Cellular and Molecular Alterations Underlying Abnormal Bone Growth in X-Linked Hypophosphatemia

X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets, is caused by inactivating mutations of the phosphate-regulating endopeptidase gene (PHEX). XLH is mainly characterized by short stature, bone deformities and rickets, while in hypophosphatemia, normal or low vitamin D levels and low renal phosphate reabsorption are the principal biochemical aspects. The cause of growth impairment in patients with XLH is not completely understood yet, thus making the study of the growth plate (GP) alterations necessary. New treatment strategies targeting FGF23 have shown promising results in normalizing the growth velocity and improving the skeletal effects of XLH patients. However, further studies are necessary to evaluate how this treatment affects the GP as well as its long-term effects and the impact on adult height.

Sex-Specific 25-Hydroxyvitamin D Threshold Concentrations for Functional Outcomes in Older Adults

25-Hydroxyvitamin D [25(OH)D] has extra-skeletal effects, but it is not known whether the minimum sufficient serum levels for such targets, like muscle, differ from those for bone health (typically recommended at 20 or 30 ng/dL). Therefore, we derived and validated sex-specific thresholds for serum 25(OH)D predictive of poor physical function using 5 cohorts comprising 16,388 community-dwelling older adults (60.9% women). Using a cohort-stratified random two-thirds sample, we found incident slow gait was best discriminated by 25(OH)D<24.0 versus 25(OH)D>=24.0 ng/mL among women (Relative Risk=1.29; 95% CI 1.10-1.50) and 25(OH)D<21.0 versus 25(OH)D >=21.0 ng/mL among men (RR=1.43; 95% CI 1.01-2.02). Estimates from the remaining one-third validation sample were similar. Empirically identified and validated sex-specific 25(OH)D thresholds from multiple well-characterized cohorts of older adults may yield more biologically meaningful definitions in important sub-populations. Such thresholds may serve as candidate reference concentrations or inform design of vitamin D intervention trials in older adults.

Partial prevention of glucocorticoid-induced osteocyte deterioration with osteocrin gene therapy

Glucocorticoid (GC)-induced osteoporosis and subsequent bone fragility are preceded by death and dysfunction at the cellular level. In particular, short-term glucocorticoid excess suppresses osteocyte remodeling of the surrounding bone mineral, causes apoptosis of osteoblasts and osteocytes, and disrupts homeostatic bone remodeling. Preventing apoptosis and preserving osteocyte morphology and function could be effective means of preventing bone loss during glucocorticoid excess. We hypothesized that osteocrin, which preserves osteocyte viability and morphology in other models where osteocyte defects exist, could prevent osteocyte death and dysfunction in a GC excess model. We used a liver-targeted adeno-associated virus (AAV8) to induce osteocrin overexpression in mice one week prior to implantation with prednisolone or placebo pellets. After 28 days, tissues were collected for micro-CT and histological analysis. GC excess caused the expected reduction in cortical bone thickness and osteocyte canalicular length in control AAV8-treated mice, and these effects were blunted in mice overexpressing osteocrin. However, GC-induced changes in cortical porosity, trabecular bone mass, and gene expression were not prevented by osteocrin. While the mechanism of osteocrin's effects on osteocyte morphology warrants further investigation, this study does not support a role for this model of osteocrin supplementation to combat the full skeletal effects of GC excess.

Short-term skeletal and dentoalveolar effects of overexpansion:

ABSTRACT Objectives To evaluate whether the amount of rapid maxillary expansion differentially affects the skeletal and dentoalveolar changes that occur. Materials and Methods This randomized controlled trial included 23 patients who had rapid maxillary expansion (RME). Subjects were randomly assigned to a conventional expansion control group (n = 12) or an overexpansion group (n = 11), who started treatment at 13.2 ± 1.5 and 13.8 ± 1 years of age, respectively. Cone beam computed tomography scans (11 cm) were obtained prior to rapid maxillary expander (RME) delivery and approximately 3.7 months later. Initial hand-wrist radiographs were used to determine the participants' skeletal maturity. Results The RME screws were activated 5.6 ± 1.2 mm and 10.1 ± 0.6 mm in the conventional and overexpansion groups, respectively. Overexpansion produced significantly greater expansion of the nasal cavity (2.1X–2.5X), maxillary base (2.3X), buccal alveolar crest (1.4X), and greater palatine foramina (1.9X). Significantly greater intermolar width increases (1.8X) and molar inclination (2.8X) changes were also produced. The nasal cavity and maxillary base expanded 23%–32% as much as the screws were activated. Skeletal expansion was positively correlated with RME screw activation (R = 0.61 to 0.70) and negatively correlated (R = −0.56 to −0.64) with the patients' skeletal maturation indicators (SMIs). Together, screw activation and the patients' SMI scores explained 48%–66% of the variation in skeletal expansion. Conclusions This pilot study shows that overexpansion produces greater changes than conventional expansion, with greater skeletal effects among less mature patients.