Summary
Damage to cells and tissues is one of the driving forces of aging and age‐related diseases. Various repair systems are in place to counteract this functional decline. In particular, the ...property of adult stem cells to self‐renew and differentiate is essential for tissue homeostasis and regeneration. However, their functionality declines with age (Rando, 2006). One organ that is notably affected by the reduced differentiation capacity of stem cells with age is the skeleton. Here, we found that circulating microvesicles impact on the osteogenic differentiation capacity of mesenchymal stem cells in a donor‐age‐dependent way. While searching for factors mediating the inhibitory effect of elderly derived microvesicles on osteogenesis, we identified miR‐31 as a crucial component. We demonstrated that miR‐31 is present at elevated levels in the plasma of elderly and of osteoporosis patients. As a potential source of its secretion, we identified senescent endothelial cells, which are known to increase during aging in vivo (Erusalimsky, 2009). Endothelial miR‐31 is secreted within senescent cell‐derived microvesicles and taken up by mesenchymal stem cells where it inhibits osteogenic differentiation by knocking down its target Frizzled‐3. Therefore, we suggest that microvesicular miR‐31 in the plasma of elderly might play a role in the pathogenesis of age‐related impaired bone formation and that miR‐31 might be a valuable plasma‐based biomarker for aging and for a systemic environment that does not favor cell‐based therapies whenever osteogenesis is a limiting factor.
Many heterogeneous causes (e.g., metabolic, inflammatory, autoimmune, vascular, and renal diseases, and even drugs), collectively grouped as secondary causes of osteoporosis, may lead to bone loss or ...damage to architecture through a number of mechanisms. Although these secondary causes of osteoporosis are the most frequently observed causes of unexpected bone loss, they can only be diagnosed via a high degree of suspicion and clinical experience and by performing the appropriate investigations. In inflammatory disorders such as rheumatoid arthritis or chronic inflammatory bowel diseases, as well as vascular diseases, T-cell activation, and consequently pro-inflammatory cascades, trigger the increased expression of T-cell-derived RANKL. In addition, a new biomarker signature of bone-related miRNAs is promising in certain clinical features. Glucocorticoids, often used to control disease activity, decrease the number and function of osteoblasts and inhibit OPG expression. The ubiquitous occurrence of disease-related secondary changes in bone metabolism implies that numerous medical disciplines need to interact. Screening for secondary causes of osteoporosis and the search for new modes of action should present a substantial aspect of osteoporosis management. In the book, the current management of osteoporosis and related metabolic bone diseases is discussed.
Many heterogeneous causes (e.g., metabolic, inflammatory, autoimmune, vascular, and renal diseases, and even drugs), collectively grouped as secondary causes of osteoporosis, may lead to bone loss or ...damage to architecture through a number of mechanisms. Although these secondary causes of osteoporosis are the most frequently observed causes of unexpected bone loss, they can only be diagnosed via a high degree of suspicion and clinical experience and by performing the appropriate investigations. In inflammatory disorders such as rheumatoid arthritis or chronic inflammatory bowel diseases, as well as vascular diseases, T-cell activation, and consequently pro-inflammatory cascades, trigger the increased expression of T-cell-derived RANKL. In addition, a new biomarker signature of bone-related miRNAs is promising in certain clinical features. Glucocorticoids, often used to control disease activity, decrease the number and function of osteoblasts and inhibit OPG expression. The ubiquitous occurrence of disease-related secondary changes in bone metabolism implies that numerous medical disciplines need to interact. Screening for secondary causes of osteoporosis and the search for new modes of action should present a substantial aspect of osteoporosis management. In the book, the current management of osteoporosis and related metabolic bone diseases is discussed.
Fracture is the major complication of osteoporosis, and it allows the identification of individuals needing medical intervention for osteoporosis. After nonvertebral fracture, patients often do not ...receive osteoporosis medical treatment despite evidence that this treatment reduces the risk of subsequent fracture. In this pre planned analysis of the results of the three-year, placebo-controlled FREEDOM trial, we evaluated the effect of denosumab administration on fracture-healing to address theoretical concerns related to initiating or continuing denosumab therapy in patients presenting with a nonvertebral fracture.
Postmenopausal women aged sixty to ninety years with osteoporosis were randomized to receive 60 mg of denosumab (n = 3902) or a placebo (n = 3906) subcutaneously every six months for three years. Investigators reported complications associated with a fracture or its management and with fracture-healing for all nonvertebral fractures that occurred during the study. Delayed healing was defined as incomplete fracture-healing six months after the fracture.
Six hundred and sixty-seven subjects (303 treated with denosumab and 364 who received a placebo) had a total of 851 nonvertebral fractures (386 in the denosumab group and 465 in the placebo group), including 199 fractures (seventy-nine in the denosumab group and 120 in the placebo group) that were treated surgically. Delayed healing was reported in seven subjects (two in the denosumab group and five in the placebo group), including one with subsequent nonunion (in the placebo group). Neither delayed healing nor nonunion was observed in any subject who had received denosumab within six weeks preceding or following the fracture. A complication associated with the fracture or intervention occurred in five subjects (2%) and twenty subjects (5%) in the denosumab and placebo groups,respectively (p = 0.009).
Denosumab in a dose of 60 mg every six months does not seem to delay fracture-healing or contribute to other complications, even when it is administered at or near the time of the fracture.
Abstract Although obesity traditionally has been considered a condition of low risk for osteoporosis, this classic view has recently been questioned. The aim of this study was to assess bone ...microarchitecture and turnover in a mouse model of high-fat diet–induced obesity. Seven-week-old male C57BL/6J mice (n = 18) were randomized into 3 diet groups. One third (n = 6) received a low-fat diet for 24 weeks, one third was kept on an extended high-fat diet (eHF), and the remaining was switched from low-fat to high-fat chow 3 weeks before sacrifice (sHF). Serum levels of insulin, leptin, adiponectin, osteocalcin, and cross-linked telopeptides of type I collagen (CTX) were measured. In addition, bone microarchitecture was analyzed by micro–computed tomography; and lumbar spine bone density was assessed by dual-energy x-ray absorptiometry. The CTX, body weight, insulin, and leptin were significantly elevated in obese animals (sHF: +48%, +24%, +265%, and +102%; eHF: +43%, +52%, +761%, and +292%). The CTX, body weight, insulin, and leptin showed a negative correlation with bone density and bone volume. Interestingly, short-term high-fat chow caused similar bone loss as extended high-fat feeding. Bone volume was decreased by 12% in sHF and 19% in eHF. Bone mineral density was 25% (sHF) and 27% (eHF) lower when compared with control mice on low-fat diet. As assessed by the structure model index, bone microarchitecture changed from plate- to rod-like appearance upon high-fat challenge. Trabecular and cortical thickness remained unaffected. Short-term and extended high-fat diet–induced obesity caused significant bone loss in male C57BL/6J mice mainly because of resorptive changes in trabecular architecture.
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