Genetic contributors to osteoporosis in pregnancy and lactation associated osteoporosis (PLO)

Pregnancy- and lactation-associated osteoporosis (PLO) describes a fragility fracture presentation around pregnancy/lactation. Presentation often includes multiple vertebral fractures, but can also involve hip, sacral/pelvic, or other fractures. Substantial bone structural deficits and low bone formation rate have been documented. Most have no known secondary cause. Many have a history of childhood fracture and/or family history of osteoporosis. These characteristics, together with early onset and disease severity, lead to the hypothesis that genetic factors may contribute to PLO. We enrolled 110 women with PLO (mean #fractures = 6, vertebral fractures in 88 %) in an exome sequencing (ES) study. Analyses identified rare (<1 % allele frequency in gnomAD) predicted deleterious variants (RPDV) in 33/110 (30 %) women. All were heterozygous; two participants had multiple RPDV. No RPDV in COL1A1/COL1A2 were identified. 28/110 (25 %) had RPDV in genes related to WNT signaling, critical to bone formation: LRP5 (n = 19), LRP6 (n = 6), WNT1 (n = 2) or WNT1&LRP5 (n = 1). Seven had RPDV related to renal/calcium handling (SLC34A1, SLC34A3, SLC9A3), or other osteoporosis mechanisms (PLS3 (n = 3), HGD (n = 1)). Those with RPDV did not differ from those without in terms of BMD, fracture characteristics, and most clinical characteristics. Among 110 PLO women, exome sequencing analyses identified a potential genetic osteoporosis contribution in 30 %, suggesting that many genetic contributors to PLO have yet to be elucidated. The finding of variants related to WNT signaling in 25 % of the cohort is consistent with the predominantly low bone formation phenotype of PLO and may have implications for prognosis and treatment response.