High fluoride and low calcium levels in drinking water is associated with low bone mass, reduced bone quality and fragility fractures in sheep.

UNLABELLED: Chronic environmental fluoride exposure under calcium stress causes fragility fractures due to osteoporosis and bone quality deterioration, at least in sheep. Proof of skeletal fluorosis, presenting without increased bone density, calls for a review of fracture incidence in areas with fluoridated groundwater, including an analysis of patients with low bone mass. INTRODUCTION: Understanding the skeletal effects of environmental fluoride exposure especially under calcium stress remains an unmet need of critical importance. Therefore, we studied the skeletal phenotype of sheep chronically exposed to highly fluoridated water in the Kalahari Desert, where livestock is known to present with fragility fractures. METHODS: Dorper ewes from two flocks in Namibia were studied. Chemical analyses of water, blood and urine were executed for both cohorts. Skeletal phenotyping comprised micro-computer tomography (µCT), histological, histomorphometric, biomechanical, quantitative backscattered electron imaging (qBEI) and energy-dispersive X-ray (EDX) analysis. Analysis was performed in direct comparison with undecalcified human iliac crest bone biopsies of patients with fluoride-induced osteopathy. RESULTS: The fluoride content of water, blood and urine was significantly elevated in the Kalahari group compared to the control. Surprisingly, a significant decrease in both cortical and trabecular bones was found in sheep chronically exposed to fluoride. Furthermore, osteoid parameters and the degree and heterogeneity of mineralization were increased. The latter findings are reminiscent of those found in osteoporotic patients with treatment-induced fluorosis. Mechanical testing revealed a significant decrease in the bending strength, concurrent with the clinical observation of fragility fractures in sheep within an area of environmental fluoride exposure. CONCLUSIONS: Our data suggest that fluoride exposure with concomitant calcium deficit (i) may aggravate bone loss via reductions in mineralized trabecular and cortical bone mass and (ii) can cause fragility fractures and (iii) that the prevalence of skeletal fluorosis especially due to groundwater exposure should be reviewed in many areas of the world as low bone mass alone does not exclude fluorosis.

Increased osteoblast and osteoclast indices in individuals with systemic mastocytosis.

UNLABELLED: Indolent systemic mastocytosis (ISM) can trigger bone loss. However, the clinical relevance of different mast cell infiltration patterns for bone remains to be clarified. Here, we report increased bone turnover in individuals with ISM, and its extent is rather related to the type of mast cell distribution within the bone marrow than to the presence or absence of cutaneous manifestations. INTRODUCTION: It is well established that ISM can trigger osteopenia or osteoporosis. However, neither the clinical relevance of the infiltration pattern of mast cells within the bone marrow nor the impact of the presence or absence of cutaneous mast cell infiltration has been elucidated. METHODS: We retrospectively analysed 300 cases with histologically proven ISM of the bone marrow and performed quantitative histomorphometry for a subgroup of 159 patients that did not receive any treatment before the biopsies were taken. Most importantly, since 66 % of the patients displayed ISM without the characteristic skin lesions, we were able to compare ISM with or without cutaneous manifestation. RESULTS: We found that both forms of ISM were not only characterized by a decreased trabecular bone mass but also by an increased number of osteoclasts and osteoblasts. Interestingly, when we analysed these data in relation to mast cell distribution, we found that the bone cell numbers in cases with mast cell granulomas were significantly increased compared to cases with diffuse mast cell distribution. Moreover, evidence of increased bone turnover was also found in 16 patients displaying osteosclerosis. CONCLUSION: Based on the largest cohort of bone biopsies from patients with ISM analysed so far, we could demonstrate high bone turnover, more specifically increased osteoblast and osteoclast numbers and surface indices, as a cause of the skeletal changes. Moreover, the severity of the bone disease is presumably rather dependent on the amount of mast cells and their distribution within the bone marrow irrespective of the presence or absence of cutaneous involvement.

Impaired bone mineralization accompanied by low vitamin D and secondary hyperparathyroidism in patients with femoral neck fracture.

SUMMARY: Although it is well established that a decrease in bone mass increases the risk of osteoporotic fractures, the proportion of fractures attributable to areal bone mineral density (BMD) is rather low. Here, we have identified bone mineralization defects together with low serum 25-hydroxyvitamin D (25-(OH) D) levels as additional factors associated with femoral neck fractures. INTRODUCTION: Osteoporotic fractures of the femoral neck are associated with increased morbidity and mortality. Although it is well established that a decrease in bone mass increases the risk of osteoporotic fractures, the proportion of fractures attributable to areal BMD is rather low. To identify possible additional factors influencing femur neck fragility, we analyzed patients with femoral neck fracture. METHODS: We performed a detailed clinical and histomorphometrical evaluation on 103 patients with femoral neck fracture including dual-energy X-ray absorptiometry, laboratory parameters, and histomorphometric and bone mineral density distribution (BMDD) analyses of undecalcified processed biopsies of the femoral head and set them in direct comparison to skeletal healthy control individuals. RESULTS: Patients with femoral neck fracture displayed significantly lower serum 25-(OH) D levels and increased serum parathyroid hormone (PTH) compared to controls. Histomorphometric analysis revealed not only a decreased bone volume and trabecular thickness in the biopsies of the patients, but also a significant increase of osteoid indices. BMDD analysis showed increased heterogeneity of mineralization in patients with femoral neck fracture. Moreover, patients with femoral neck fracture and serum 25-(OH) D levels below 12 µg/l displayed significantly thinner trabecular bone. CONCLUSION: Taken together, our data suggest that impaired bone mineralization accompanied by low serum 25-(OH) D levels is of major importance in the etiology of femoral neck fractures. Therefore, balancing serum 25-(OH) D levels and thereby normalizing PTH serum levels may counteract pronounced mineralization defects and might decrease the incidence of femoral neck fractures.

Large animal model for osteoporosis in humans: the ewe.

Osteoporosis is a chronic systemic disease characterised by bone loss and microarchitectural deterioration. Since the underlying regulatory mechanisms are still not fully understood and treatment options are not satisfactorily resolved, massive efforts are underway to further investigate this critical illness. Large animal models are stipulated, e.g. by the Food and Drug Administration, for preclinical prevention and intervention studies related to osteoporosis research; in this context, the ewe has already proven its value for orthopaedic research. Although oestrogen deficiency doubtless influences bone metabolism in sheep, the ovariectomised ewe seems unsuitable as a model for postmenopausal osteoporosis and bone loss induction due to its unreliable impact on bone mass and structure. In contrast, glucocorticoid treatment has a major impact on bone turnover and leads to bone conditions comparable to those found in steroid-treated humans. However, adverse side effects can be dramatic resulting in unacceptable discomfort and illness of the experimental animals. Further improvements are therefore essential to judge this model as ethically appropriate. Additionally, models for osteoporosis induced by surgical interventions of central regulatory mechanisms seem to be attractive, as remarkable bone loss is induced by only one surgical procedure without any further treatment. Taken together, different ewe models for osteoporosis have been successfully established and are invaluable for orthopaedic research. However, the search for a 'perfect' large remodelling animal model - in terms of mimicking the human disease and compatibility of bone loss, and without ethical concerns - is still on-going.

Management of traumatic spinopelvic dissociations: review of the literature.

PURPOSE: Spinopelvic dissociation is a rare high-energy injury pattern in adults associated with high morbidity and an increased rate of neurological deficits. The purpose of this article is the conception of fracture type-associated treatment recommendations. METHODS: This article is based on our own experience with spinopelvic dissociations and a review of the current literature. RESULTS: Bilateral vertical plus an optional transverse fracture component configures spinopelvic dissociations as "U"- or "H"-shaped, with the result of a spinopelvic dissociation. "Y"-, "T"- or "II"-shaped fractures do not necessarily belong to this entity but can be subsumed to this entity in a wider sense. The surgical treatment of these injuries remains challenging. Initial haemodynamic stabilisation represents the main goal of primary care until definitive treatment can be performed. Anatomical reduction is demanding and even more complex in fracture areas with large comminution. Surgical treatment options depend on the fracture type, including transsacral screws, sacral banding and spinopelvic fixation, plus combinations of these procedures. CONCLUSIONS: Spinopelvic dissociations remain highly complex injuries. "U"- and "H"-shaped fractures usually require triangular fixation, whereas "II"-, "Y"- and "T"-shaped fractures might be sufficiently stabilised with transsacral screws.

Skeletal mineralization defects in adult hypophosphatasia--a clinical and histological analysis.

UNLABELLED: Histomorphometry and quantitative backscattered electron microscopy of iliac crest biopsies from patients with adult hypophosphatasia not only confirmed the expected enrichment of non-mineralized osteoid, but also demonstrated an altered trabecular microarchitecture, an increased number of osteoblasts, and an impaired calcium distribution within the mineralized bone matrix. INTRODUCTION: Adult hypophosphatasia is an inherited disorder of bone metabolism caused by inactivating mutations of the ALPL gene, encoding tissue non-specific alkaline phosphatase. While it is commonly accepted that the increased fracture risk of the patients is the consequence of osteomalacia, there are only few studies describing a complete histomorphometric analysis of bone biopsies from affected individuals. Therefore, we analyzed iliac crest biopsies from eight patients and set them in direct comparison to biopsies from healthy donors or from individuals with other types of osteomalacia. METHODS: Histomorphometric analysis was performed on non-decalcified sections stained either after von Kossa/van Gieson or with toluidine blue. Bone mineral density distribution was quantified by backscattered electron microscopy. RESULTS: Besides the well-documented enrichment of non-mineralized bone matrix in individuals suffering from adult hypophosphatasia, our histomorphometric analysis revealed alterations of the trabecular microarchitecture and an increased number of osteoblasts compared to healthy controls or to individuals with other types of osteomalacia. Moreover, the analysis of the mineralized bone matrix revealed significantly decreased calcium content in patients with adult hypophosphatasia. CONCLUSIONS: Taken together, our data show that adult hypophosphatasia does not solely result in an enrichment of osteoid, but also in a considerable degradation of bone quality, which might contribute to the increased fracture risk of the affected individuals.

[Skeletal and dermatological manifestations of the nevoid Basal cell carcinoma syndrome (Gorlin-Goltz syndrome). Results of 8 patients in 12 years]. / Skelettale und kutane Charakteristika des nävoiden Basalzellkarzinomsyndroms (Gorlin-Goltz-Syndrom). Ergebnisse von 8 Patienten aus 12 Jahren.

PURPOSE: In 1960 Gorlin and Goltz defined the nevoid basal cell carcinoma syndrome (NBCCS, Gorlin-Goltz Syndrome) as a syndrome comprising multiple basal cell carcinoma, odontogenic keratocysts, and skeletal anomalies. NBCCS is an autosomal dominantly inherited disease with an estimated prevalence of 1:150,000 and diagnosis of this syndrome is often an accidental finding of radiological investigations. The purpose of this study was to report the varied radiological and dermatological manifestations of our patients affected with NBCCS and to present this rare syndrome as a differential diagnosis of skeletal anomalies. MATERIALS AND METHODS: Between 1994 and 2005 the demographic, clinical, radiological and histological data of 8 patients with NBCCS were retrospectively analyzed. Nevoid basal cell carcinoma syndrome was diagnosed in the event of two major or one major and two minor criteria. The major criteria are more than 2 basal cell carcinoma, odontogenic keratocysts, three or more palmar pits, and calcification of the falx cerebri. RESULTS: Between 1994 and 2005 8 patients (3 females and 5 males) with NBCCS were treated in our departments. The average age at the time of diagnosis of NBCCS was 49.9 years. All patients had a minimum of two major criteria. The major criteria with the most frequency were the basal cell carcinoma (6 patients) and the odontogenic keratocysts (5 patients), followed by the calcification of the falx cerebri and palmoplantar pits (4 patients). There was no gender-related or age-related predilection and only one patient was affected with pain in his fingers which radiologically correlated to small cystic bone lesions ("flame-shaped lucencies"). CONCLUSION: Due to limitations in identification of mutations in the PTCH1 gene, clinical and radiological examination still remains a very important factor in the treatment of patients suffering from NBCCS. The knowledge of the varied skeletal manifestations and constellations is therefore essential and correlates with therapeutic consequences. Often chest, rib, spine, skull, and jaw X-rays show the way. Due to the risk of the development of an associated medulloblastoma, neurological surveillance in 6-month intervals in addition to an annual MRI of the cerebrum up to an age of 7 is strongly recommended.

[Subdental synchondrosis. Computed tomographic and histologic investigation on morphological aspects of fracture at the base of the dens in 36 human axis specimens]. / Die subdentale Synchondrose. Eine computertomographische und histologische Untersuchung zu morphologischen Aspekten der Densbasisfraktur an 36 humanen Axispräparaten.

BACKGROUND: During development of the axis, four different ossification centers are formed. The two cranial ossification centers are demarcated from the ossification center of the vertebral corpus by a subdental synchondrosis. During further development the subdental synchondrosis--which is thought to close spontaneously--might not close completely, which leads to the necessity for differentiating synchondrotic remnants from a fracture at the base of the dens (type II according to Anderson and D'Alonzo). RESULTS: To characterize the architecture of the axis with particular attention to the subdental synchondrosis, the axis was harvested from 36 age- and gender-matched patients covering the human aging process from adolescence to senescence. In all specimens bone mineral density (BMD) was measured by peripheral quantitative computed tomography (pQCT). Morphological analysis after undecalcified processing of all specimens revealed a persistency of the subdental synchondrosis in 87% of all patients. Histological characterization of the subdental synchondrosis showed a cartilaginous structure interspersed with focal mineralization. Furthermore, static histomorphometric analysis revealed that trabecular bone volume and cortical thickness were significantly reduced within the base of the axis as compared to the dens and the corpus, respectively. CONCLUSION: Taken together, these results provide evidence that the base of the axis is a structurally distinct region. Besides well-recognized biomechanical aspects, these results suggest that the structure of the base of the axis might contribute to the occurrence of fractures of the axis and offer an additional explanation for the observation of nonunion after type II dens fractures.

[The calcaneus as the site of manifestation for osteoporosis-associated fractures: age- and sex-specific changes in calcaneal morphology correlate with the incidence and severity of intra-articular calcaneal fractures]. / Der Kalkaneus als Manifestationsort osteoporoseassoziierter Frakturen: Alters- und geschlechtsabhängige Veränderungen der Kalkaneusmorphologie korrelieren zur Inzidenz und Schwere intraartikulärer Kalkaneusfrakturen.

BACKGROUND: While it is recognized that trauma energy at the time of injury is an important factor in the pathogenesis and severity of calcaneal fractures, the possible role of changes in calcaneal microarchitecture remains largely undefined. The purpose of this study was to determine whether the calcaneal bone structure changes with age and to address if local bone mass is of clinical relevance in respect to the occurrence and complexity of calcaneal fractures. MATERIAL AND METHODS: The radiographic and clinical data of 182 patients with intra-articular calcaneal fractures were analyzed to provide correlative clinical evidence for a relation between local bone mass and fractures of the calcaneus. To measure bone mass, 60 calcanei were harvested from 30 age- and gender-matched patients at autopsy. RESULTS: The average age at the time of fracture was higher in females (46.0+/-18.3 years) than in males (39.9+/-13.9 years). Furthermore, the relative frequency of fractures during aging shifted from males to females and the frequency of compound fractures was higher in females (65%) than in males (48%). The calcaneal bone mass was significantly reduced by 19% in older females (female symbol 20-40 years: 292 mg/cm(3); female symbol 61-80 years: 237 mg/cm(3); p<0.05). CONCLUSION: The calcaneus displayed age- and gender-related changes in its microarchitecture that are known to reduce the biomechanical stability of trabecular bone. These results suggest that bone mass and structure are risk factors in respect to the occurrence and severity of calcaneal fractures.

[Simple bone cysts of the calcaneus. Differential diagnosis and therapy]. / Kalkaneuszysten. Differentialdiagnose und Therapie.

Fifty-two calcaneal simple bone cysts from our clinic were evaluated. The lesions had a pathognomonic radiologic appearance and diagnosis was histologically confirmed in all operatively treated cases. Four cases presented with pathological fractures, three of which were treated by open reduction internal fixation and bone grafting, while one was treated nonoperatively. In addition, six patients with large cysts without apparent fracture but spontaneous pain were treated by curettage and subsequent autogenous bone grafting or calcium phosphate cement filling, and there were no recurrences. The majority of cysts (42 of 52) were however asymptomatic and thus followed up nonoperatively. This review reports on one of the largest series of cysts in this location. The results indicate that nonoperative management is justified in most asymptomatic cases. However, the potential risk of fracture as indicated by four fractured calcaneal cysts in this series suggests that large cysts should be clinically monitored and that operative intervention is useful in all symptomatic cases to prevent pathologic fractures. In the latter cases, curettage and bone grafting as well as the use of bone substitute material yielded uniformly good results.

Osteopenic mice: animal models of the aging skeleton.

While our understanding of the developmental biology of the skeleton, like that of virtually every other subject in biology, has been transformed by recent advances in human and mouse genetics, we still know very little, in molecular and genetic terms, about skeletal physiology. Thus, among the many questions that are largely unexplained are the following: why is osteoporosis mainly a women's disease? How is bone mass maintained nearly constant between the end of puberty and the arrest of gonadal functions? Molecular genetics has emerged as a powerful tool to study previously unexplored aspects of the physiology of the skeleton. Among mammals, mice are the most promising animals for this experimental work. This has been previously demonstrated e.g. through the tremendous impact of the different osteopetrotic models on our molecular understanding of osteoclastic bone resorption. Until recently the only way of studying bone loss situations and osteoporosis in mice was by using ovariectomy with all its limitations. Today, however, we have access to more sophisticated osteoporotic mouse-models from four different origins: Transgenic mice (HSV-TK), knock-out mice (OPG), inbred-strains (SAMP6), and through physiological modulation (icv application). These new models have already taught us several important lessons. The first is, that bone remodeling is more than just an autocrine/paracrine process. Multiple experimental evidence has demonstrated that the latter regulation exists, but genetics prove that there is no functional cross-control between resorption and formation. The second lesson is, that remodeling is, at least in part, subject to central regulation. Thus, osteoporosis is partly a central or hypothalamic disease. However, the most dramatic change and the most important advantage we feel is, that today we have models to test a new hypothesis regarding the etiology of osteoporosis before it turns to dogma. Taken together, mouse-studies may lead to a shift in our physiological understanding of skeleton biology and to the emergence of novel paradigms. These, in turn, should help us to devise new treatments for degenerative diseases of the skeleton such as osteoporosis and its associated clinical problems.

Transgenic and knock out mice in skeletal research. Towards a molecular understanding of the mammalian skeleton.

Our understanding of the biology of the skeleton, like that of virtually every other subject in biology, has been transformed by recent advances in human and mouse genetics. Among mammals, mice are the most promising animals for this experimental work. Because extensive genetic information exists, many mouse mutations are known, and cells from early mouse developmental stages are accessible, scientists have developed transgenic mice - mice in which a gene is introduced or ablated in the germ line. Thus far, we have analyzed more than 100 different transgenic and knock out models with various skeletal phenotypes, covering the major aspects of both skeletal development and skeletal maintenance. Based on these results we here present a first perspective on transgenic and gene knock out animals in skeletal research, including insights in signaling pathways controlling endochondral bone formation, in the regulation of osteoblast function, osteoclastic bone resorption and in bone tumorigenesis, as well as the central control of bone formation. The use of transgenic mice to dissect and analyze regulatory mechanisms in bone cell physiology and the pathogenesis of human bone diseases is an extremely powerful experimental tool. The data presented here demonstrate that the successful convergence of novel genetic approaches with the established and fundamental knowledge of bone biology has made a beginning.

[Indirect traumatic diaphragmatic ruptures after blunt abdominal or thoracic trauma]. / Indirekte traumatische Zwerchfellrupturen nach stumpfem Bauch- oder Thoraxtrauma.

Traumatic diaphragmatic rupture after blunt thoracic or abdominal trauma is an indicator of serious associated injuries, but is itself often occult. Its diagnosis is still a challenge. In 14 consecutive patients with diaphragmatic rupture we developed a strategy for diagnostic work-up and therapy of diaphragmatic disruption. Ultrasound showed a sensitivity of 89% versus 50 and 29% in chest X-ray and CT scan, respectively. Ultrasound of the diaphragm directly after admission and after stabilization of the trauma patient in order to find diaphragmatic disruption early is compulsory. Early treatment will avoid associated complications.

[Radiation-exposure studies of CT diagnosis with the standard and spiral technics]. / Untersuchungen zur Strahlenexposition der CT-Diagnostik mit der Standard- und Spiraltechnik.

Comparison of the radiation exposure during CT quoted in the literature shows considerable variation; this depends on differences in apparatus, methods of examination and measurements. A systematic investigation into radiation dose during CT is therefore necessary to obtain accurate radiation doses during various examinations in order to balance risks against usefulness. The present paper deals with the radiation dose received by the patient during examinations of the cerebrum, neck, thorax, upper and lower abdomen and pelvis, using standard and spiral CT techniques. Organ doses for all organs at risk, surface dose, total body dose and dose profiles along the body axis for each type of examination have been established, which will allow the user to evaluate radiation dose.