Emerging evidence that adaptive bone formation inhibition by non-steroidal anti-inflammatory drugs increases stress fracture risk

There is mounting evidence suggesting that the commonly used analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), may inhibit new bone formation with physical training and increase risk of stress fractures in physically active populations. Stress fractures are thought to occur when bones are subjected to repetitive mechanical loading, which can lead to a cycle of tissue microdamage, repair, and continued mechanical loading until fracture. Adaptive bone formation, particularly on the periosteal surface of long bones, is a concurrent adaptive response of bone to heightened mechanical loading that can improve the fatigue resistance of the skeletal structure, and therefore may play a critical role in offsetting the risk of stress fracture. Reports from animal studies suggest that NSAID administration may suppress this important adaptive response to mechanical loading. These observations have implications for populations such as endurance athletes and military recruits who are at risk of stress fracture and whose use of NSAIDs is widespread. However, results from human trials evaluating exercise and bone adaptation with NSAID consumption have been less conclusive. In this review, we identify knowledge gaps that must be addressed to further support NSAID-related guidelines intended for at-risk populations and individuals.     

Stéroides sexuels et ostéoporose chez l'homme

Several epidemiological studies have shown that about 25 per cent of hip fractures and 20 per cent of symptomatic vertebral fractures occur in men. The lifetime risk of hip fracture was estimated to be about 6 to 8 per cent and the risk of any osteoporotic fracture was estimated to be about 18 per cent in 50-year-old white men. In about 60% of cases in men, bone loss is secondary to several pathological conditions, such as long-term steroid therapy, severe hypogonadism, smoking or alcohol abuse or gastrointestinal disorders. In 40% of cases, osteoporosis is primary or idiopathic in men between the ages of 40 and 60 years. Genetic factors, a defect of boneforming cells or abnormal serum levels of bioavailable sex steroids could explain bone loss and fragility fractures in these men. It has been shown that hypogonadism is associated with a marked increase in bone remodelling and particularly in bone resorption with a dramatic loss in trabecular bone. It is now known that testosterone is partly transformed into estradiol by aromatase. Testosterone may therefore act on bone in two ways: it directly stimulates bone formation and estradiol regulates bone remodelling and inhibits bone resorption. Finally, in men over the age of 60 without hypogonadism, it has been shown that bone mineral density and fracture risk were better correlated with serum levels of bioavailable estradiol and Sex Hormone Binding Globulin than with serum testosterone levels.     

Septal fracture in simple nasal bone fracture

SUMMARY: Nasal bone fractures are the most common type of facial fractures. Previous studies have shown that most nasal fractures involve the septum, which can provide an obstacle to the successful reduction of nasal bone fractures. In particular, septal fractures in combination with simple nasal bone fractures are usually unrecognized and untreated at the time of injury. Furthermore, systemized treatment protocols and diagnostic tools for septal fractures in the case of simple nasal bone fracture have not previously been presented. In this study, the clinical findings of septal fractures in cases of simple nasal bone fracture were correlated with symptoms, signs, and computed tomography findings and assessed statistically. The patterns of septal fractures in simple nasal bone fractures were assessed by direct vision via hemitransfixion incision. Of the 52 patients with simple nasal bone fracture who presented over a 3-year period and were included in this study, 10 were female and 42 were male, with an average age of 33.8 years (age range, 18 to 61 years). Fifty of these patients (96.2 percent) showed septal fractures, and septoplasty or submucosal resection was performed on 41 patients (78.8 percent) who manifested severe septal fractures of perioperative septal grade 3 or higher. Closed reduction of the nasal bone fracture only was performed on the remaining 11 patients. Among the signs evident at physical examination, mucosal tearing was found to be statistically significant for septal fracture. Computed tomography was found to be very helpful in diagnosing septal fracture but could not predict its severity accurately (Spearman correlation coefficient between computed tomography septal grading and perioperative septal grading, 33.5 percent). Therefore, computed tomography could not be used as a definitive diagnostic modality for septal fractures in terms of deciding whether septoplasty or submucous resection was needed. It is evident that septal fractures are frequent in simple nasal bone fractures that are not combined with other facial bone fractures. This study confirms that there are differences between radiologic findings and perioperative findings. To reduce the incidence of posttraumatic nasal deformity, meticulous physical examinations with subsequent septoplasty or submucosal resection are needed in the treatment of simple nasal bone fracture.     

Atypical subtrochanteric femoral shaft fractures: role for mechanics and bone quality

Bisphosphonates are highly effective agents for reducing osteoporotic fractures in women and men, decreasing fracture incidence at the hip and spine up to 50%. In a small subset of patients, however, these agents have recently been associated with ''atypical femoral fractures'' (AFFs) in the subtrochanteric region or the diaphysis. These fractures have several atypical characteristics, including occurrence with minimal trauma; younger age than typical osteoporotic fractures; occurrence at cortical, rather than cancellous sites; early radiographic appearance similar to that of a stress fracture; transverse fracture pattern rather than the familiar spiral or transverse-oblique morphologies; initiation on the lateral cortex; and high risk of fracture on the contralateral side, at the same location as the initial fracture. Fracture is a mechanical phenomenon that occurs when the loads applied to a structure such as a long bone exceed its load-bearing capacity, either due to a single catastrophic overload (traumatic failure) or as a result of accumulated damage and crack propagation at sub-failure loads (fatigue failure). The association of AFFs with no or minimal trauma suggests a fatigue-based mechanism that depends on cortical cross-sectional geometry and tissue material properties. In the case of AFFs, bisphosphonate treatment may alter cortical tissue properties, as these agents are known to alter bone remodeling. This review discusses the use of bisphosphonates, their effects on bone remodeling, mechanics and tissue composition, their significance as an effective therapy for osteoporosis, and why these agents may increase fracture risk in a small population of patients.     

Propagation of surface fatigue cracks in human cortical bone

An understanding of how fatigue cracks grow in bone is of importance as fatigue is thought to be the main cause of clinical stress fractures. This study presents new results on the fatigue-crack growth behavior of small surface cracks (approximately 75-1000 microm in size) in human cortical bone, and compares their growth rates with data from other published studies on the behavior of both surface cracks and many millimeter, through-thickness large cracks. Results are obtained with a cyclically loaded cantilever-beam geometry using optical microscopy to examine for crack growth after every 100-500 cycles. Based on the current and previous results, small fatigue cracks appear to become more resistant to fatigue-crack growth with crack extension, analogous to the way the fracture resistance of cortical bone increases with crack growth. Mechanistically, a theory attributing such behavior to the development of bridges in the wake of the crack with crack growth is presented. The existence of such bridges is directly confirmed using optical microscopy.     

Contribution of bone mineral density and bone turnover markers to the estimation of risk of osteoporotic fracture in postmenopausal women

In osteoporosis, the main cause for concern is the increase in the risk of fractures. The level of bone mineral density (BMD) measured by various techniques has been shown to be a strong predictor of fracture risk in postmenopausal women. However, half of patients with incident fractures have BMD value above the diagnostic threshold of osteoporosis defined as a T-score of -2.5 SD or more below the average value of young healthy women. Clearly there is a need for improvement in the identification of patients at risk for fracture. Several prospective studies have shown that an increased bone resorption evaluated by specific biochemical markers was associated with increased risk of the hip, spine and non-vertebral fractures independently of BMD. The use of bone markers in individual patients may be appropriate in some situations, especially in women who are not detected at risk by BMD measurements. For example, in the OFELY study including 668 postmenopausal women followed prospectively over 9 years, we found that among the 115 incident fractures, 54 (47%) actually occurred in non-osteoporotic women. Among these women, the combination of bone markers and history of previous fracture was highly predictive of fracture risk. Thus, bone markers may be used in the assessment of fracture risk in selected cases in which BMD and clinical risk factors are not enough to take a treatment decision. Advances in our knowledge of bone matrix biochemistry, most notably of post-translational modifications in type I collagen, may allow identification of biochemical markers that reflect changes in the material property of bone, which is an important determinant of bone strength. Preliminary in vitro studies indicate that the extent of post-translational modifications of collagen--which can be reflected in vivo by the measurement of the urinary ratio between native and isomerised type I collagen--play a role in determining the mechanical competence of cortical bone, independently of BMD. Further studies in osteoporosis should explore the changes in these biochemical parameters of bone matrix as they may represent a key component of bone quality.     

Role of angiogenesis on bone formation

Angiogenesis and bone formation are coupled during skeletal development and fracture healing. This relationship, although known for some time, has not been properly explored. Advances in the discovery of how angiogenesis is regulated in physiological processes like embryogenesis, endometrial regeneration and wound healing or in pathologies such as cancer have provided a deeper understanding of how angiogenic factors may interact with bone cells to improve bone formation and bone regeneration. The lack of oxygen (hypoxia) and the subsequent generation of angiogenic factors have been shown to be critical in the development of a regular skeleton and achieving successful bone regeneration and fracture healing. Given that vascular status is important for a proper bone homeostasis, defining the roles of osteoblasts, osteoclasts, endothelial cells and angiogenic factors and their interactions in bone is a key issue for the development of new strategies to manage bone pathologies and nonfused fractures.     

Relevance of bone mineral density, bone quality and falls in reduction of vertebral and non-vertebral fractures

All epidemiological studies conclude that without prompt, concerted and well-designed prevention programs, the increasing cost related to osteoporotic fractures will become an unbearable burden for the community within the next fifteen years. However, the most effective way of setting up such preventive strategies is not yet unequivocally defined. Low bone mass and microarchitectural damage of bone tissue may account for a large part of the epidemiology of vertebral fractures. Extraskeletal determinants, including low muscle strength, poor balance and gait, all resulting in an increased propensity to fall, also play a major role in the occurrence of hip fracture. Depending on the localization of the fractures, the relative importance of skeletal and extraskeletal risk factors can significantly differ. For prevention of vertebral fractures, drugs affecting bone mass and skeletal architecture may provide a substantial benefit while hip fracture prevention will be more successfully targeted by multi-faceted strategies concentrating not only on the skeletal dimension of the fracture but also aiming, either pharmacologically or through multi-intervention programs, at a reduction in the incidence and in the consequences of falls in the elderly.     

Spontaneous incomplete transverse subtrochanteric femoral fracture with cortical thickening possibly secondary to risedronate use: a case report

ABSTRACT: INTRODUCTION: Osteoporosis is an asymptomatic disease characterized by bone weakening and predisposition to fragility (insufficiency) fractures and can have devastating effects on individual life and great financial impact on the economy. Bisphosphonates are used worldwide for the primary and secondary prevention of osteoporotic fractures. However, increasing evidence raises concern that bisphosphonates can be associated with atypical fractures. CASE PRESENTATION: A 65-year-old Caucasian woman on long-term steroid treatment for polymyalgia rheumatica was admitted with severe and constant pain in the right hip, radiating to the right knee. She had a history of steroid-induced osteoporosis, for which she was started on risedronate four years earlier. She had no history of trauma. Her blood results were unremarkable. Her X-rays confirmed that she had an incomplete right subtrochanteric femoral fracture. A bone scan confirmed the diagnosis and also ruled out any other associated fractures. Our patient successfully underwent internal nail fixation of the fracture. She was reviewed by a rheumatology team, which stopped the risedronate. She was started on treatment with denosumab injection. CONCLUSIONS: Previous case series have reported that long-term bisphosphonate use is associated with atypical fractures of the femur, and certain criteria have been established to help identify such rare fractures. Delayed union or non-union is expected in such fractures following definitive orthopedic treatment because of the long half life of bisphosphonates. In this case report, we try to raise questions related to this important subject, like the duration and safety of bisphosphonate use and the alternative medications used in osteoporosis in this rare condition. We consider this case report not only interesting but also important and unusual because it is about a patient who developed a potentially rare and serious side effect of long-term bisphosphonate use, estimated to affect 2.3 in every 10,000 patients, and who presented with a pelvic X-ray that showed the characteristic features of atypical fractures secondary to risedronate use. In addition, most of the documented cases have been associated with many years of bisphosphonate use whereas our patient had been on risedronate for only four years.     

Osteoporosis: the current status of mesenchymal stem cell-based therapy

Osteoporosis, or bone loss, is a progressive, systemic skeletal disease that affects millions of people worldwide. Osteoporosis is generally age related, and it is underdiagnosed because it remains asymptomatic for several years until the development of fractures that confine daily life activities, particularly in elderly people. Most patients with osteoporotic fractures become bedridden and are in a life-threatening state. The consequences of fracture can be devastating, leading to substantial morbidity and mortality of the patients. The normal physiologic process of bone remodeling involves a balance between bone resorption and bone formation during early adulthood. In osteoporosis, this process becomes imbalanced, resulting in gradual losses of bone mass and density due to enhanced bone resorption and/or inadequate bone formation. Several growth factors underlying age-related osteoporosis and their signaling pathways have been identified, such as osteoprotegerin (OPG)/receptor activator of nuclear factor B (RANK)/RANK ligand (RANKL), bone morphogenetic protein (BMP), wingless-type MMTV integration site family (Wnt) proteins and signaling through parathyroid hormone receptors. In addition, the pathogenesis of osteoporosis has been connected to genetics. The current treatment of osteoporosis predominantly consists of antiresorptive and anabolic agents; however, the serious adverse effects of using these drugs are of concern. Cell-based replacement therapy via the use of mesenchymal stem cells (MSCs) may become one of the strategies for osteoporosis treatment in the future.     

Osteoporosis: pathogenesis and clinical intervention

Osteoporosis is a very common disorder and much has been learnt in recent years about the many pathogenic processes that contribute to bone loss and fragility. Drug treatments are now available to prevent bone loss and reduce fracture, and there are prospects for modifying some of the pathogenic processes themselves. In common with other structures, the tissues of the musculoskeletal system undergo many changes with aging, and some of the commonest skeletal disorders are seen in the elderly. The changes in bone lead to osteoporosis and fractures, whereas muscle changes (sarcopenia) contribute to frailty, and changes in cartilage lead to osteoarthritis.     

A histologic evaluation of fracture repair in the midface

Although much has been written regarding the treatment of facial bone fractures, at the present time there are no available investigations of human microscopic sections to verify the exact nature of the healing process. The consensus in the literature is that following fractures of the midface, the bone segments are united by fibrous union. Biopsies of the healed fracture sites were obtained in 10 consecutive patients who underwent secondary reconstructive procedures to correct residual deformities. Clinical assessment confirmed that the fractures were completely healed and stable. Histologic sections were obtained across the healed fracture sites, sent for H&E staining, and then examined by light microscopy. All specimens showed that the defects between the segments were obliterated by the formation of a mature compact bone. This bridging bone was characterized by concentric lamellae surrounded by a typical bony architecture. From this study it can be concluded that fractures of the midface heal by direct bony union.     

Metabolic bone disease: atypical femoral fractures

Since 2005 reports have been published describing unusual femoral shaft fractures primarily in postmenopausal women treated for prolonged periods with a bisphosphonate drug for osteoporosis. In some patients pain develops in the femur prior to a completed fracture. Bilateral fractures have occurred in some patients. It is unclear whether oversuppression of bone cell activity is a major factor in the pathogenesis of the fractures, or whether these are a rare manifestation of the underlying bone disease. Such fractures do occur in other metabolic bone disorders in which there are marked abnormalities of bone structure.     

Fatigue of bovine trabecular bone

Fatigue loading of bone, from the activities of daily living in the elderly, or from prolonged exercise in the young, can lead to increased risk of fracture. Elderly patients with osteoporosis are particularly prone to fragility fractures of the vertebrae, where load is carried primarily by trabecular bone. In this study, specimens of bovine trabecular bone were loaded in compressive fatigue at four different normalized stresses to one of six maximum strains. The resulting change in modulus and residual strain accumulation were measured over the life of the fatigue test. The number of cycles to reach a given maximum compressive strain increased with decreasing normalized stress. Modulus reduction and specimen residual strain increased with increasing maximum compressive strain, but few differences were observed between specimens loaded to the same maximum strain at different normalized stresses.     

Pathological fractures of the femoral neck

In a review of subcapital fractures due to metastases in the femoral neck it was found that in the majority of cases pain in the region of the hip developed a few days prior to fracture. While the majority of subcapital fractures are sustained as the result of a single incident of trauma, in cases with metastases trabecular stress fractures occur in increasing numbers until finally femoral neck fracture occurs. It would seem that once a critical number of trabecular stress fractures has been reached the patient develops pain. Immediate radiologic examination should be performed, and if there is evidence of bone destruction approaching 50% of the cortex, prophylactic hip pinning is strongly indicated.     

Recommendations on the management of fragility fracture risk in women younger than 70 years

The risk for fragility fracture represents a problem of enormous magnitude. It is estimated that only a small fraction of women with this risk take the benefit of preventive measures. The relationship between estrogen and bone mass is well known as they are the other factors related to the risk for fracture. There are precise diagnostic methods, including a tool to diagnose the risk for fracture. Yet there continues to be an under-diagnosis, with the unrecoverable delay in instituting preventive measures. Women under the age of 70 years, being much more numerous than those older, and having risk factors, are a group in which it is essential to avoid that first fragility fracture. Today it is usual not to differentiate between the treatment and the prevention of osteoporosis since the common aim is to prevent fragility fractures. Included in this are women with osteoporosis or with low bone mass and increased risk for fracture, for whom risk factors play a primary role. There is clearly controversy over the type of treatment and its duration, especially given the possible adverse effects of long-term use. This justifies the concept of sequential treatment, even more so in women under the age of 70, since they presumably will need treatment for many years. Bone metabolism is age-dependent. In postmenopausal women under 70 years of age, the increase in bone resorption is clearly predominant, related to a sharp drop in estrogens. Thus a logical treatment is the prevention of fragility fractures by hormone replacement therapy (HRT) and, in asymptomatic women, selective estradiol receptor modulators (SERMs). Afterwards, there is a period of greater resorption, albeit less intense but continuous, when one could utilise anti-resorptive treatments such as bisphosphonates or denosumab or a dual agent like strontium ranelate. Bone formation treatment, such as parathyroid hormone (PTH), in women under 70 years will be uncommon. That is because it should be used in cases where the formation is greatly diminished and there is a high risk for fracture, something found in much older women.     

Prediction of osteoporotic fractures by postural instability and bone density.

OBJECTIVE--To investigate the utility of risk factors such as bone mineral density, lifestyle, and postural stability in the prediction of osteoporotic fractures. DESIGN--Longitudinal, epidemiological, and population based survey. SETTING--City of Dubbo, New South Wales. SUBJECTS--All residents of Dubbo aged > or = 60 on 1 January 1989. MAIN OUTCOME MEASURE--Incidence of fracture for individual subjects. RESULTS--The overall incidence of atraumatic fractures in men and women was 1.9% and 3.1% per annum respectively. The predominant sites of fracture were hip (18.9%), distal radius (18.5%), ribs and humerus (11.9% in each case), and ankle and foot (9.1% and 6.6% respectively). Major predictors of fractures in men and women were femoral neck bone mineral density, body sway, and quadriceps strength. Age, years since menopause, height, weight, and lifestyle factors were also correlated with bone mineral density and body sway and hence were indirect risk factors for fracture. Discriminant function analysis correctly identified 96% and 93% (sensitivities 88% and 81%) of men and women, respectively, who subsequently developed atraumatic fractures. Predictions based on this model indicated that a woman with a bone mineral density in the lowest quartile in the hip together with high body sway had a 8.4% probability of fracture per annum. This represented an almost 14-fold increase in risk of fracture compared with a woman in the highest bone mineral density quartile with low postural sway. An individual with all three predictors in the "highest risk" quartile had a 13.1% risk of fracture per annum. CONCLUSIONS--Bone mineral density, body sway, and muscle strength are independent and powerful synergistic predictors of fracture incidence.     

Genetic research in osteoporosis: Where are we? Where should we go next?

Fractures resulting from low bone mass and excessive skeletal fragility (osteoporosis) are common worldwide both in males and females, particularly in later years of life. Both fractures, and the most important predictor of fractures, bone mass, are now known to be strongly heritable. This fact, plus the current growth in genetic science, has led to a surge of genetic research in osteoporosis, mostly in the search for genes and their polymorphisms that are responsible for variation in bone mass. Finding the genetic basis underlying variation in bone mass will lead us to deeper understanding of the biology of bone mass accumulation, maintenance and adaptation to load. This, plus finding the genetic basis for overall variation in fracture risk per se, will facilitate the development of interventions, both pharmaceutical and non-pharmaceutical, to prevent and/or treat osteoporosis successfully. This research has produced a rather large number of gene loci that seem to influence bone mass. The challenge now is to refine the statistical genetics and the phenotypes involved so that we can confidently identify those gene loci that truly influence bone mass, and to find ways to study the genetic basis for the most direct disease outcome of interest, fracture.     

Microcrack accumulation at different intervals during fatigue testing of compact bone

Fatigue damage in bone occurs in the form of microcracks. This microdamage contributes to the formation of stress fractures and acts as a stimulus for bone remodelling. A technique has been developed, which allows microcrack growth to be monitored during the course of a fatigue test by the application of a series of fluorescent chelating agents. Specimens were taken from bovine tibiae and fatigue tested in cyclic compression at a stress range of 80MPa. The specimens were stained before testing with alizarin and up to three other chelating agents were applied during testing to label microcracks formed at different times. Microcracks initiated in interstitial bone in the early part of a specimen's life. Further accumulation of microcracks is then suppressed until the period late in the specimen's life. Microcracks were found to be longer in the longitudinal than in the transverse direction. Only a small proportion of cracks are actively propagating; these are longer than non-propagating cracks. These results support the concept of a microstructural barrier effect existing in bone, whereby cracks initiate easily but slow down or stop at barriers such as cement lines.