Age dependence of systemic bone loss and recovery following femur fracture in mice

Abstract

The most reliable predictor of future fracture risk is a previous fracture of any kind. The etiology of this increased fracture risk is not fully known, but it is possible that fracture initiates systemic bone loss leading to greater fracture risk at all skeletal sites. In this study we investigated systemic bone loss and recovery following femoral fracture in young (3 month old) and middleaged (12 month old) mice. Transverse femur fractures were created using a controlled impact, and whole-body bone mineral density (BMD), trabecular and cortical microstructure, bone mechanical properties, bone formation and resorption rates, mouse voluntary movement, and systemic inflammation were quantified at multiple time points post-fracture. We found that fracture led to decreased whole-body BMD in both young and middle-aged mice 2 weeks postfracture; this bone loss was recovered by 6 weeks in young, but not middle-aged mice. Similarly, trabecular bone volume fraction (BV/TV) of the L5 vertebral body was significantly reduced in fractured mice relative to control mice 2 weeks post-fracture (-11% for young mice, -18% for middle-aged mice); this bone loss was fully recovered by 6 weeks post-fracture in young mice.At 3 days post-fracture we observed significant increases in serum levels of interleukin-6 and significant decreases in voluntary movement in fractured mice compared to control mice, with considerably greater changes in middle-aged mice than in young mice. At this time point we also observed increased osteoclast number on L5 vertebral body trabecular bone of fractured mice compared to control mice. These data show that systemic bone loss occurs after fracture in both young and middle-aged mice, and recovery from this bone loss may vary with age. This systemic response could contribute to increased future fracture risk following fracture, and these data may inform clinical treatment of fractures with respect to improving long-term skeletal health.

Incident fracture is associated with a period of accelerated loss of hip BMD: the Study of Osteoporotic Fractures

“…However, because disuse is less likely to be a contributor to hip BMD loss following an upper body fracture, hip bone loss following an upper body fracture may be driven by other non-mechanical mechanisms. In our studies of post-fracture bone loss in mice, we observed considerable systemic inflammation as well as mechanical unloading at early time points post-fracture, along with increased osteoclastogenesis in trabecular bone [19]. These same mechanisms may contribute to post-fracture bone loss in people, since immobility and injury-induced inflammation are operative in this population.…”

“…This bone loss was associated with decreased voluntary movement of mice (mechanical unloading), increased levels of circulating inflammatory cytokines, and increased osteoclast number at early time points (3–4 days) post-injury [19]. This bone loss observed in mice may also occur in elderly individuals post-fracture, since prolonged immobility and inflammation post-fracture in elderly women and men may contribute to fracture risk.…”

Fluorine‐contained hydroxyapatite suppresses bone resorption through inhibiting osteoclasts differentiation and function in vitro and in vivo

“…24 Osteoclasts hyperfunction could then increase the risk rating of poor bone healing and fractures. 25,26 Moreover, generalized osteoporosis was reported to negatively influence implant stability and implant failures are mostly due to poor bone quality. 27,28 In recent years, scaffolds combined with specific actives substance (eg vascular endothelial growth factor and bone morphogenetic protein 2) were utilized to regulate cell behaviour in acellular therapy to promote bone formation.…”

Advances and Promises of Nutritional Influences on Natural Bone Repair

“…This increase in osteoclast-mediated mobilization of calcium can result in a 2-15% reduction in bone mass of intact bones. [42][43][44][45] These metabolic responses to fracture are of extreme clinical relevance as the incidence of clinical or more commonly sub-clinical malnutrition is high in orthopedic trauma patients. 34,46 Malnutrition when present in the context of the hypermetabolic response to trauma can impede healing.…”

“…55 Preventing bone loss in the intact skeleton may have immense clinical utility especially in geriatric patients, considering that posttraumatic bone loss is exacerbated with age. 42 Although these simple interventions can have profound impacts on post-fracture pathophysiology and recovery, poor compliance has been identified as an important factor that may limit the effectiveness of nutritional supplements. 101 Future studies should address the barriers along with strategies to overcome them to inform the best approach to deliver nutritional supplements after fracture.…”