the development of male fetuses compared with female fetuses (DiPietro and Voegtline, 2017) due to sex-specific differences in placental function and hormone concentrations (Clifton, 2010), and/or potential maternal placental proteins like metal-lothionein, involved in placental heavy metal binding such as Cd (Al-Saleh et al., 2011). This hypothesis where heavy metals affect more severely the male fetus could align with our cadmium findings, where we observed stronger inverse associations on bone strength in mothers carrying a female during pregnancy. This could be possible because the harmful effects from metal exposure during pregnancy could be partially absorbed by the mother herself instead of carrying the burden to the fetus. However, this hypothesis should be further tested, given that to our knowledge, our study is the first examining fetal sex differences of a metal mixture effect on bone health.

We also recognize a few limitations in our study. Our sample size was restricted to non-missing bone data throughout the follow-up time period to accommodate our longitudinal BVCKMR mixture method. Although BVCKMR does not test for effect modification, we provide stratified analyses by subgroups of a potential effect modifier. Future studies should generate a method that can accommodate for interaction analyses with both exposure-mixtures and longitudinal outcome trajectories. There also could be potential measurement error for some of our covariates as it is common for pregnant women to underreport compromising lifestyle information such as smoking exposure (Ernhart et al., 1988; Shipton et al., 2009). It may also be possible there could be reverse causality or attenuated findings naturally from the period of pregnancy but also from postpartum due to potential contraceptive use (i.e. medroxyprogesterone acetate (DMPA) is known to affect bone turnover and toxic metal release) (Paiva et al., 1998; Upson et al., 2020). Moreover, we did not have available data on inflammatory conditions like inflammatory bowel diseases (IBD), which are a known risk factor for bone loss (Lima et al., 2015) and could be potential confounders. Future studies should consider collecting data pertaining to inflammatory disorders when examining bone health. However, the longitudinal design ensured temporality of associations between exposures and outcomes. Our population was not compared with a control population of women but future studies should be conducted with a non-pregnant comparison group to help disentangle whether our findings examining bone-seeking metal exposures on bone strength are pregnancy-specific. Our population was also Mexican and future studies should include other races and ethnicities to generalize findings, however, the homogeneity of the cohort increased the internal validity of our findings. On the other hand, this study represents the first study on deleterious bone-seeking metal mixtures and bone health examined longitudinally during the period of peri-pregnancy. Additional longitudinal studies should be conducted in pregnant women with a longer follow-up beyond the postpartum period, incorporating a larger number of bone-seeking metals not available in our cohort (i.e. uranium, radium), and/or using different complementary bone health outcomes such as bone mineral density. Future studies could also examine mediation or effect modification by calcium, vitamin D and K, magnesium, or phosphorus as they are major indicators of bone health and healthy aging, as well as by bone biomarkers (i.e. RANK-L, FGF-23, P1NP) which can provide insights on bone turnover stages. Lastly, this study could also benefit stakeholders in support of preventive measures targeted particularly towards pregnant women and in favor of regulation of toxicants and heavy metal exposures.

5. Conclusion

Our study findings indicate overall inverse associations from a mixture of bone-seeking metals on bone strength in pregnancy and at postpartum in women of childbearing age. The heavy metal cadmium particularly decreased bone strength between the end of pregnancy and six months postpartum while also exhibiting potential fetal sex-dependent effects in mothers.

Supplementary Material

1
2

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.ecoenv.2025.118698.

Acknowledgements

We thank Emily Thomas for her initial comments on this manuscript.

Funding

R01ES032242 (PI: E Colicino, H Wu); R01ES034521 (PI: E Colicino, T Jusko); P30ES023515 (PI: R O Wright), ConduITS Clinical & Translational Science Award (CTSA) Program for the Mount Sinai Health UL1TR004419 (PI: R J Wright).

Footnotes

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

Julio Landero: Writing – review & editing. Damaskini Valvi: Writing – review & editing. Adriana Mercado-García: Writing – review & editing. Lauren Petrick: Writing – review & editing. Martha María Téllez-Rojo: Writing – review & editing. Andrea Baccarelli: Writing – review & editing. Elena Colicino: Writing – review & editing, Methodology, Funding acquisition. Sandra India-Aldana: Writing – original draft, Visualization, Software, Methodology, Investigation, Formal analysis, Data curation. Robert Wright: Writing – review & editing. Marcela Tamayo-Ortiz: Writing – review & editing. Hachem Saddiki: Writing – review & editing, Methodology, Data curation. Katerina Margetaki: Software, Conceptualization.

Data availability

Data will be made available on request. Main codes are available on GitHub: https://github.com/sia3434/Metals-and-Bone-Health

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1
NIHMS2104488-supplement-1.docx (4.8MB, docx)
2
NIHMS2104488-supplement-2.xlsx (16.8KB, xlsx)

Data Availability Statement

Data will be made available on request. Main codes are available on GitHub: https://github.com/sia3434/Metals-and-Bone-Health

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