ABSTRACT
Osteogenesis imperfecta (OI) is a rare bone fragility disorder caused by mutations in genes encoding collagen type I or that affect its processing. Alterations in osteoclasts were suggested to contribute to OI pathophysiology. We aimed to systematically identify studies reporting measures of osteoclast formation and function in patients and mouse models of OI, to quantify OI-induced changes. The systematic search of Medline, Ovid, and Web of Science identified 798 unique studies. After screening, we included 23 studies for meta-analysis, reporting osteoclast parameters in 310 patients with OI of 9 different types and 16 studies reporting osteoclast parameters in 406 animals of 11 different OI mouse models. The standardized mean difference with 95% confidence interval (CI) was used as the effect size, and random-effects meta-analysis was performed. In patients with OI, collagen degradation markers were significantly higher compared with age-matched controls, with an effect size of 1.23 (CI: 0.36, 2.10]. Collagen degradation markers were the most elevated in the 3- to 7-year-old age group and in patients with more severe forms of OI. Bone histomorphometry demonstrated the trends for higher osteoclast numbers (1.16; CI: -0.22, 2.55) and osteoclast surface (0.43; CI: -0.63, 1.49), and significantly higher eroded surface (3.24; CI: 0.51, 5.96) compared with age-matched controls. In OI mice, meta-analysis demonstrated significant increases in collagen degradation markers (1.59; CI: 1.07, 2.11), in osteoclast numbers (0.94; CI: 0.50, 1.39), osteoclast surface (0.73; CI: 0.22, 1.23), and eroded surface (1.31; CI: 0.54, 2.08). The largest differences were in OI mice with the mutations in Col1a1 and Col1a2 genes. There were no differences between males and females in clinical or animal studies. Quantitative estimates of changes in osteoclast indices and their variance for patients with OI are important for planning future studies. We confirmed that similar changes are observed in mice with OI, supporting their translational utility.
ABSTRACT
Excessive salt intake has been associated with the development of non-communicable diseases, including hypertension with several cardiovascular consequences. Although the detrimental effects of high salt on the skeleton have been reported, longitudinal assessment of calcium balance together with changes in bone microarchitecture and strength under salt loading has not been fully demonstrated. To address these unanswered issues, male Sprague-Dawley rats were fed normal salt diet (NSD; 0.8% NaCl) or high salt diet (HSD; 8% NaCl) for 5 months. Elevation of blood pressure, cardiac hypertrophy and glomerular deterioration were observed in HSD, thus validating the model. The balance studies were performed to monitor calcium input and output upon HSD challenge. The HSD-induced increase in calcium losses in urine and feces together with reduced fractional calcium absorption led to a decrease in calcium retention. With these calcium imbalances, we therefore examined microstructural changes of long bones of the hind limbs. Using the synchrotron radiation x-ray tomographic microscopy, we showed that trabecular structure of tibia and femur of HSD displayed a marked increase in porosity. Consistently, the volumetric micro-computed tomography also demonstrated a significant decrease in trabecular bone mineral density with expansion of endosteal perimeter in the tibia. Interestingly, bone histomorphometric analyses indicated that salt loading caused an increase in osteoclast number together with decreases in osteoblast number and osteoid volume. This uncoupling process of bone remodeling in HSD might underlie an accelerated bone loss and bone structural changes. In conclusion, long-term excessive salt consumption leads to impairment of skeletal mass and integrity possibly through negative calcium balance.