Bone mineral density in patients with inherited bone marrow failure syndromes

Shankar, Roopa Kanakatti; Giri, Neelam; Lodish, Maya; Sinaii, Ninet; Reynolds, James C.; Savage, Sharon A.; Stratakis, Constantine A.; Alter, Blanche P.

doi:10.1038/pr.2017.117

Cited by 12 publications

(12 citation statements)

References 18 publications

(26 reference statements)

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“…Several skeletal defects characteristic of FA have been described, but few studies have looked at bone metabolism and structure. Patients with FA were shown to have low BMD, more so after hematopoietic stem cell transplantation . Given FA patients’ short stature, some argue that correction for height‐age is required for patients with FA, which eliminates the prevalence of low BMD .…”

Section: Discussionmentioning

confidence: 99%

“…(8)(9)(10)(11) Furthermore, they were shown to have early onset osteopenia or osteoporosis, putting them at higher risk of fractures than the general population and more dramatically so after HSCT. (6,7,12) Several risk factors associated with bone loss are prevalent in patients with FA and include endocrine and pituitary abnormalities, hypogonadism, and prolonged glucocorticoid therapy. (12)(13)(14) However, mechanisms leading to skeletal defects in these patients remain elusive.…”

Section: Introductionmentioning

confidence: 99%

“…Patients with FA also have abnormal growth parameters, low birth weight, and short stature . It has been suggested that these patients present low bone mineral density (BMD); however, some studies argue that BMD is normal when adjusted for height . Despite height adjustment, most studies agree that patients with FA present reduced BMD scores after bone marrow or hematopoietic stem cell transplantation (HSCT) procedures .…”

Section: Introductionmentioning

confidence: 99%

“…Despite height adjustment, most studies agree that patients with FA present reduced BMD scores after bone marrow or hematopoietic stem cell transplantation (HSCT) procedures . Furthermore, they were shown to have early onset osteopenia or osteoporosis, putting them at higher risk of fractures than the general population and more dramatically so after HSCT . Several risk factors associated with bone loss are prevalent in patients with FA and include endocrine and pituitary abnormalities, hypogonadism, and prolonged glucocorticoid therapy .…”

Section: Introductionmentioning

confidence: 99%

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Deletion of the Fanconi Anemia C Gene in Mice Leads to Skeletal Anomalies and Defective Bone Mineralization and Microarchitecture

Mazon¹,

Julien²,

Ung³

et al. 2018

Journal of Bone and Mineral Research

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Fanconi anemia (FA) is a rare genetic disorder associated with a progressive decline in hematopoietic stem cells leading to bone marrow failure. FA is also characterized by a variety of developmental defects including short stature and skeletal malformations. More than half of children affected with FA have radial-ray abnormalities, and many patients have early onset osteopenia/osteoporosis. Although many Fanconi anemia genes have been identified and a molecular pathway defined, the underlying mechanism leading to bone defects remains elusive. To understand the role of FA genes in skeletal development and bone microarchitecture, we evaluated bone physiology during embryogenesis and in adult FancA- and FancC-deficient mice. We found that both FancA and FancC embryos have abnormal skeletal development shown by skeletal malformations, growth delay, and reduced bone mineralization. FancC adult mice present altered bone morphology and microarchitecture with a significant decrease in cortical bone mineral density in a sex-specific manner. Mechanical testing revealed that male but not female FancC mice show reduced bone strength compared with their wild-type littermates. Ex vivo cultures showed that FancA and FancC bone marrow-derived mesenchymal stem cells ( MSC) have impaired differentiation capabilities together with altered gene expression profiles. Our results suggest that defective bone physiology in FA occurs in utero and possibly results from altered MSC function. These results provide valuable insights into the mechanism involved in FA skeletal defects. © 2018 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deletion of the Fanconi Anemia C Gene in Mice Leads to Skeletal Anomalies and Defective Bone Mineralization and Microarchitecture

Mazon¹,

Julien²,

Ung³

et al. 2018

Journal of Bone and Mineral Research

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“…It is important to highlight that BMD Z ‐scores were adjusted for height in subjects aged 5 to 20 years, because short stature is a common feature in growing subjects with nephropathic cystinosis . Standard BMD Z ‐scores were used for analysis in adults subjects, despite the availability of BMAD as a height adjustment method in adults, because only 28% of adult subjects had short stature; BMAD has insufficient normative data and has not been proven to predict fracture risk …”

Section: Discussionmentioning

confidence: 99%

Skeletal Consequences of Nephropathic Cystinosis

Florenzano

Ferreira

Nesterova

et al. 2018

Journal of Bone and Mineral Research

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Nephropathic cystinosis is a rare lysosomal storage disorder. Patients present in the first year of life with renal Fanconi syndrome that evolves to progressive chronic kidney disease (CKD). Despite the multiple risk factors for bone disease, the frequency and severity of skeletal disorders in nephropathic cystinosis have not been described. We performed systematic bone and mineral evaluations of subjects with cystinosis seen at the NIH (n = 30), including history and physical examination, serum and urine biochemistries, DXA, vertebral fracture assessment, skeletal radiographs, and renal ultrasound. Additionally, histomorphometric analyses are reported on six subjects seen at the UCLA Bone and Mineral Metabolism Clinic. In NIH subjects, mean age was 20 years (range, 5 to 44 years), 60% were CKD stages G1 to G4, and 40% had a renal transplant. Mean bone mineral density (BMD) Z-scores were decreased in the femoral neck, total hip, and 1/3 radius (p < 0.05). Low bone mass at one or more sites was present in 46% of subjects. Twenty-seven percent of subjects reported one or more long bone fractures. Thirty-two percent of subjects had incidental vertebral fractures, which were unrelated to transplant status. Long-bone deformity/bowing was present in 64%; 50% had scoliosis. Diffuse osteosclerosis was present in 21% of evaluated subjects. Risk factors included CKD, phosphate wasting, hypercalciuria, secondary hyperparathyroidism, hypovitaminosis D, male hypogonadism, metabolic acidosis, and glucocorticoid/immunosuppressive therapy. Sixty-one percent of the non-transplanted subjects had ultrasonographic evidence of nephrocalcinosis or nephrolithiasis. Histomorphometric analyses showed impaired mineralization in four of six studied subjects. We conclude that skeletal deformities, decreased bone mass, and vertebral fractures are common and relevant complications of nephropathic cystinosis, even before renal transplantation. Efforts to minimize risk factors for skeletal disease include optimizing mineral metabolism and hormonal status, combined with monitoring for nephrocalcinosis/nephrolithiasis. © 2018 This article is a U.S. Government work and is in the public domain in the USA.

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