Mutational analysis uncovers monogenic bone disorders in women with pregnancy-associated osteoporosis: three novel mutations in LRP5, COL1A1, and COL1A2

Butscheidt, Sebastian; Delsmann, Alena; Rolvien, Tim; Barvencik, Florian; Al-Bughaili, Mohammed; Mundlos, Stefan; Schinke, Thorsten; Amling, Michael; Kornak, Uwe; Oheim, Ralf

doi:10.1007/s00198-018-4499-4

Cited by 43 publications

(30 citation statements)

References 43 publications

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“…The significant finding of low bone turnover, both in terms of serum markers and at the tissue level, should be viewed in this context. We acknowledge that we can never be certain that all women were assessed at their baseline bone remodeling status, and moreover, that it is possible that some women with PLO have a different or longer trajectory of bone remodeling and BMD change postpartum than normal healthy women . However, if postpartum bone remodeling changes were extended in PLO women, we would expect them to have higher rather than lower bone remodeling parameters compared to other groups.…”

Section: Discussionmentioning

confidence: 97%

“…We acknowledge that we can never be certain that all women were assessed at their baseline bone remodeling status, and moreover, that it is possible that some women with PLO have a different or longer trajectory of bone remodeling and BMD change postpartum than normal healthy women. (45) However, if postpartum bone remodeling changes were extended in PLO women, we would expect them to have higher rather than lower bone remodeling parameters compared to other groups. We believe that our finding of low bone remodeling, unexpected at any postpartum time point, is of mechanistic interest.…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 98%

“…(1)(2)(3)(4)(5)(6)(7)(8) This assumption reflects data available from a great many studies of bone density and bone remodeling changes that occur with normal pregnancy, lactation, and weaning in healthy women. As in healthy women, studies of PLO women document large postpartum and postweaning BMD increases (45,48) ; however, it is not known whether PLO women experience the same trajectory of bone density and remodeling recovery as normal women. Thus, it is possible that some PLO women had further BMD increase after the study time point.…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 99%

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Women With Pregnancy and Lactation–Associated Osteoporosis (PLO) Have Low Bone Remodeling Rates at the Tissue Level

Cohen

Kamanda‐Kosseh

Dempster

et al. 2019

Journal of Bone and Mineral Research

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Pregnancy and lactation–associated osteoporosis (PLO) is a rare, severe, early form of osteoporosis in which young women present with fractures, usually multiple vertebral fractures, during late pregnancy or lactation. In studies of idiopathic osteoporosis (IOP) in premenopausal women, we enrolled 78 women with low‐trauma fractures and 40 healthy controls, all with normal menses and no secondary cause of bone loss. In 15 of the affected women, the PLO subgroup, fractures had occurred during late pregnancy or lactation. We hypothesized that clinical, bone structural, and metabolic characteristics would differ between women with PLO and those with (non‐PLO) IOP and controls. All were evaluated > 12 months postpartum, when structural and remodeling characteristics would be expected to reflect baseline premenopausal status rather than transient postpartum changes. As previously reported, affected subjects (PLO and IOP) had BMD and microarchitectural deficiencies compared to controls. Women with PLO did not differ from those with IOP in terms of age, BMI, body fat, menarcheal age, parity, or age at first pregnancy. However, women with PLO had a more severe clinical presentation than those with IOP: more fractures (5.5 ± 3.3 versus 2.6 ± 2.1; p = 0.005); more vertebral fractures (80% versus 17%; p < 0.001); and higher prevalence of multiple fractures. BMD deficits were more profound and cortical width tended to be lower in PLO. PLO subjects also had significantly lower tissue‐level mineral apposition rate and bone formation rates (0.005 ± 0.005 versus 0.011 ± 0.010 mm2/mm/year; p = 0.006), as well as lower serum P1NP (33 ± 12 versus 44 ± 18 µg/L; p = 0.02) and CTX (257 ± 102 versus 355 ± 193 pg/mL; p = 0.01) than IOP. The finding that women with PLO have a low bone remodeling state assessed more than a year postpartum increases our understanding of the pathogenic mechanism of PLO. We conclude that women with PLO may have underlying osteoblast functional deficits which could affect their therapeutic response to osteoanabolic medications. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 97%

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 98%

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 99%

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Women With Pregnancy and Lactation–Associated Osteoporosis (PLO) Have Low Bone Remodeling Rates at the Tissue Level

Cohen

Kamanda‐Kosseh

Dempster

et al. 2019

Journal of Bone and Mineral Research

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“…Bone microstructure of the patients with detected ENPP1 mutation was further analyzed using high-resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT, Scanco Medical, Bruttisellen, Switzerland) at the nondominant distal radius and tibia in a standardized procedure as previously described using the in vivo protocol. (24,26) Bone geometric parameters included cortical bone area (Ct. bone area, mm 2 ) and trabecular bone area (Tb. bone area, mm 2 ); volumetric bone mineral density (vBMD) measurements included total vBMD (total BMD, mgHA/cm 3 ), cortical BMD (Ct.BMD, mgHA/cm 3 ), and trabecular BMD (Tb.BMD, mgHA/cm 3 ).…”

Section: Assessment Of Bone Metabolism and Skeletal Status In Humansmentioning

confidence: 99%

Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency

Oheim

Zimmerman

Maulding

et al. 2019

Journal of Bone and Mineral Research

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Biallelic ENPP1 deficiency in humans induces generalized arterial calcification of infancy (GACI) and/or autosomal recessive hypophosphatemic rickets type 2 (ARHR2). The latter is characterized by markedly increased circulating FGF23 levels and renal phosphate wasting, but aberrant skeletal manifestations associated with heterozygous ENPP1 deficiency are unknown. Here, we report three adult men with early onset osteoporosis who presented with fractures in the thoracic spine and/or left radius, mildly elevated circulating FGF23, and hypophosphatemia. Total hip bone mineral density scans demonstrated osteoporosis (Z‐score < −2.5) and HRpQCT demonstrated microarchitectural defects in trabecular and cortical bone. Next‐generation sequencing revealed heterozygous loss‐of‐function mutations in ENPP1 previously observed as biallelic mutations in infants with GACI. In addition, we present bone mass and structure data as well as plasma pyrophosphate (PPi) data of two siblings suffering from ARHR2 in comparison to their heterozygous and wild‐type family members indicative of an ENPP1 gene dose effect. The skeletal phenotype in murine Enpp1 deficiency yielded nearly identical findings. Ten‐week‐old male Enpp1 asj/asj mice exhibited mild elevations in plasma FGF23 and hypophosphatemia, and micro‐CT analysis revealed microarchitectural defects in trabecular and cortical bone of similar magnitude to HRpQCT defects observed in humans. Histomorphometry revealed mild osteomalacia and osteopenia at both 10 and 23 weeks. The biomechanical relevance of these findings was demonstrated by increased bone fragility and ductility in Enpp1 asj/asj mice. In summary, ENPP1 exerts a gene dose effect such that humans with heterozygous ENPP1 deficiency exhibit intermediate levels of plasma analytes associated with bone mineralization disturbance resulting in early onset osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

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“…Some researches [4,5] have shown that mothers of PLO patients have a higher incidence of fractures and the children of PLO patients have a lower bone mass than the general population, suggesting that PLO is genetically related. Butscheidt, S et al [6] detected some new mutations in LRP5, COL1A1 and COL1A2 genes in 7 patients with PLO, which played an important role in the occurrence and development of Pregnancy and lactation-associated osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

Challenges in the Management of Pregnancy and Lactation-Associated Osteoporosis (PLO) in Women of Childbearing age With Multiple Vertebral Fractures

Liu¹,

Jiao²,

Li³

2019

ijSciences

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Pregnancy and lactation-associated osteoporosis (PLO) is a rare but serious and difficult to be diagnosed disease, which occurs in the late gestation and early lactation, mainly manifested by low back pain, vertebral fracture and reduction of hip bone density. It is difficult to diagnose and has a high rate of misdiagnosis and mistreatment. We present the case of a 39-year-old woman who suffered from acute low back pain and walking difficulty after a sudden stoop in 2 months postnatal. The X-ray and MRI examination showed that fractures occurred in the first, second and fifth lumbar vertebrae. Bone mineral density (BMD) examination confirmed osteoporosis. After stopping lactation, calcium and vitamin K2 supplemented, compared with zoledronic acid injection, the low back pain was relieved and the BMD increased gradually. The incidence of PLO is seriously underestimated in clinical practice. Women in pregnancy and lactation with acute low back pain should be highly alert to the occurrence of PLO, and early treatment need to be taken in case of further serious consequences such as vertebral compression fracture or hip fracture.

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Mutational analysis uncovers monogenic bone disorders in women with pregnancy-associated osteoporosis: three novel mutations in LRP5, COL1A1, and COL1A2

Cited by 43 publications

References 43 publications

Women With Pregnancy and Lactation–Associated Osteoporosis (PLO) Have Low Bone Remodeling Rates at the Tissue Level

Women With Pregnancy and Lactation–Associated Osteoporosis (PLO) Have Low Bone Remodeling Rates at the Tissue Level

Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency

Challenges in the Management of Pregnancy and Lactation-Associated Osteoporosis (PLO) in Women of Childbearing age With Multiple Vertebral Fractures

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