High bone turnover and accumulation of osteoid in patients with neurofibromatosis 1

Abstract

Taken together, our data provide the first complete histomorphometric analysis from NF1 patients. Moreover, they suggest that low vitamin D levels significantly contribute to the skeletal defects associated with the disease.

Skeletal abnormalities in neurofibromatosis type 1: Approaches to therapeutic options

“…A bi-allelic deficiency of Nf1 in committed osteoblasts, generated using transgenic mice expressing Cre-recombinase under the control of the osteoblast-specific 2.3 kb collagen type 1 promoter (Nf 1 À=À ob mice), produced mice with no patterning or size defects, but with high bone turn-over [Elefteriou et al, 2006]. The bones of Nf 1 À=À ob mice exhibited increased collagen synthesis and delayed mineralization, causing a prominent increase in osteoid surfaces similar to what is observed in human NF1 bone histological sections [Elefteriou et al, 2006;Brunetti-Pierri et al, 2008;Seitz et al, 2009] (Fig. 7).…”

“…The recent change in reference standards for serum 25-OH-D from 10 ng/ml, considered the ''rachitic'' value for many years, to 20 ng/ml (50 nmol/L) [Wagner and Greer, 2008;Mimouni and Shamir, 2009], has implications on the need for intervention and effective dosing. A study using 1,000 IU vitamin D to correct serum levels in four patients with NF1 reported increased BMD [Seitz et al, 2009], while a lower dose of 400 IU in another study did not improve BMD [Bruenetti-Pierri et al, 2008]. Sample size in both studies is too small for definitive conclusions on effective dose.…”

“…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]. Despite the consensus that children with NF1 present with low BMD, interpretation of these studies is challenging because bone densitometry measures in adult populations cannot be extrapolated to children, for reasons that include confounding of DXA results by growth and differences in fracture epidemiology in children and adolescents .…”

“…An increased incidence of fractures in patients with NF1 has been reported, but sample sizes were small [Brunetti-Pierri et al, 2008;Tucker et al, 2008]. Another challenge to interpreting low BMD in patients with NF1 correctly is posed by recent reports of low vitamin D (14-21 ng/ml serum 25-dihydroxy-vitamin D, 25-OH-D) and osteomalacia in a subset of patients with NF1 [Lammert et al, 2005;Seitz et al, 2009]. Controlled studies that are adequately powered, normalize calcium homeostasis and consider age, sex, and race/ ethnicity norms, are needed to determine if the apparent high prevalence of low BMD in patients with NF1 predicts increased fracture risk and a need for intervention.…”

The Skeleton Abnormalities in Patients with Neurofibromatosis Type 1: Important Consequences of Abnormal Gene Function

“…Defects in vitamin D metabolism, osteoclastogenesis or bone cell response to systemic signals regulating bone remodeling are likely involved. An inadequate increase in bone remodeling is also indirectly confirm by both bone histomorphometry and changes in circulating bone markers (Stevenson et al, 2008;Seitz et al, 2010). However, an increased incidence of fractures has not been firmly established.…”