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

Abstract

Although neurofibromatosis type 1 (NF1) is a neurocutaneous disorder, skeletal abnormalities such as long-bone dysplasia, scoliosis, sphenoid wing dysplasia, and osteopenia are observed. To investigate the role of bone resorption as a mechanism for the bony abnormalities, we selected urinary pyridinium crosslinks (collagen degradation products excreted in urine) as a measure of bone resorption in NF1. Bone resorption was evaluated by quantitative assessment of the urinary excretion of pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Total (free plus peptide-bound) pyridinium crosslinks from the first morning urines from 59 NF1 children (ages 5-19) were extracted and analyzed (17 children with a localized skeletal dysplasia, and 42 without). The data were compared with a healthy reference population without NF1 (n ϭ 99). Multivariate analyses, controlling for age showed statistically significant increases for Dpd (p Ͻ 0.001) and the Dpd/Pyd ratio (p Ͻ 0.001) in NF1 individuals with and without a skeletal dysplasia. NF1 children have an increase in the urinary excretion of pyridinium crosslinks, reflecting increased bone resorption. The effects of NF1 haploinsufficiency likely contribute to abnormal bone remodeling, either directly or indirectly by aberrant Ras signaling, potentially predisposing NF1 individuals to localized skeletal defects. (Pediatr Res 63: 697-701, 2008) N eurofibromatosis type 1 (NF1), a common autosomal dominant disorder affecting Ϸ1/3500 individuals worldwide, has variable expressivity. Clinical manifestations include café-au-lait macules, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway tumors, and distinctive osseous lesions (1-3). The prototypical skeletal manifestations of NF1 are proportionate short stature, macrocephaly, longbone dysplasia, progressive scoliosis, and sphenoid wing dysplasia. Long-bone dysplasia most often affects the tibia and presents with anterolateral bowing often leading to fracture and nonunion or pseudarthrosis (4,5). The long-bone dysplasia in NF1 is very distinctive, and the presence of tibial pseudarthrosis alone should raise the potential diagnosis of NF1, as 50 -80% of individuals with pseudarthrosis have NF1 (6 -8).Scoliosis is the most common orthopedic manifestation in NF1 with reports documenting between 10 and 33% of NF1 individuals having scoliosis (9). Other osseous manifestations of NF1 include bone cysts, spinal canal widening, vertebral body narrowing, rib-penciling, vertebral scalloping with dural ectasias, and decreased bone mineral density. In isolation, each skeletal abnormality associated with NF1 is rare, but, as a whole, the osseous defects are relatively frequent.The NF1 gene, located on the long arm of chromosome 17, encodes the protein neurofibromin, which is a Ras-GAP protein (10). The "tumor suppressor" properties of this protein do not easily explain the mesodermally derived osseous manifestations observed in NF1. The frequent association of osseous dysplasias seen in NF1 suggests, ...

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

“…Moreover, biochemical bone resorption parameters, such as desoxypyridonoline crosslinks, were elevated (Supplement Table 1) in the patients, which is in line with a recently published study of 59 children with NF1 [31]. In addition, by measuring the BMDD in NF1 patients, we observed a novel aspect of their skeletal abnormalities, namely decreased overall calcium content because of an increasing amount of bone packets underlying primary mineralization, as well as an eroded pattern of mineralized bone, when compared to the biopsies from healthy control individuals.…”

Skeletal abnormalities in neurofibromatosis type 1: Approaches to therapeutic options

“…7). The bones of Nf 1 À=À ob mice also exhibited increased osteoclast numbers and bone resorption similar to humans with NF1 [Stevenson et al, 2008]. These in vivo studies indicated that neurofibromin in osteoblasts inhibits collagen synthesis, promotes mineralization, and also regulates osteoclastogenesis by limiting the expression of receptor activator for nuclear factor k B ligand (RANKL), the major osteoblast-derived cytokine promoting the formation of mature osteoclasts.…”

“…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 .…”

Clinical and genetic aspects of neurofibromatosis 1

“…68 -74 The pathogenesis of these bony changes is not understood, 75 but patients with NF1 may have lower than expected serum 25-hydroxyvitamin D concentrations, elevated serum parathyroid hormone levels, and evidence of increased bone resorption. 72,74,76,77 …”