Diagnostic Performance of a Panel of miRNAs (OsteomiR) for Osteoporosis in a Cohort of Postmenopausal Women.

A specific signature of 19 circulating miRNAs (osteomiRs) has been reported to be associated with fragility fractures due to postmenopausal osteoporosis. However, it is unknown whether osteoporotic fractures or low BMD phenotypes are independently contributing to changes in osteomiR serum levels. The first aim was to characterize the abundance, sensitivity to hemolysis, and correlation of osteomiR serum levels, the second objective to evaluate the diagnostic accuracy of osteomiRs for osteoporosis according to the WHO criteria and on basis of major osteoporotic fracture history. Fifty postmenopausal women with osteoporosis (with or without fragility fracture) and 50 non-osteoporotic women were included in this cross-sectional study. The diagnostic performance of osteomiRs for osteoporosis based on the WHO definition or fracture history was evaluated using multiple logistic regression and receiver-operator curve (AUC) analysis. The osteomiR® signature is composed of four clusters of miRNAs providing good performance for the diagnosis of osteoporosis in postmenopausal women defined by WHO criteria (AUC = 0.830) and based on history of major osteoporotic fractures (AUC = 0.834). The classification performance for the WHO criteria and for fracture risk is driven by miR-375 and miR-203a, respectively. OsteomiRs, a signature of 19 emerging miRNA bone biomarkers, are measurable in human serum samples. They constitute a panel of independent bone and muscle biomarkers, which in combination could serve as diagnostic biomarkers for osteoporosis in postmenopausal women.

Microstructural analysis of bony alterations in a historic case of actinomycosis.

OBJECTIVE: Actinomycosis infection of bone is rare and its diagnosis challenging. Here, we aim to identify and verify its microstructural features and the potential value for differential diagnosis. MATERIALS: We investigated the dry preparation of the lumbar vertebrae and pelvic ring of a purported case of actinomycosis documented by a post-mortem examination in 1891. METHODS: Macroscopic inspection, conventional radiology, µCT, 3D reconstruction, and histological examination were employed. RESULTS: All approaches revealed new periosteal bone deposition with increased vascularisation of the os coxa, vertebrae, and sacrum. The µCT revealed cortical loss underneath the new bone formation; the 3D reconstruction and histological examination revealed plexiform bone and granular structures. CONCLUSIONS: The plexiform bone is the result of reactive rapid growth and remodelling processes, and is consistent with pathomorphological findings summarised in the autopsy report (soft tissue abscesses and formation of fistulas caused by "Actinomycosis intestine et ossis ilei sin."). SIGNIFICANCE: This is the first case of a historically documented case of actinomycosis infection investigated by µCT and histology. Different degrees of tissue damage and inflammatory reaction in form of plexiform bone, which has not been reported previously, was identified. LIMITATIONS: The noted bone tissue modifications are not solely pathognomic of actinomycosis; they characterise other diseases, as well. Histological evaluation is not appropriate for identifying the aetiology of the granular structures observed here; but clinically such aggregations appear in tissue affected by actinomycosis. SUGGESTIONS FOR FURTHER RESEARCH: Histochemical and molecular-genetic analyses are obligatory to affirm the diagnosis based on micromorphological features.

Bone microarchitecture and bone turnover in hepatic cirrhosis.

Liver cirrhosis leads to bone loss. To date, information on bone quality (three-dimensional microarchitecture) and, thus, bone strength is scarce. We observed decreased bone quality at both assessed sites, independent of disease severity. Therefore, all patients should undergo early-stage screening for osteoporosis. INTRODUCTION: Recent studies found low bone mineral density in cirrhosis, but data on bone microstructure are scarce. This study assessed weight-bearing and non-weight-bearing bones in patients with cirrhosis and healthy controls. The primary objective was to evaluate trabecular and cortical microarchitecture. METHODS: This was a single-center study in patients with recently diagnosed hepatic cirrhosis. Thirty-two patients and 32 controls participated in this study. After determining the type of cirrhosis, the parameters of bone microarchitecture were assessed by high-resolution peripheral quantitative computed tomography. RESULTS: Both cortical and trabecular microarchitectures showed significant alterations. At the radius, trabecular bone volume fraction was 17% lower (corrected p = 0.028), and, at the tibia, differences were slightly more pronounced. Trabecular bone volume fraction was 19% lower (p = 0.024), cortical bone mineral density 7% (p = 0.007), and cortical thickness 28% (p = 0.001), while cortical porosity was 32% higher (p = 0.023), compared to controls. Areal bone mineral density was lower (lumbar spine - 13%, total hip - 11%, total body - 9%, radius - 17%, and calcaneus - 26%). There was no correlation between disease severity and microarchitecture. Areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) correlated well with parameters of cortical and trabecular microarchitecture. CONCLUSIONS: Hepatic cirrhosis deteriorates both trabecular and cortical microarchitecture, regardless of disease severity. Areal bone mineral density is diminished at all sites as a sign of generalized affection. In patients with hepatic cirrhosis, regardless of its origin or disease severity, aBMD measurements are an appropriate tool for osteologic screening.

Preceding and subsequent high- and low-trauma fracture patterns-a 13-year epidemiological study in females and males in Austria.

This study investigated the implication of a preceding high-trauma fracture on subsequent high- and low-trauma fractures at different skeletal sites in postmenopausal women and similarly aged men at an age range of 54 to 70 years. A preceding high-trauma fracture increases the risk of future low-trauma non-vertebral fractures including hip. INTRODUCTION: Little is known about the impact of the skeletal fracture site in conjunction with the severity of a past fracture (high- or low-trauma preceding fracture) and its effect on future fracture risk. METHODS: Patients with de novo high- and low-trauma fractures admitted to seven large trauma centers across Austria between 2000 and 2012 were stratified into sex and different age groups. Kaplan-Meier estimates, Cox proportional hazards regression models (HR), and likelihood calculations estimated effects of age, sex, and the anatomic region on the probability of a subsequent fracture in the same patient. RESULTS: Included in the study were 433,499 female and male patients at an age range of 0 to 100 years with 575,772 de novo high- and low-trauma fractures. In the age range of 54-70 years, subsequent fractures were observed in 16% of females and 12.1% of males. A preceding high-trauma fracture was associated with 12.9% of subsequent fractures, thereof 6.5% of high- and 6.4% of low-trauma in origin, usually at the hip, humerus, or pelvis. The highest effect sizes were observed for femur, humerus, and thorax fractures with hazard ratios (HR) of 1.26, 1.18, and 1.14. After splitting into high-trauma preceding and subsequent low-trauma fractures, the femoral neck (HR = 1.59), the female sex (HR = 2.02), and age (HR = 1.03) were discriminators for increased future fracture risk. CONCLUSIONS: Preceding high-trauma fractures increase the risk of future low-trauma non-vertebral fractures including hip. For each patient with a fracture, regardless of the severity of the trauma, osteoporosis should be taken into clinical consideration.

A principal components analysis: how pneumatization and edentulism contribute to maxillary atrophy.

OBJECTIVE: The aim of this retrospective cohort study was to investigate the role of sinus pneumatization and residual ridge resorption in maxillary bone loss in 400 computed tomography (CT) scans. MATERIALS AND METHODS: In 200 dentate and 200 edentulous patients, both sinuses were analysed using CT scans. The image analysis sequence consisted of manual placement of 24 reference points, followed by automated segmentation and final manual refinement. Finally, a principal components analysis was performed. RESULTS: A total of 788 sinuses were included into the analysis. The edentulous group (98 female: 67.77 ± 11.28 years, 99 male: 65.22 ± 9.87) was significantly older than the group with teeth (99 female: 46.89 ± 16.77 years, 96 male: 49.74 ± 16.2). Female and male patients did not differ regarding age. The alveolar height differed significantly between the groups (edentulous: 7.1 ± 4.3 mm, with teeth: 9.7 ± 4.1 mm), but not between gender (female: 8.3 ± 4.4 mm, male: 8.5 ± 4.4 mm). Principal components analysis was able to explain 90% of the variation in sinus morphology. CONCLUSIONS: Prolonged edentulism in the maxillary molar region leads to centripetal and to minor degrees centrifugal ridge resorption. Minor pneumatization occurs in the sinus walls, but the sinus depth underlies the anatomical variation independent of dentition.

Stanozolol Decreases Bone Turnover Markers, Increases Mineralization, and Alters Femoral Geometry in Male Rats.

Stanozonol (ST) is a synthetic derivative of testosterone; it has anabolic/androgenic activity, increasing both the turnover of trabecular bone and the endocortical apposition of bone. The present study aimed to examine the effects of ST on bone status in rats by bone mineral content, markers of formation and resorption, bone density, and structural and microarchitectural parameters. Twenty male Wistar rats were randomly distributed into two experimental groups corresponding to placebo or ST administration, which consisted of weekly intramuscular injections of 10 mg/kg body weight of ST. Plasma parameters were analyzed by immunoassay. Bone mineral content was determined by spectrophotometry. Bone mineral density (BMD) and structural parameters were measured by peripheral quantitative computed tomography, and trabecular and cortical microarchitecture by micro-computed tomography. Plasma Ca, Mg, and alkaline phosphatase were higher, and urinary Ca excretion, corticosterone, and testosterone concentrations lower in the ST group. Femur Ca content was higher and P content was lower in the ST, whereas osteocalcin, aminoterminal propeptides of type I procollagen, and C-terminal telopeptides of type I collagen were lower. Total cross-sectional, trabecular, and cortical/subcortical areas were lower in the ST. No differences were observed on BMD and area parameters of the diaphysis as well as on trabecular and cortical microarchitecture. The use of ST increases bone mineralization, ash percentage, and Ca and Mg content in femur. In spite of an absence of changes in BMD, geometric metaphyseal changes were observed. We conclude that ST alters bone geometry, leads to low bone turnover, and thus may impair bone quality.

Micro-CT analyses of historical bone samples presenting with osteomyelitis.

OBJECTIVE: Osteomyelitis is an inflammation of the bone marrow mainly caused by bacteria such as Staphylococcus aureus. It typically affects long bones, e.g. femora, tibiae and humeri. Recently micro-computed tomography (µCT) techniques offer the opportunity to investigate bone micro-architecture in great detail. Since there is no information on long bone microstructure in osteomyelitis, we studied historic bone samples with osteomyelitis by µCT. MATERIALS AND METHODS: We investigated 23 femora of 22 individuals suffering from osteomyelitis provided by the Collection of Anatomical Pathology, Museum of Natural History, Vienna (average age 44 ±19 years); 9 femora from body donors made available by the Department of Applied Anatomy, Medical University of Vienna (age range, 56-102 years) were studied as controls. Bone microstructure was assessed by µCT VISCOM X 8060 II with a minimal resolution of 18 µm. RESULTS: In the osteomyelitic femora, most prominent alterations were seen in the cortical compartment. In 71.4% of the individuals with osteomyelitis, cortical porosity occurred. 57.1% of the individuals showed cortical thinning. In 42.9% trabecularisation of cortical bone was observed. CONCLUSION: Osteomyelitis is associated with severe alterations of cortical bone structure otherwise typically observed at old age such as cortical porosity and cortical thinning.

Anatomical preconditions for the palatal sinus floor augmentation­A three-dimensional feasibility study.

OBJECTIVE: The aim of this study was to evaluate the anatomical feasibility of palatal sinus floor augmentation. MATERIAL AND METHODS: In 100 men and 100 women, both sinuses were analyzed using computed tomography. The patients were divided into four anatomical groups according to the remaining alveolar bone height: group 1 (0 ≤ × < 4), group 2 (4 ≤ × < 8), group 3 (8 ≤ × < 12), and group 4 (≥12). RESULTS: The 400 maxillary sinuses consisted of 23.5% (n = 94) group 1, 42.75% (n = 171) group 2, 23.5% (n = 98) group 3, and 9.25% (n = 37) group 4 sinuses. Optimal anatomical preconditions for palatal sinus floor augmentations (i.e., ≥5 mm height and <5 mm thickness of the window lid) were found in 93.6% of group 1 sinuses, 73.7% of group 2 sinuses, 23.5% of group 3 sinuses, and 5.4% of group 4 sinuses. CONCLUSION: The palatal approach is feasible in 93.6% of patients with remnant alveolar height of up to 4 mm. Limitations are alveolar heights of ≤5 mm as well as great palatal thickness and thus limited dimensions for a possible palatal window.

[Imaging of diabetic osteopathy]. / Bildgebung der diabetischen Osteopathie.

CLINICAL ISSUE: Diabetic bone diseases are more than just osteoporosis in patients with diabetes mellitus (DM): a relatively high bone mineral density is paired with a paradoxically high risk of fragility fractures. Diabetics exhibit low bone turnover, osteocyte dysfunction, relative hypoparathyroidism and an accumulation of advanced glycation end products in the bone matrix. Besides typical insufficiency fractures, diabetics show a high risk for peripheral fractures of the lower extremities (e.g. metatarsal fractures). The correct interdisciplinary assessment of fracture risks in patients with DM is therefore a clinical challenge. STANDARD RADIOLOGICAL METHODS: There are two state of the art imaging methods for the quantification of fracture risks: dual energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT). Radiography, multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) are suitable for the detection of insufficiency fractures. METHODICAL INNOVATIONS AND PERFORMANCE: Novel research imaging techniques, such as high-resolution peripheral quantitative computed tomography (HR-pQCT) provide non-invasive insights into bone microarchitecture of the peripheral skeleton. Using MR spectroscopy, bone marrow composition can be studied. Both methods have been shown to be capable of discriminating between type 2 diabetic patients with and without prevalent fragility fractures and thus bear the potential of improving the current standard of care. Currently both methods remain limited to clinical research applications. PRACTICAL RECOMMENDATIONS: DXA and HR-pQCT are valid tools for the quantification of bone mineral density and assessment of fracture risk in patients with DM, especially if interpreted in the context of clinical risk factors. Radiography, CT and MRI are suitable for the detection of insufficiency fractures.

Current controversies in clinical management of postmenopausal osteoporosis.

Osteoporosis is a frequent disease in postmenopausal women. Despite the fact that fragility fractures cause many problems - a bio-psycho-social burden for the individual and an economic burden for the society - osteoporosis is still underdiagnosed and undertreated. Controversies exist concerning assessment with different tools for initiating a disease-specific treatment, patient monitoring with bone turnover markers, and treatment duration due to potential side effects in long-term treatment. This manuscript outlines and discusses these controversies and the presented cases, representatives for frequent clinical problems, may give guidance for the clinician in deciding how and how long to treat his/her patient. Re-evaluations of the patients on a regular basis are essential to warrant the necessity of treatment continuation and may improve patients' compliance.

Cathepsin S controls adipocytic and osteoblastic differentiation, bone turnover, and bone microarchitecture.

Cathepsin S is a cysteine protease that controls adipocyte differentiation and has been implicated in vascular and metabolic complications of obesity. Considering the inverse relation of osteoblasts and adipocytes and their mutual precursor cell, we hypothesized that cathepsin S may also affect osteoblast differentiation and bone remodeling. Thus, the fat and bone phenotypes of young (3 months old) and aged (12 or 18 months old) cathepsin S knock-out (KO) and wild-type (WT) mice were determined. Cathepsin S KO mice had a normal body weight at both ages investigated, even though the amount of subscapular and gonadal fat pads was reduced by 20%. Further, cathepsin S deficiency impaired adipocyte formation (-38%, p<0.001), which was accompanied by a lower expression of adipocyte-related genes and a reduction in serum leptin, IL-6 and CCL2 (p<0.001). Micro-CT analysis revealed an unchanged trabecular bone volume fraction and density, while tissue mineral density was significantly lower in cathepsin S KO mice at both ages. Aged KO mice further had a lower cortical bone mass (-2.3%, p<0.05). At the microarchitectural level, cathepsin S KO mice had thinner trabeculae (-8.3%), but a better connected trabecular network (+24%). Serum levels of the bone formation marker type 1 procollagen amino-terminal-propeptide and osteocalcin were both 2-3-fold higher in cathepsin S KO mice as was the mineralized surface. Consistently, osteogenic differentiation was increased 2-fold along with an increased expression of osteoblast-specific genes. Interestingly, serum levels of C-terminal telopeptide of type I collagen were also higher (+43%) in cathepsin S KO mice as were histological osteoclast parameters and ex vivo osteoclast differentiation. Thus, cathepsin S deficiency alters the balance between adipocyte and osteoblast differentiation, increases bone turnover, and changes bone microarchitecture. Therefore, bone and fat metabolisms should be monitored when using cathepsin S inhibitors clinically.

[Diabetes and osteoporosis: pathophysiological interactions and clinical importance for geriatric patients]. / Diabetes und Osteoporose: Pathophysiologische Interaktionen und klinische Bedeutung für geriatrische Patienten.

Osteoporosis is an age-associated disease, resulting in impaired bone quality and increased risk for bone fractures. Patients with type 2 diabetes mellitus have--despite a normal or even increased bone mineral density--an increased risk for fractures, which is related to an imbalance between osteoblastic bone formation and osteoclastic resorption. Complex pathophysiological mechanisms associated with insulin resistance and hyperglycemia are involved in the deleterious effects on osteoblast function and bone formation. The quality and regimen of antidiabetic therapy are discussed as modulators of bone metabolism. Of great clinical importance is an assessment of the fall risk especially for diabetic patients, because late complications, such as neuropathy, but also side effects of medication can result in a significantly increased risk for falls. Lifestyle intervention is of advantage with respect to diabetes and osteoporosis prevention and therapy. Vitamin D supplementation results in favorable effects with a reduced risk for falls and also improvements of insulin sensitivity. According to published data, the safety and efficacy of specific medication for the treatment of osteoporosis (bisphosphonates, denosumab, selective estrogen receptor modulators) reveal no difference between patients with and without diabetes mellitus.

How long should women with postmenopausal osteoporosis be treated with a bisphosphonate?

Bisphosphonates are very frequently prescribed to women suffering from postmenopausal osteoporosis with or without fragility fractures. The present review was aimed to update the available information on the most efficient treatment duration. Studies on bisphosphonate treatment duration were identified by Medline up to January 2013. Bisphosphonates are very effective in the short as well as in the medium-term. However, the optimal duration of use has not been determined yet. Therefore, this review summarizes the long-term effects of bisphosphonates on surrogate parameters of fracture prevention, bone mineral density measurements, and bone turnover markers. An initial treatment period of 3-5 years is recommended. Then, the patient has to be re-evaluated for fracture risk, which depends on fracture status as well as on other health issues. Beyond that, life style factors such as regular physical activity as well as a sufficient intake of calcium and vitamin D or, if necessary supplementation of calcium and/or vitamin D play an essential part in fracture prevention.

[Osteoporotic treatment options in geriatric patients]. / Therapie der Osteoporose beim geriatrischen Patienten.

Due to the demographic changes of the last few decades, there has been a significant increase in the number of osteoporotic fractures. After a fracture, geriatric patients are at particularly high risk for an increase of their functional impairments as well as a loss of independence and quality of life. In spite of the severe medical and socioeconomic consequences of fragility fractures, osteoporotic treatment and prevention are still insufficient. Based on the current literature, the pharmacological and nonpharmacological treatment options as well as new surgical techniques for geriatric patients are reviewed.

Bone metabolism in patients with primary hyperparathyroidism before and after surgery.

Primary hyperparathyroidism (PHPT) is accompanied with a reduced bone mineral density (BMD) and an increased risk of fracture. Surgery is the only option for cure. It is hypothesized that in patients with PHPT bone metabolism normalizes after parathyroidectomy (PTX) and that BMD gradually increases. Fifty-two patients with PHPT who underwent surgery were prospectively followed for 1 year. Biochemical analyses were performed at baseline and 1, 4, 7 days; 6 weeks; and 3, 6, and 12 months, and BMD before and one year after surgery. Parathyroid hormone (PTH), calcium, and the bone resorption marker dropped immediately, but transiently after PTX, bone formation decreased more slowly. Osteoprotegerin (OPG) as well as cathepsin K did not show significant changes. BMD of the lumbar spine, but not of the femoral neck, increased significantly within one year after surgery. Moderate correlations existed between the changes of total calcium, ionized calcium, as well as bone-specific alkaline phosphatase and changes of the lumbar BMD. Patients who needed postoperative supplementation with calcium and vitamin D had significantly higher PTH levels. Some gender-specific differences in patients with PHPT were observed. In patients with PHPT, males appear to be more severely affected than females. Within the first year after PTX, bone metabolism normalized, and BMD of the lumbar spine increased. Patients who needed a supplementation with calcium and vitamin D after PTX preoperatively had higher serum levels of PTH.

OPG-Fc treatment in growing pigs leads to rapid reductions in bone resorption markers, serum calcium, and bone formation markers.

Inhibition of the receptor activator of NF-κB ligand (RANKL) is a novel therapeutic option in the treatment of osteoporosis and related diseases. The aim of this study was to evaluate bone metabolism and structure in pigs after RANKL inhibition. 12 growing pigs were assigned to 2 groups with 6 animals each. The OPG group received recombinant human OPG-Fc (5 mg/kg IV) at day 0, the control group was given 0.9% NaCl solution. Serum levels of OPG-Fc, calcium (Ca), phosphorus (P), and bone turnover markers were evaluated every 5 days, and pigs were euthanized on day 20. Serum OPG-Fc concentration peaked at day 5 and coincided with significantly decreased Ca, P, and bone turnover markers. By day 15, measureable OPG-Fc serum levels could only be detected in 2/6 animals. With OPG-Fc clearance starting at day 10, serum Ca and P concentrations were not different between the 2 groups. TRACP5b, P1CP, and BAP levels significantly decreased by 40-70% relative to vehicle controls in the OPG-Fc group between days 5 and 10, indicating that pharmacologic concentration of OPG-Fc led to systemic concomitant inhibition of bone formation and resorption in young growing pigs. Dual X-ray absorptiometry data derived from the proximal femur did not differ between the 2 groups. µCT analysis of selected bone sites demonstrated an OPG-Fc-induced improvement of specific bone architectural indices and bone mineralization.

Bone and cellular immune system of multiparous sows are insensitive to ovariectomy and nutritive calcium shortage.

Research in osteoporosis, which is a complex systemic disease, demands suitable large animal models. In pigs, most research has been done in growing minipigs, which probably are not ideal models for postmenopausal osteoporosis. Therefore, our aim was to analyze the effects of ovariectomy (OVX) and nutritive calcium shortage on multiparous Large White sows. 32 animals were randomly assigned to 4 groups in a cross design with OVX vs. sham and physiological calcium supplementation (0.75% calcium) vs. dietary calcium shortage (0.3% calcium). The observation period was 10 months with blood sampling every 2 months for hematological, immunological, and biochemical bone marker measurements. At the termination of the experiment, animals were sacrificed. Samples of trabecular bone of distal radius, proximal tibia, and sixth lumbar vertebra were subjected to micro-computed tomography imaging and ashed afterwards. Dual X-ray absorptiometry scans of the proximal femora were performed with prepared bones being placed in a water bath for mimicking soft tissue. Analyses of bone marker and cytokine profile kinetics, distribution of leukocyte subpopulations, and morphometrical and densitometrical analyses showed no evidence of any impact of OVX or calcium shortage. In conclusion, the skeleton of adult sows of a conventional breed is seemingly protected from effects of OVX and calcium shortage.

Diabetes and bone.

Traditionally, patients with type 1 diabetes were regarded to be at an increased risk of fractures whereas type 2 diabetics were assumed to be protected from fractures since many of them have high bone mineral density. Nevertheless, several clinical studies consistently demonstrated that type 2 diabetes is a paradigm of a disease with an increased risk of fractures in the presence of high bone mass. The pathophysiology of decreased bone strength in diabetes mellitus is multifactorial: insulin deficiency, insulin resistance, osteoblast insufficiency, vitamin D deficiency, formation of advanced glycation end-products in bone, and microvascular complications appear to contribute. Drugs used for the treatment of type 2 diabetes also may influence bone fragility: thiazolidinedione use has been associated with an increased risk of fractures.

Effect of teriparatide on early bone loss after kidney transplantation.

Kidney transplantation is associated with bone loss and a high risk of fractures. Prophylactic treatment of bone is therefore recommended in the early posttransplant period. As a large number of transplant recipients develop adynamic renal osteodystrophy, recombinant parathyroid hormone (rPTH) could be a promising therapeutic option. In a 6-month double-blind, randomized trial, 26 kidney transplant recipients were treated with daily subcutaneous injections of 20 microg teriparatide (PTH 1-34) or placebo. Bone mineral density (BMD) of the femoral neck, lumbar spine and radial bone was measured at transplantation and after 6 months. Paired bone biopsies for histomorphometric analysis were obtained in six, and for measurement of bone matrix mineralization in five patients of each group. Serologic bone markers were measured at baseline and every 3 months. A total of 24 out of 26 patients completed the study. Femoral neck BMD was stable in the teriparatide group, but decreased significantly in the placebo group. Lumbar spine and radial BMD, histomorphometric bone volume and bone matrix mineralization status remained unchanged in both groups. Serologic bone markers were similarly reduced in both groups throughout the study. We conclude that teriparatide does not improve BMD early after kidney transplantation. Neither histological analysis nor bone markers provide evidence of improved bone turnover or mineralization.

Strategies for novel therapeutic approaches targeting cytokines and signaling pathways of osteoclasto- and osteoblastogenesis in the fight against immune-mediated bone and joint diseases.

For many bone and joint diseases in humans, including postmenopausal osteoporosis, rheumatoid arthritis, and ankylosing spondylitis, an immune-mediated etiology has either been proven or is considered as a co-factor in pathogenesis. The identification of the receptor activator of nuclear factor kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG)-interplay and the in-depth characterization of the signaling pathways induced upon RANK activation, including molecules such as TNF receptor-associated factor 6 (TRAF6), nuclear factor-kappaB (NF-kappaB), and signal transducer and activator of T cells (STAT)-3, now promise to give the opportunity to target osteoclastogenesis specifically. Additionally, many byways influencing osteoclastogenesis have been elucidated, thus giving rise to additional therapeutic approaches. These are based mainly upon the effects of diverse cytokines on osteoclast differentiation with interleukin (IL)-17 and interferone (IFN)-gamma being most prominent at the moment. The same applies for the recently established signaling pathways in osteoblastogenesis, which have attracted much attention in the recent years. In this respect, much attention has been attributed towards bone morphogenetic proteins (BMPs) and the Wnt signaling cascade. In this review, an overview on the key molecules, which (could) serve as promising targets for novel therapeutic interventions with the aim of enhancing osteoblast formation or suppressing osteoclast development, is given. Further on, antibody-based therapeutical schemes as well as methodologically novel, albeit predominantly theoretical at the moment, strategies in the fight against immune-mediated osteopathologies are discussed.