Bone Mineral Density in Children and Adolescents with Neurofibromatosis Type 1

Abstract

Objective-To assess if children and adolescents with neurofibromatosis type 1 (NF1) have decreased bone mineral density (BMD).Study design-Bone densitometry of the whole body, hip and lumbar spine was utilized in a case:control design (84 individuals with NF1: 293 healthy individuals without NF1). Subjects were 5-18 years of age. Individuals with NF1 were compared to controls using an analysis-of-covariance with a fixed set of covariates (age, weight, height, Tanner stage, and sex).Results-Individuals with NF1 had decreased areal bone mineral density (aBMD) of the hip (p<0.0001), femoral neck (p<0.0001), lumbar spine (p=0.0025), and whole body subtotal (p<0.0001). When individuals with NF1 were separated into groups with and without a skeletal abnormality, the NF1 individuals without a skeletal abnormality still had statistically significant decreases compared to controls (p<0.0001 for whole body subtotal aBMD) albeit less pronounced than those with osseous abnormalities.Conclusions-These data suggest that individuals with NF1 have a unique generalized skeletal dysplasia, predisposing them to localized osseous defects. Dual energy x-ray absorptiometry may prove useful to identify individuals with NF1 who are at risk for clinical osseous complications, and monitoring therapeutic trials. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A generalized intrinsic abnormality could predispose some patients to develop a localized defect of the long bones (causing unilateral bowing, fracture and frank pseudarthrosis), the vertebrae (causing scoliosis), and the sphenoid wing. Elucidation of the bone mineral density in NF1 pediatric population will provide insight into the etiology of localized abnormalities and aid in development of potential therapeutic options. This report uses dual energy x-ray absorptiometry (DXA) to assess bone health in NF1 children and adolescents. NIH Public Access MethodsNF1 individuals were recruited from an NF1 clinic at the University of Utah; all fulfilled the diagnostic criteria. 1,2 A total of 84 individuals with NF1 (ages 5-18) were included in the study. Those with other chronic illnesses known to influence bone health, e.g. illnesses requiring systemic steroids, anorexia, pregnancy, lactation, oral contraception or any hormone replacement were excluded. A cohort of 293 healthy children without NF1 (ages 3-21), collected by the Center for Pediatric Nutrition Research at the University of Utah were utilized as controls. Children <3 years were generally not included due to difficulty in cooperating with imaging procedures.Medical histories wer...

Skeletal abnormalities in neurofibromatosis type 1: Approaches to therapeutic options

“…Decreased BMD in both sexes at an early age has been reported in up to 50% of individuals with NF1 [Illes et al, 2001;Kuorilehto et al, 2004b;Lammert et al, 2005;Dulai et al, 2007;Stevenson et al, 2007;Yilmaz et al, 2007;Brunetti-Pierri et al, 2008;Duman et al, 2008]. This may be related to an inadequate increase in bone remodeling observed by both bone histomorphometry and changes in circulating bone markers [Stevenson et al, 2008;Seitz et al, 2009].…”

“…The anterolateral bowing seen in patients with NF1 is distinct from the bilateral physiological bowing common in children as they begin to walk. Radiographically, tibial bowing in NFL patients prior to fracture usually appears as cortical thickening and medullary canal narrowing at the apex of the convexity, typically near the junction of the middle and distal thirds of the tibia [Stevenson et al, 2007] (Fig. 2).…”

Evidence of Increased Bone Resorption in Neurofibromatosis Type 1 Using Urinary Pyridinium Crosslink Analysis

“…Several studies have reported decreased bone mineral density in NF1 individuals (11)(12)(13)(14)(15)(16), thus pointing to an underlying disorder of skeletal homeostasis and mineralization in humans with NF1. One of these studies reported that all postmenopausal NF1 women in the cohort had either osteoporosis or osteopenia (13).…”

Variable expression of neurofibromatosis 1 in monozygotic twins

“…There is increasing evidence from animal models and human data that the heterozygous NF1 state can cause generalized bone abnormalities such as osteopenia [Kuorilehto et al, 2004;Lammert et al, 2005;Stevenson et al, 2007;Brunetti-Pierri et al, 2008]. Other skeletal complications occur with a great deal of variability of expression; some such as tibial dysplasia/pseudarthrosis occur very rarely, with an incidence of only 3-5% of NF1 patients.…”