Bone
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A stabilized tibia fracture model was used in young (8-week old) and aged (1-year old) mice to define the relative bone regenerative potential and the relative responsiveness of the periosteal progenitor population with aging and PTH 1-34 (PTH) systemic therapy. Bone regeneration was assessed through gene expressions, radiographic imaging, histology/histomorphometry, and biomechanical testing. Radiographs and microCT showed increased calcified callus tissue and enhanced bone healing in young compared to aged mice. ⋯ PTH increased active β-catenin staining in the osteoblast populations of both young and aged mice, but had a lesser effect in cartilage. Altogether the findings show that reduced fracture healing in aging involves decreased proliferation and differentiation of stem cells lining the bone surface. While PTH 1-34 enhances the proliferation and expansion of the periosteal stem cell population and accelerates bone formation and fracture healing, the effects are proportionately reduced in aged mice compared to young mice. β-Catenin is induced by PTH in early and late fracture healing and is a potential target of PTH 1-34 effects.
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Although osteoporosis is considered a disease of women, 25% of the individuals with osteoporosis are men. BMD measurement by DXA is the gold standard used to diagnose osteoporosis and assess fracture risk. Nevertheless, BMD does not take into account alterations of microarchitecture. TBS is an index of bone microarchitecture extracted from the spine DXA. Previous studies have reported the ability of the spine TBS to predict osteoporotic fractures in women. This is the first case-controlled study in men to evaluate the potential diagnostic value of TBS as a complement to bone mineral density (BMD), by comparing men with and without fractures. ⋯ This study showed the potential use of TBS in men. TBS revealed a significant difference between fractured and age- and spine BMD-matched nonfractured subjects. These results are consistent with those previously reported on for men of other nationalities.
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Mammalian chitinases consisting of CHIA, CHIT1, CHI3L1, CHI3L2 and CHID1 exert important biological roles in the monocyte lineage and chronic inflammatory diseases. Pathological bone resorption is a cause of significant morbidity in diseases affecting the skeleton such as rheumatoid arthritis, osteoporosis, periodontitis and cancer metastasis. The biologic role of chitinases in bone resorption is poorly understood. ⋯ Indeed, silencing CHIT1 and CHI3L1 with siRNA resulted in a significant decrease in bone resorption activity. In addition, transfection with CHIT1 or CHI3L1 siRNA and co-transfection with both decreased the levels of the pro-differentiative marker MMP9. Overall, these discoveries reveal a novel and crucial role for both CHIT1 and CHI3L1 in promoting bone resorption and identifying new potential candidate markers for therapeutic targeting.
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Osteoclasts are unique cells capable of bone resorption and therefore have become a major target in osteoporosis treatment strategies. Bisphosphonates suppress bone turnover via interference with the internal enzymatic cell system of osteoclasts leading to cytoskeletal disruption. This mechanism found its clinical relevance in reducing bone resorption, stabilizing bone mass and reducing fracture risk in osteoporosis patients. ⋯ Characteristic large-sized osteoclasts were uniquely found in patients treated with nitrogen-containing bisphosphonates, thus being clearly distinguishable from giant-osteoclasts in other bone disorders such as Paget disease, secondary hyperparathyroidism or osteopetrosis. The resorption indices of large-sized osteoclasts, specifically the eroded perimeter and erosion depth, revealed significantly reduced values but not an entirely inhibited resorption capability. Bisphosphonate-osteoclasts' viability and affinity to bone seem significantly disturbed while the apoptotic process may be prolonged for a yet unknown period of time in favor of maintaining a low bone turnover.
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Review Meta Analysis
Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review.
Osteoporosis is a progressive skeletal disorder that requires long-term treatment. However, there is little guidance regarding optimal treatment duration and what the treatment discontinuation and retreatment criteria should be. Given that bisphosphonates are the most commonly prescribed class of agent for the treatment of osteoporosis, we reviewed the long-term data relating to these therapies and discussed the considerations for using bisphosphonates in postmenopausal women with osteoporosis. ⋯ Clinical studies in postmenopausal women with osteoporosis showed that long-term use of bisphosphonates resulted in persistent antifracture and bone mineral density (BMD) increasing effects beyond 3 years of treatment. No unexpected adverse events were identified in these studies and the long-term tolerability profiles of bisphosphonates remain favorable. Data from the withdrawal extension studies of alendronate and zoledronic acid also showed that residual fracture benefits were seen in patients who discontinued treatment for 3 to 5 years after an initial 3- to 5-year treatment period. BMD monitoring and fracture risk assessments should be conducted regularly to determine whether treatment could be stopped or should be reinitiated. Patients exhibiting T-scores<-2.5 or who have suffered a new fracture while on treatment should continue treatment, while patients with T-scores>-2.5 could be considered for discontinuation of active treatment while undergoing continued monitoring of their bone health. The duration and potential discontinuation of treatment should be personalized for individual patients based on their response to treatment, fracture risk and comorbidities.