Is centrally induced alveolar bone loss in a large animal model preventable by peripheral hormone substitution?

OBJECTIVES: Alveolar bone structures are mostly investigated in small animal models. The majority of these studies examined local influences on the alveolar bone, but only a few examined systemic influencing factors. The hypothalamic-pituitary axis is known to be essential for a vital bone balance. The aim of this study was to analyse the effects that selective hormone treatments have on alveolar bone structure and quality in a sheep model for alveolar bone loss, induced by hypothalamic-pituitary disconnection (HPD). METHODS: Thirty sheep were randomly selected into six groups of five each: control (C), ovariectomy-OVX (O), O + HPD (OH), OH with oestrogen treatment (OHE), OH with thyroxine (T4) treatment (OHT), and OH with a combined treatment of oestrogen and thyroxine (OHTE). After OVX and HPD procedures and an additional 9-month observation/treatment period, structural bone analyses of the mandible were performed by contact radiography, micro-CT, and static histomorphometry. RESULTS: The HPD procedure caused structural alveolar bone parameters to decrease significantly compared to controls (C). Treatment with oestrogen (OHE) was protective and bone structure was maintained at baseline levels. Thyroxine treatment (OHT) promoted significant bone loss, but the combined treatment (OHTE) improved bone structure and volume parameters even above baseline levels. CONCLUSIONS: Alveolar bone homeostasis significantly underlies systemic regulatory systems. Centrally induced (HPD) bone loss can be prevented by combined peripheral treatment with oestrogen and thyroxine. CLINICAL RELEVANCE: These results demonstrate the significance of a balanced hormonal regulatory system for steady bone remodelling and maintenance of healthy alveolar bone.

Intra-articular osteoid osteoma as a differential diagnosis of diffuse mono-articular joint pain.

BACKGROUND: The aim of this retrospective study was to investigate the frequency of intra-articular osteoid osteoma (iaOO) in a large study cohort and to demonstrate its clinical relevance as an important differential diagnosis of non-specific mono-articular joint pain. METHODS: We searched the registry for bone tumours of the University Medical Centre Hamburg-Eppendorf for osteoid osteomas in the last 42 years. Herein, we present three selected iaOO which were detected in the three major weight-bearing joints. Computed tomography (CT) or magnetic resonance imaging (MRI) scans were performed for initial diagnosis. RESULTS: Out of a total of 367 osteoid osteomas, 19 (5.2 %) tumours were localized intra-articularly. In all three presented tumours, a history of severe mono-articular pain was reported; however, the mean time to correct diagnosis was delayed to 20.7 months. Clearly, the nidus seen in CT and MRI images in combination with inconsistent salicylate-responsive nocturnal pain led to the diagnosis of iaOO. CONCLUSIONS: Rarely, osteoid osteoma can occur in an intra-articular location. In cases of diffuse mono-articular pain, iaOO should be considered both in large and smaller joints to avoid delays in diagnosis and therapy of this benign bone tumour.

Deterioration of teeth and alveolar bone loss due to chronic environmental high-level fluoride and low calcium exposure.

OBJECTIVES: Health risks due to chronic exposure to highly fluoridated groundwater could be underestimated because fluoride might not only influence the teeth in an aesthetic manner but also seems to led to dentoalveolar structure changes. Therefore, we studied the tooth and alveolar bone structures of Dorper sheep chronically exposed to very highly fluoridated and low calcium groundwater in the Kalahari Desert in comparison to controls consuming groundwater with low fluoride and normal calcium levels within the World Health Organization (WHO) recommended range. MATERIALS AND METHODS: Two flocks of Dorper ewes in Namibia were studied. Chemical analyses of water, blood and urine were performed. Mineralized tissue investigations included radiography, HR-pQCT analyses, histomorphometry, energy-dispersive X-ray spectroscopy and X-ray diffraction-analyses. RESULTS: Fluoride levels were significantly elevated in water, blood and urine samples in the Kalahari group compared to the low fluoride control samples. In addition to high fluoride, low calcium levels were detected in the Kalahari water. Tooth height and mandibular bone quality were significantly decreased in sheep, exposed to very high levels of fluoride and low levels of calcium in drinking water. Particularly, bone volume and cortical thickness of the mandibular bone were significantly reduced in these sheep. CONCLUSIONS: The current study suggests that chronic environmental fluoride exposure with levels above the recommended limits in combination with low calcium uptake can cause significant attrition of teeth and a significant impaired mandibular bone quality. CLINICAL RELEVANCE: In the presence of high fluoride and low calcium-associated dental changes, deterioration of the mandibular bone and a potential alveolar bone loss needs to be considered regardless whether other signs of systemic skeletal fluorosis are observed or not.

Mandibular bone loss in ewe induced by hypothalamic-pituitary disconnection.

PURPOSE: It is supposed that the demographic change will lead to an increase in patients with impaired alveolar bone conditions. Large animal models are of particular interest in this context as they are suitable for developing and testing new dental implants. Recently, we demonstrated that surgical hypothalamo-pituitary disconnection (HPD) causes a pronounced low-turnover situation leading to cortical and trabecular bone loss in sheep. In this study, we aimed to investigate the influence of the HPD procedure on the alveolar bone. METHODS: Ten adult Merino ewes were randomly assigned to two groups: Control and HPD. After 6 months, we analysed the cortical and trabecular bone of all mandibles by histomorphometry and high-resolution peripheral quantitative computed tomography (HR-pQCT). RESULTS: HPD ewes showed a significant decrease in cortical thickness by ~20%, a significant increase in cortical porosity by ~20% and a significant decrease in bone volume by ~30% in comparison with Control ewes. CONCLUSION: Our results underline the importance of central regulatory mechanisms of bone turnover. However, further studies are needed to understand these central regulatory elements of bone turnover in detail and to judge the value of the HPD sheep for dental research.

Incidence, histopathologic analysis and distribution of tumours of the hand.

BACKGROUND: The aim of this large collective and meticulous study of primary bone tumours and tumourous lesions of the hand was to enhance the knowledge about findings of traumatological radiographs and improve differential diagnosis. METHODS: This retrospective study reviewed data collected from 1976 until 2006 in our Bone Tumour Registry. The following data was documented: age, sex, radiological investigations, tumour location, histopathological features including type and dignity of the tumour, and diagnosis. RESULTS: The retrospective analysis yielded 631 patients with a mean age of 35.9 ± 19.2 years. The majority of primary hand tumours were found in the phalanges (69.7%) followed by 24.7% in metacarpals and 5.6% in the carpals. Only 10.6% of all cases were malignant. The major lesion type was cartilage derived at 69.1%, followed by bone cysts 11.3% and osteogenic tumours 8.7%. The dominant tissue type found in phalanges and metacarpals was of cartilage origin. Osteogenic tumours were predominant in carpal bones. Enchondroma was the most commonly detected tumour in the hand (47.1%). CONCLUSIONS: All primary skeletal tumours can be found in the hand and are most often of cartilage origin followed by bone cysts and osteogenic tumours. This study furthermore raises awareness about uncommon or rare tumours and helps clinicians to establish proper differential diagnosis, as the majority of detected tumours of the hand are asymptomatic and accidental findings on radiographs.

The SERM raloxifene improves diaphyseal fracture healing in mice.

Although several studies reported that raloxifene treatment improves postmenopausal osteoporotic bone structure and reduces fracture risk, only a few animal and no human studies have examined its effects on the fracture healing process. Thus the aim of the present study was to determine, whether systemic application of the selective estrogen receptor modulator raloxifene promotes fracture healing compared to untreated control-, estrogen-deficient-, as well as estrogen-treated mice using a standardized femoral osteotomy model (n = 60 mice). Ten days after surgery, contact radiography and undecalcified histomorphometric analysis revealed that raloxifene administration significantly improved the early stage of fracture healing compared to all other groups. At day 20, raloxifene and estrogen treatment led to a significant increase in callus mineralization and trabecular thickness compared to control mice. µCT analyses revealed no evidence of complete bony bridging of the fracture site in any control-, nor estrogen-deficient mouse after 20 days, while all femoral fractures in the raloxifene and estrogen group already healed adequately at this time. These data indicate that raloxifene treatment significantly improves all phases of fracture healing at least in mice. Therefore, raloxifene could be a possible pharmaceutical to enhance fracture healing in women, without the known side effects of estrogen.

The distal radius, the most frequent fracture localization in humans: a histomorphometric analysis of the microarchitecture of 60 human distal radii and its changes in aging.

BACKGROUND: The distal radius is the most frequent fracture localization in humans. Although younger patients receive a distal radius fracture after an adequate trauma, elderly patients suffer fractures through low-energy mechanisms. Low-energy fractures are hallmarks of osteoporosis. Osteoporotic changes of the distal radius are well described by DXA and peripheral quantitative computed tomography measurements. However, to date, the effects of aging on the microarchitecture of the distal radius have not been investigated. METHODS: To investigate whether the microarchitecture of the human distal radius shows osteoporotic changes in bone mass and structure during aging, we dissected out 60 complete human distal radii from 30 age- and gender-matched patients at autopsy. Each of the three different age groups (group I: 20-40 years, group II: 41-60 years, group III: 61-80 years) was represented by 10 autopsy cases and 20 specimens (double-sided extraction), respectively. The specimens were analyzed by peripheral quantitative computed tomography, contact-radiography, and histomorphometry. RESULTS: We observed a significant age-related decrease in bone mass, bone mineral density and an increase in typical osteoporotic changes of the bone microarchitecture in female distal radius specimens. Comparable observations of age-related changes have not been made in male specimens. CONCLUSIONS: The distal radius is a location of osteoporosis-specific bone changes. Our data provide evidence for the occurrence of typical osteoporotic changes, especially postmenopausal osteoporotic changes, in the distal radius during aging.

Effects of increased bone formation on fracture healing in mice.

BACKGROUND: Fracture healing is a complex and sequential process. One important step in fracture healing is callus remodeling. As we could previously show, an increase of osteoclast bone resorption as a result of estrogen deficiency impairs the fracture healing process. Therefore, the aim of our study was to analyze whether an increased bone formation, as the counterpart of bone resorption in callus remodeling, would accelerate the fracture healing process. METHODS: Standardized femoral fractures were produced in 10-week-old control, leptin-deficient (ob/ob), and leptin receptor-deficient (db/db) mice using a guillotine-like fracture device. Accordingly, the fractures were intramedullary stabilized. The ob/ob and db/db mice are known to have a twofold increase in bone formation in comparison with normal wildtype mice. At different stages of fracture healing, contact X-ray, histologic, and biomechanical analyses were performed. RESULTS: We observed that a twofold increase in bone formation leads to an accelerated periosteal callus formation followed by callus remodeling. As compared with the control group, chondrocytes area was increased, and the subsequent mineralization appeared earlier. In the late stage of fracture healing, the ob/ob and db/db mice showed a thinner but increased mineralized cortex. Biomechanical testing confirmed the beneficial effects of an increased bone formation on restoration of biomechanical competence. CONCLUSION: These results indicate that bone formation is of major importance in all stages of fracture healing. A twofold increase in bone formation is able to significantly accelerate the fracture healing process of long bones at least in mice. Therefore, an increase in bone formation would be a possible pharmaceutical target to enhance fracture healing.

How much vitamin D do we need for skeletal health?

BACKGROUND: Vitamin D is critical for musculoskeletal health and has been implicated in the risk of extraskeletal diseases, including cancer, cardiovascular diseases, and autoimmune diseases, as well as overall mortality. Although numerous studies deal and have dealt with vitamin D deficiency and its consequences, experts cannot agree on the right 25-hydroxyvitamin D levels. This survey aims to shed light on the ongoing vitamin D controversy from different angles. QUESTIONS/PURPOSES: We discuss the minimum threshold for the 25-hydroxyvitamin D level to guarantee optimal health, why vitamin is D critical to musculoskeletal and extraskeletal functions, and new evidence for the success of prevention measures such as food fortification. METHODS: We searched PubMed, Google Scholar, and reference lists of articles using several keywords. The most recent search was in February 2011. RESULTS: While the use of parathyroid hormone as a surrogate measure did not lead to a consensus concerning the required 25-hydroxyvitamin D serum level, the combined analysis of bone mineralization and vitamin D status has established minimum levels of more than 75 nmol/L (30 ng/mL) to guarantee at least skeletal health. An effective measure to approach this status is food fortification, which has been demonstrated by countries such as Canada, the United States, and Finland. CONCLUSIONS: Given the health economic implications of failure to maintain a balanced vitamin D status, action is recommended to integrate current scientific knowledge on vitamin D into physicians' treatment of patients and governmental policies on food fortification.

Effects of estrogen on fracture healing in mice.

BACKGROUND: Fracture healing is a complex and sequential process. One important step in fracture healing is callus remodeling. Estrogen deficiency is known to increase osteoclast bone resorption, whereas estrogen replacement can reverse this effect. Therefore, the aim of our study was to analyze whether estrogen deficiency and estrogen treatment, respectively, would affect callus remodeling in the fracture healing process. METHODS: Standardized femoral fractures were produced in 10 weeks old C57BL/6 mice using a guillotine-like fracture device. Mice were separated into three groups. The first group obtained a continuous administration of estrogen. Ovariectomy (OVX) was performed in the second group to generate an estrogen-deficiency model. The control group obtained no special treatment. At different stages of fracture healing, contact X-ray, micro-computed tomography, histologic, and biomechanical analyses were performed. RESULTS: We observed that, in early stages of fracture healing, OVX leads to an impaired periosteal callus formation. When compared with the control group, chondrocytes area was decreased, and the subsequent mineralization was less distinctive. In the late stage of fracture healing, the OVX mice showed a thin and porous cortex. In sharp contrast, estrogen treatment led to an enhanced fracture healing. Chondrocyte areas were larger, callus mineralization was increased, and the neocortex was thicker. Biomechanical testing confirmed the beneficial effects of estrogen on restoration of biomechanical competence. CONCLUSION: These results indicate that estrogen seems to be an important factor in all stages of fracture healing. The application of estrogens enhances fracture healing of long bones at least in mice.

Sheep model for osteoporosis: The effects of peripheral hormone therapy on centrally induced systemic bone loss in an osteoporotic sheep model.

Hypothalamic-pituitary disconnection (HPD) leads to low bone turnover followed by bone loss and reduced biomechanical properties in sheep. To investigate the role of peripheral hormones in this centrally induced systemic bone loss model, we planned a hormone replacement experiment. Therefore, estrogen (OHE), thyroxin (OHT) or a combination of both (OHTE) was substituted in ovariectomized HPD sheep, as both hormones are decreased in HPD sheep and are known to have a significant but yet not fully understood impact on bone metabolism. Bone turnover and structural parameters were analyzed in comparison to different control groups - untreated sheep (C), ovariectomized (O) and ovariectomized+HPD sheep (OH). We performed histomorphometric and HR-pQCT analyses nine months after the HPD procedure, as well as biomechanical testing of all ewes studied. In HPD sheep (OH) the low bone turnover led to a significant bone loss. Treatment with thyroxin alone (OHT) mainly increased bone resorption, leading to a further reduction in bone volume. In contrast, the treatment with estrogen alone (OHE) and the combined treatment with estrogen and thyroxin (OHTE) prevented HPD-induced bone loss completely. In conclusion, peripheral hormone substitution was able to prevent HPD-induced low-turnover osteoporosis in sheep. But only the treatment with estrogen alone or in combination with thyroxin was able to completely preserve bone mass and structure. These findings demonstrate the importance of peripheral hormones for a balanced bone remodeling and a physiological bone turnover.

Leptin inhibits bone formation not only in rodents, but also in sheep.

UNLABELLED: This study examines the effect of long-term ICV administration of leptin in ewes. We found that central application significantly decreased osteoblast activity as measured by serum analysis as well as by histomorphometry, resulting in decreased trabecular bone volume. These data provide additional evidence that bone formation and therefore bone remodeling is at least in part centrally controlled. INTRODUCTION: Genetic studies in mice have identified leptin as a potent inhibitor of bone formation acting through the central nervous system and unraveled the central nature of bone mass control and its disorders. Although these studies have radically enhanced our understanding of skeletal physiology because they have established a hypothalamic regulation of bone remodeling through the sympathetic nervous system, controversy remains about the physiological relevance of these observations because leptin's effect on bone after intracerebroventricular (ICV) application has only been shown in mice. To address whether leptin has a role in regulating bone mass beyond rodents, we treated ewes with long-term ICV application of leptin and analyzed the bone phenotype after a treatment period of 3 months. MATERIALS AND METHODS: Three groups of corriedale sheep were compared: (1) control entire (control), (2) ovariectomy (OVX) and ICV application of cerebrospinal fluid (CSF); and (iii) OVX and ICV application of leptin (leptin). Analysis included histomorphometric characterization of iliac crest, spine and femur by histology and biomechanical testing and measurement of bone turnover parameters in serum and urine. RESULTS: Central application of leptin decreased bone formation by 70% and mineralizing surface (MS/BS, 39.4 +/- 3.3% versus 16.1 +/- 2.1%) significantly (p < 0.01). Whereas OVX increased osteoclast indices and urinary cross-lap excretion by two and three times, respectively, serum parameters of osteoblast activity were significantly reduced by ICV application of leptin (p < 0.01). Consequently, ewes treated with leptin were osteopenic (iliac crest BV/TV entire, 22.7 +/- 1.3%; CSF, 18.9 +/- 2.4%; leptin, 12.4 +/- 2.6%), whereas bone torsional failure load reflecting the cortex of the tibia was not yet changed after 3 months of treatment (p < 0.01). CONCLUSIONS: Taken together, these data suggest that leptin controls bone formation after ICV application, leading to reduction of trabecular bone mass in sheep. Most importantly, however, they show that the central regulation of bone formation is not limited to rodents, but is also found in large animals, providing further evidence that bone remodeling in vertebrates is centrally controlled.

Deleterious tissue reaction to an alkylene bis(dilactoyl)-methacrylate bone adhesive in long-term follow up after screw augmentation in an ovine model.

Biomaterials are designed to support orthopedic surgeons and once implanted they will help the body to heal itself. In this way one of the most attractive substances are biomaterials that allow gluing of bone fragments and implant fixation. Although no bone adhesive is established for practical use in clinical practice yet, there is evidence in vitro and in vivo that a new class of bone adhesives based on alkylene bis(dilactoyl)-methacrylates may meet the requirements to bridge the gap between bench and bedside. The purpose of this experimental study was to investigate the long-term biocompatibility as well as the integration in the remodeling process of a new polymer of this group of substances that was used for both fragment adaptation and implant fixation in a large-scale animal model. In 24 sheep the lateral tibial condyle was osteotomized and refixed by three cortical screws. In 12 of them overdrilling the bone thread of one screw was performed to simulate the poor mechanical properties of osteoporotic bone and the polymer was used in this setting for screw augmentation, furthermore the osteotomy surface was covered with polymer before osteosynthesis to analyze the influence of the material on bone healing. In the other 12 sheep that served as controls osteosynthesis was performed without a polymer. All animals were permitted to walk immediately after surgery under full weight bearing conditions. Six animals of the polymer group and six animals of the control group were analyzed after 6 weeks and 6 months, respectively. Bone healing and implant integration was evaluated by contact X-rays, histology and histomorphometric quantification. After 6 weeks integrity of the healing bone in the polymer group was preserved as compared to the controls, albeit signs of prolonged aseptic inflammation were observed in the polymer group, which is in line with previous reports. In sharp contrast after 6 months, extensive tissue destruction was observed in all animals of the polymer group that was attributed to a massive foreign body reaction at the histological level. These long-term results suggest that (i) short-term observation not always allow valid conclusions regarding the biocompatibility of biomaterials, (ii) that biocompatibility might vary between species, and (iii) that the polymer used in this setting, although previously attributed to be a good candidate for clinical use in patients, does not meet the necessary criteria and tremendously interferes with the physiology of skeletal repair.

Bone microarchitecture of the calcaneus and its changes in aging: a histomorphometric analysis of 60 human specimens.

Bone structure and quality are an important parameter in the propensity of bone to fracture. Although the calcaneus is used as diagnostic reference site for osteoporosis by ultrasound, its structure has never been analyzed in detail. The purpose of this study was therefore to histomorphometrically analyze the trabecular microarchitecture of the calcaneus, and to determine whether the calcaneal bone structure is changing with age. Sixty complete human calcanei were harvested from thirty age- and gender-matched patients at autopsy. Each of the three different age groups (group I: 20 to 40, group II: 41 to 60, group III: 61 to 80 years of age) was represented by 20 specimens. The specimens were subjected to radiographic, microCT, and histologic analysis. Bone structure and bone mass of the calcaneus were quantified for three different regions of interest: the anterior ROI, the superior ROI (the subtalar region under the posterior facet), and the posterior ROI. An iliac crest biopsy was obtained from all patients to exclude any metabolic bone disease. Histomorphometric analysis revealed significant differences in bone volume within the calcaneus with highest values in the superior ROI: age group I: 31.3% (27.8-34.8%); II: 25.5% (22.1-28.9%); III: 18.9% (16.6-21.2%) and lowest bone volumes in the anterior ROI; age group I: 6.2% (4.8-7.6%); II: 3.6% (2.1-5.1%); III: 3.9% (2.9-4.9%). There was a significant age-related decrease in bone volume (BV/TV) in aging. Interestingly, this bone loss was most prominent in the superior ROI, with a 39% decrease in BV/TV between age group I and III (p < 0.001). Qualitative and structural analysis of trabecular number, thickness, and spacing demonstrated that the bone loss in the thalamic portion of the calcaneus was due to the transition of plate-like trabecular elements into a rod-like structure. In conclusion, our study demonstrated that the calcaneus displayed age-related changes in its microarchitecture that are known to reduce the biomechanical stability of trabecular bone, and that the age-related bone loss was most prominent in the region adjacent to the posterior facet (superior ROI). These results suggest that bone mass and structure are risk factors in respect to the occurrence and severity of calcaneal fractures, and indicate that calcaneal fractures are at least in part osteoporotic fractures.

Can we induce osteoporosis in animals comparable to the human situation?

Osteoporosis is a chronic systemic bone disease of growing relevance due to the on-going demographic change. Since the underlying regulatory mechanisms of this critical illness are still not fully understood and treatment options are not satisfactorily resolved, there is still a great need for osteoporosis research in general and animal models in particular. Ovariectomized rodents are standard animal models for postmenopausal osteoporosis and highly attractive due to the possibility to specifically modify their genetic background. However, some aspects can only be addressed in large animal models; such as metaphyseal fracture healing and advancement of orthopedic implants. Among other large animal models sheep in particular have been proven invaluable for osteoporosis research in this context. In conclusion, today we are able to influence the bone metabolism in animals causing a more or less pronounced systemic bone loss and structural deterioration comparable to the situation found in patients suffering from osteoporosis. However, there is no perfect model for osteoporosis, but a variety of models appropriate for answering specific questions. Though, the appropriateness of an animal model is not only defined in regard to the similarity to human physiology and the disease itself, but also in regard to acquisition, housing requirements, handling, costs, and particularly ethical concerns and animal welfare.

Absence of mouse pleiotrophin does not affect bone formation in vivo.

Pleiotrophin (Ptn) is an extracellular matrix protein that regulates hippocampal synaptic plasticity and learning behavior in vivo. Since the overexpression of Ptn in transgenic mice leads to increased bone formation, we analyzed whether a deficiency in Ptn expression would have a negative effect on bone remodeling. Bones from Ptn-deficient mice and wild-type littermates were analyzed using radiography, muCT imaging and undecalcified histology. Biomechanical stability was determined in a three-point-bending assay. Cellular activities were assessed using dynamic histomorphometry and the determination of urinary collagen degradation products. Skeletons of Ptn-deficient mice have no gross abnormalities, displayed a normal size, and showed no differences in growth plate organization compared to wild-type littermates. There were no obvious differences in bone mass as determined by radiographic and muCT imaging. The absence of a bone remodeling phenotype in Ptn-deficient mice was further confirmed using static histomorphometry and biomechanical testing. Finally, the number, morphology, and function of osteoclasts, osteoblasts, and osteocytes were not altered in Ptn-deficient mice compared to wild-type littermates. The complete skeletal analysis of Ptn-deficient mice presented here demonstrates that the lack of Ptn in mice does not affect bone formation in vivo. Therefore, Ptn does not play a significant role in normal bone physiology.

Sheep model for osteoporosis: sustainability and biomechanical relevance of low turnover osteoporosis induced by hypothalamic-pituitary disconnection.

Hypothalamo-pituitary disconnection (HPD) leads to low bone turnover and osteoporosis in sheep. To determine the sustainability of bone loss and its biomechanical relevance, we studied HPD-sheep 24 months after surgery (HPD + OVX-24) in comparison to untreated control (Control), ovariectomized sheep (OVX), and sheep 12 months after HPD (HPD + OVX-12). We performed histomorphometric, HR-pQCT, and qBEI analyses, as well as biomechanical testing of all ewes studied. Twenty-four months after HPD, histomorphometric analyses of the iliac crest showed a significant reduction of BV/TV by 60% in comparison to Control. Cortical thickness of the femora measured by HR-pQCT did not change between 12 and 24 months after HPD but remained decreased by 30%. These structural changes were caused by a persisting depression of osteoblast and osteoclast cellular activity. Biomechanical testing of the femora showed a significant reduction of bending strength, whereas calcium content and distribution was found to be unchanged. In conclusion, HPD surgery leads to a persisting low turnover status with negative turnover balance in sheep followed by dramatic cortical and trabecular bone loss with consequent biomechanical impairment.

Giant cell tumour of bone: reconstruction of the index metacarpophalangeal joint with an osteochondral graft from the lateral femoral condyle.

We describe the successful reconstruction of the index finger metacarpophalangeal joint with an osteochondral autograft from the lateral femoral condyle following failed curettage and cementation of a giant cell tumour of the proximal phalanx base. At the 2-year follow-up, a good functional outcome was noted with 0-80° range of motion of the metacarpophalangeal joint and no clinical or radiographic evidence of tumour recurrence.

Metaphyseal fracture healing in a sheep model of low turnover osteoporosis induced by hypothalamic-pituitary disconnection (HPD).

We recently established a large animal model of osteoporosis in sheep using hypothalamic-pituitary disconnection (HPD). As central regulation is important for bone metabolism, HPD-sheep develop severe osteoporosis because of low bone turnover. In this study we investigated metaphyseal fracture healing in HPD-sheep. To elucidate potential pathomechanisms, we included a treatment group receiving thyroxine T4 and 17ß-estradiol. Because clinically osteoporotic fractures often occur in the bone metaphysis, HPD-sheep and healthy controls received an osteotomy in the distal femoral condyle. Half of the HPD-sheep were systemically treated with thyroxine T4 and 17ß-estradiol during the healing period. Fracture healing was evaluated after 8 weeks using pQCT, µCT, and histomorphometrical analysis. Bone mineral density (BMD) and bone volume/total volume (BV/TV) were considerably reduced by 30% and 36%, respectively, in the osteotomy gap of the HPD-sheep compared to healthy sheep. Histomorphometry also revealed a decreased amount of newly formed bone (-29%) and some remaining cartilage in the HPD-group, suggesting that HPD disturbed fracture healing. Thyroxine T4 and 17ß-estradiol substitution considerably improved bone healing in the HPD-sheep. Our results indicate that fracture healing requires central regulation and that thyroxine T4 and 17ß-estradiol contribute to the complex pathomechanisms of delayed metaphyseal bone healing in HPD-sheep.

Targeting the lateral but not the third ventricle induces bone loss in ewe: an experimental approach to generate an improved large animal model of osteoporosis.

BACKGROUND: Osteoporosis is a chronic disease characterized by bone loss and increased skeletal fragility. Large animal models are required for preclinical testing of new therapeutic approaches. We have recently demonstrated that continuous intracerebroventricular (ICV) application of leptin into the lateral ventricle (LV) induces bone loss in ewe. On the basis of these findings, we reasoned that the third ventricle (TV) is an even better target because of its closer location to the hypothalamus that mediates leptin effects on bone. METHODS: Corriedale sheep were randomly mixed to four groups of four ewe each: control entire (control), ovarectomy plus ICV application of cerebrospinal fluid (OVX), OVX plus ICV application of leptin into the LV (leptin-LV); and ICV application of leptin into the TV (leptin-TV). After 3 months, histomorphometric characterization and bone turnover parameters were analyzed. RESULTS: Highly significant loss of trabecular bone was observed only in leptin-LV group. Increased osteoclast indices and urinary cross-lap excretion were observed in OVX and leptin-TV group. In contrast, serum parameters of osteoblast activity were only significantly decreased in leptin-LV group. Autopsy of ewe brain showed fibrosis around the stainless steel cannula in leptin-TV group. CONCLUSIONS: ICV application of leptin into the LV strongly reduces bone formation and leads to a highly significant trabecular bone loss in ewe. In contrast, ICV application of leptin into the TV is technically more demanding and results are unpredictable, because the required use of stainless steel cannula induces peri-implant fibrosis that might prevent leptin to enter the cerebrospinal fluid.