The challenges of investigating causes and recovery from osteoporosis associated with pregnancy and lactation

Editorial commentary

Pregnancy and lactation stress maternal physiology to deliver substantial calcium to the developing fetus and neonate.

During pregnancy, the primary adaptation is a doubling of intestinal calcium absorption.¹ Pregnant women typically absorb more calcium than needed, such that hypercalciuria is a normal finding.¹ Minimal to no loss of areal BMD (aBMD) occurs in calcium-replete women between prepregnancy and postpartum measurements.^1,2 However, if maternal calcium intake is insufficient or calcium absorption is impaired, then bone resorption must be invoked to replace the required minerals that the placenta takes from the maternal circulation.

During lactation, the maternal skeleton is preferentially resorbed to provide most of the calcium content of milk.¹ This resorption is stimulated by parathyroid hormone-related protein (PTHrP) secreted from the breasts and systemic low estradiol levels.¹ aBMD of the spine declines 5%-10% over 6 mo of near-exclusive lactation, with half or less that loss at the hip.¹ The magnitude of bone loss correlates with the volume of milk output but is independent of maternal calcium intake.^1,3

Therefore, breastfeeding programs cause an obligatory but temporary loss of aBMD and strength.¹ Following 6 to 12 mo after weaning the baby, aBMD of spine and hip return to baseline (variably prepregnancy or early postpartum values).¹ Limited HR-pQCT studies of the radius and ultradistal tibia have shown persistent deficits in trabecular and cortical parameters, indicating that skeletal structure may be permanently altered.^4,5 Despite these changes, bone strength appears to become normal, since more than six dozen epidemiological studies have found that parity and lactation are associated with no effect, or a protective effect, on the risk of low aBMD and osteoporosis in the long term.¹

These changes in bone metabolism are normally silent. Rarely for some women, fragility fractures occur during reproductive cycles, sometimes with a frightening cascade of multiple vertebral compression fractures. This is not a new problem: vertebral fractures are evident in the archeological remains of young women who died several millennia ago.⁶ This is pregnancy and lactation-associated osteoporosis (PLO).

Approximately 80%-90% of fragility fractures occur while breastfeeding,^1,7 consistent with the physiological bone loss that ensues. They also occur most often in seemingly healthy primigravid women; consequently, the aBMD prior to pregnancy is usually unknown.^1,7 Vertebral fractures are most common, although hip, pelvic, and other appendicular fractures have been recognized.⁷ A recent estimate from Japan is that 4.6/10 000 women had a fragility fracture between 5 mo before and 12 mo after delivery.⁸ This is certainly an underestimate of PLO, since most compression fractures occur silently. Back pain from fractures is readily dismissed as an expected consequence of pregnancy and breastfeeding, such that women with PLO experienced an average delay of 12 wk from the onset of pain to a diagnostic spine radiograph being done.⁹ The literature is replete with women who had frightening cascades of 5-10 compression fractures, but this likely reflects the bias of reporting the worst cases. After weaning, women who fractured experience spontaneous increases of 10%-20% in spine aBMD.^1,7 Recurrence rates in subsequent pregnancies were <25% in most studies, suggesting that reversible causes (such as nutritional deficiency) were corrected before another pregnancy.^1,7

In most women presenting with PLO, it is uncertain whether the skeleton was normal or abnormal before pregnancy. If calcium intake or absorption were low during pregnancy, then bone loss was inevitable. But if the skeleton had reduced strength beforehand, then the normal lactational loss of bone may be sufficient to precipitate fractures. Data from available case reports and series fit with both scenarios. Approximately 30% of women were found to have pathogenic mutations in such genes as COL1A1, LRP5, and WNT.⁷ Those with mutations tend to have more severe disease with more vertebral fractures and lower aBMD.

In this issue of JBMR, Agarwal and colleagues used DXA and HR-pQCT to assess treatment-naive women with PLO.¹⁰ The women were also subdivided into “recent” (<12 mo postpartum) and “distant” (>12 mo postpartum), that is the time of their first assessment by the investigators. In cross-sectional analyses, women with PLO were compared to two sets of historical premenopausal controls: healthy women and women with idiopathic osteoporosis (IOP).

Women with PLO had lower aBMD and worse HR-pQCT parameters of cortical and trabecular bone than healthy women. Women with PLO also had lower aBMD than women with IOP and worse HR-pQCT parameters at the radius, whereas there were few differences between PLO and IOP at the distal tibia. When subdivided into “recent” and “delayed” PLO, it is clearer that aBMD of “distant” PLO was no different than IOP.

There are multiple limitations with these cross-sectional analyses. The controls were not matched for age, parity, and lactation (duration or time since weaning). Some controls were nulliparous, which implies confounding factors that may contribute to both nulliparity and altered bone structure. This is a difficult condition to study due to its rarity and because many factors influence the flux in aBMD: intensity and duration of breastfeeding, degree of estrogen deficiency, return of ovarian function, use of hormonal contraception, timing and completeness of weaning, etc.

Categorization as to “recent” vs “distant” is an intriguing approach to infer longitudinal data from a cross-sectional study. The elapsed time in the “recent” group (8.3 mo postpartum and 3.7 mo postweaning) was insufficient to allow for recovery of BMD. Conversely, most of the women in the “distant” group had sufficient time (59 ± 60 mo) to have recovered to their baseline.

Overall, the study suggests that, at least in this PLO cohort, and subject to the limitations of cross-sectional design, women with “distant” PLO were similar to those with IOP. Therefore, they likely entered pregnancy with lower aBMD and bone strength, with most of them suffering their fractures while breastfeeding.

A clinician most commonly deals with the aftermath of PLO, trying to determine why it developed and whether pharmacological treatment is needed. But this study’s findings suggest the tentative conclusion that PLO might be prevented for women with known IOP by counseling them about the potential consequences of transient bone loss during breastfeeding, although further prospective research is needed for certainty.

Author contributions

Christopher Kovacs (Conceptualization, Writing—original draft, Writing—review & editing)

Funding

Canadian Institutes of Health Research (#165969) and Faculty of Medicine and Discipline of Medicine, Memorial University [to C.S.K.].

Conflicts of interest

None declared.