Description of closed projects and published manuscripts of the year 2009
Atlanto-axial segmentation defects and Os Odontoideum in two male siblings with Opsismodysplasia
We report two siblings aged 11 and 7 years, respectively, who presented with the clinical and radiographic features of opsismodysplasia (non-lethal type). 3D computed tomography scans of the craniocervical region revealed a split atlas and os odontoideum in both siblings. To the best of our knowledge, this is the first clinical report detailing craniocervical malformations in two siblings with opsismodysplasia.
Skeletal Radiology 38:293
Effects of tumor-induced osteomalacia on the bone mineralization process
Fibroblast growth factor 23 (FGF23) overexpression has been identified as a causative factor for tumor-induced osteomalacia (TIO) characterized by hypophosphatemia due to increased renal phosphate wasting, low 1,25(OH)(2)D(3) serum levels, and low bone density. The effects of long-lasting disturbed phosphate homeostasis on bone mineralization are still not well understood. We report on a patient with a 12-year history of TIO, treated with 1,25(OH)(2)D(3) and phosphate, who finally developed hyperparathyroidism with gland hyperplasia before the tumor could be localized in the scapula and removed. During surgery a transiliac bone biopsy was obtained. FGF23 expression in the tumor cells was confirmed by in situ hybridization. Serum FGF23 levels as measured by ELISA were found to be extremely elevated before and decreased after removal of the tumor. Bone histology/histomorphometry and measurement of bone mineralization density distribution using quantitative backscattered electron imaging were performed on the bone biopsy. The data showed important surface osteoidosis and a slightly increased osteoblast but markedly decreased osteoclast number. The mineralized bone volume (-11%) and mineralized trabecular thickness (-18%) were low. The mean degree of mineralization of the bone matrix (-7%), the most frequent calcium concentration (-4.1%), and the amounts of fully mineralized bone (-40.3%) were distinctly decreased, while the heterogeneity of mineralization (+44.5%) and the areas of primary mineralization (+131.6%) were dramatically increased. We suggest that the elevated levels of FGF23 and/or low phosphate concentrations disturb the mineralization kinetics in vivo without affecting matrix mineralization of pre-existing bone packets.
Calcif Tissue Int 84:313
Treatment of osteoporosis with parathyroid hormone and teriparatide
Nowadays osteoporosis treatment is based primarily on therapy with antiresorptive agents, like the bisphosphonates. Parathyroid hormone (Preotact) and human recombinant parathyroid hormone peptide 1-34 (Teriparatide) are relatively new for the treatment of osteoporosis and belong to the group of anabolic agents. Both agents demonstrated an increase in bone mineral density and a significant reduction in vertebral fractures in postmenopausal women with osteoporosis when given for 18-24 months. Data on nonvertebral fractures are, however, not clear-cut, and so far only bisphosphonates and strontium ranelate have been demonstrated to reduce all types of fractures and therefore remain the front-line option for treatment of osteoporosis. As the safety, tolerability, and cost of the therapy also influence the choice of therapy, Preotact and Teriparatide might be useful additions to the armamentarium for (second-line) treatment of osteoporosis.
Calcif Tissue Int 84:159
Advanced ossification of the carpal bones, and monkey wrench appearance of the femora, features suggestive of a propable mild form of Desbeqious dysplasia: a case report and review of the literature
INTRODUCTION: Advanced bone maturation is a radiographic feature that might be encountered in a number of different forms of skeletal dysplasias such as Desbuquois dyspalsia, Larsen syndrome, the Reunion Island form of Larsen syndrome, diastrophic dysplasia, acrodysostosis, Catel-Manzke syndrome, a variant of metatropic dysplasia and Maroteaux-lamy syndrome. CASE PRESENTATION: We report on a 2-year- old boy from Slovakia was born to non-consanguineous parents. Prenatal and postnatal growth parameters were normal. Clubfoot and genu valgum were the most prominent orthopaedic abnormalities. Radiographic documentation showed bone age of 4 years and 8 months associated with the appearance of accessory ossification centers. Monkey wrench appearance of the proximal femora was a characteristic finding associated with significant vertebral changes. CONCLUSION: The major skeletal changes in our patient include advanced carpal ossification, monkey wrench appearance of the proximal femora associated with significant vertebral changes. No joint dislocations, no hitchhiker thumbs and or dysmorphic facial features were present. The normality of his growth, facial features, intelligence, and palate as well as the characteristic radiographic features were to certain extent in favour of a mild form of Desbuquois dysplasia. Additional laboratory findings allowed us to exclude other disorders with abnormal metabolic parameters such as mucopolysaccharoidosis.
Cases Journal 2:45
Professional awareness is needed to distinguish between child physical abuse from other disorders that can mimic signs of abuse (Skull base sclerosis in infant manifesting features of infantile cortical hyperostosis): a case report and review of the literature
BACKGROUND: Infantile cortical hyperostosis is characterised by hyperirritability, acute inflammation of soft tissue, and profound alterations of the shape and structure of the underlying bones, particularly the long bones, mandible, clavicles, or ribs. CASE PRESENTATION: We report on a clinical case of a 3-months-old baby girl of non-consanguineous parents. Multiple long bone swellings were the motive of referral to our department for clinical evaluation. Radiographic documentation was consistent with infantile cortical hyperostosis (Caffey disease). Interestingly, skull base sclerosis associated with excessive thickening was the most unusual malformation. We report a baby with mixed endochondral and intramembraneous ossification defects. CONCLUSION: Bone dysplasias, mucopolysaccharidoses, and metabolic diseases are a group of disorders that cause abnormal growth, density, and skull base shape. Skull base sclerosis/thickening is a well-known malformation in connection with other forms of sclerosing bone disorders such as dysosteosclerosis, frontometaphyseal dysplasia, and progressive diaphyseal dysplasia with skull base involvement. It is noteworthy that our present patient had an unusually sclerosed/thickened skull base. Narrowing of skull foramina due to sclerosis of skull base is likely to result in cranial nerves deficits. In this baby, the pathology has been judged to be the result of child abuse and it is not, in this case considerable harm to his parents, and the doctor-parent relationship was the outcome.
Cases Journal 2:133
Osteocalcin attenuates T3- and increases vitamin D3-induced expression of MMP-13 in mouse osteoblasts
Osteocalcin (OCN), the most abundant non-collagenous protein of the bone matrix, whose function is not fully understood, was recently suggested to act as endocrine factor regulating energy metabolism. Besides OCN, osteoblasts also express MMP-13, a matrix metallo-proteinase important for bone development and remodeling. Although differentially, both genes are regulated by 1,25-dihydroxy vitamin D3 (1,25D3) and T3, important hormones for bone metabolism. In mouse osteoblasts with a distinct differentiation status, T3 increases the expression of both proteins. By contrast, 1,25D3 stimulates the expression of MMP-13 but inhibits the expression of OCN in these cells. In humans, however, 1,25D3 upregulates both genes while T3 inhibits the OCN expression. Using northern blot hybridization we studied gene expression in the mouse osteoblastic cell line MC3T3-E1. We show that MMP-13 expression was strongly increased by T3 when the stimulation of OCN was low and, inversely, that the MMP-13 increase was low when T3 strongly stimulated the OCN expression. These findings suggest an interrelationship between OCN and MMP-13 expression. In fact, we observed that externally added OCN attenuated the T3 induced MMP-13 expression dose dependently and, furthermore, increased the 1,25D3 stimulated MMP-13 expression. Using a protein kinase A inhibitor we were able to show that this inhibitor mimics the effect of OCN suggesting a PKA dependent pathway to be involved in this regulatory process. We therefore hypothesize that OCN is a modulator of the hormonally regulated MMP-13 expression.
Endocrine Journal 56:441
Osteochondritis dissecans and Osgood Schlatter disease in a family with Stickler syndrome
ABSTRACT: PURPOSE: Stickler syndrome is among the most common autosomal dominant connective tissue disorders but is often unrecognised and therefore not diagnosed by clinicians. Despite much speculation, the cause of osteochondrosis in general and osteochondritis dissecans (OCD) and Osgood Schlatter syndrome (OSS) in particular remain unclear. Etiological understanding is essential. We describe a pair of family subjects presented with OCD and OSS as a symptom complex rather than a diagnosis. METHODS: Detailed clinical and radiographic examinations were undertaken with emphasis on the role of MRI imaging. Magnetic resonance imaging may allow early prediction of articular lesion healing potential in patients with Stickler syndrome. RESULTS: The phenotype of Stickler syndrome can be diverse and therefore misleading. The expectation that the full clinical criteria of any given genetic disorder such as Stickler syndrome will always be present can easily lead to an underestimation of these serious inheritable disorders. We report here two family subjects, a male proband and his aunt (paternal sister), both presented with the major features of Stickler syndrome. Tall stature with marfanoid habitus, astigmatism/congenital vitreous abnormality and submucus cleft palate/cleft uvula, and enlarged painful joints with early onset osteoarthritis. Osteochondritis dissecans (OCD) and Osgood Schlatter syndrome (OSS) were the predominating joint abnormalities. CONCLUSION: We observed that the nature of the articular and physeal abnormalities was consistent with a localised manifestation of a more generalised epiphyseal dysplasia affecting the weight-bearing joints. In these two patients, OCD and OSS appeared to be the predominant pathologic musculoskeletal consequences of an underlying Stickler's syndrome. It is empirical to consider generalised epiphyseal dysplasia as a major underlying causation that might drastically affect the weight-bearing joints.
Pediatr Rheumatol Online 7:4
Bone matrix quality and plasma homocysteine levels
It has recently been reported in the clinical literature that blood homocysteine levels correlate well with fracture risk, although a couple of reports exist to the opposite. Bone strength depends on both bone quantity and quality. The purpose of the present study was to investigate possible correlations between plasma homocysteine levels and bone material properties (Bone Mineral Density Distribution; BMDD, and collagen cross-link ratio). In the present study, femoral heads from subjects (N=19, females, age range 70-95 years old) with known homocysteine plasma levels were investigated. The bone material was collected during hemiarthroplasty surgery. We have determined collagen cross-link ratio and bone mineralization density distribution (BMDD) in bone tissue from patients with acute femoral neck fractures, by Fourier Transform Infrared Imaging (FTIRI) and quantitative Backscattered Electron Imaging (qBEI), respectively. The collagen cross-link ratio that was spectroscopically determined was pyridinoline/divalent cross-links (pyr/divalent). The BMDD variables quantified were: CaMean: the weighted mean calcium concentration; CaPeak: the most frequent Ca concentration; CaWidth: the width of the distribution, a measure of the mineralization homogeneity; CaLow: the percentage of bone area that is mineralized below the 5th percentile in the reference range; CaHigh: the percentage of bone area that is mineralized above the 95th percentile in the reference range. There was a significant correlation between plasma homocysteine levels and collagen cross-link ratio in areas of primary mineralized bone (p<0.0001), unlike the case of trabecular bone surfaces undergoing resorption (p>0.05). On the other hand there was no correlation in any of the BMDD parameters and plasma homocysteine levels (p>0.05). The results are consistent with the known effect of homocysteine on collagen post-translational modifications. These changes were independent of bone mineral characteristics. The results of the present study offer a mechanism by which homocysteine affects bone quality, but caution should be exercised since all patients examined had sustained fracture.
Normative data on mineralization density distribution in iliac bone biopsies of children, adolescents and young adults
Bone mineralization density distribution (BMDD) as assessed by quantitative backscattered electron imaging (qBEI) in iliac crest bone biopsies has become in the last years a powerful diagnostic tool to evaluate the effect of metabolic bone diseases and/or therapeutic interventions on the mineralization status of the bone material. However until now, normative reference data are only available for adults. The aim of the present study is to close this gap and establish normative data from children and compare them with reference BMDD data of adults. qBEI analyses were performed on bone samples from 54 individuals between 1.5 and 23 years without metabolic bone diseases, which were previously used as study population to establish normative histomorphometric standards. In the trabecular compartment, none of the BMDD parameters showed a significant correlation with age. The BMDD was shifted towards lower mineralization density (CaMean -5.6%, p<0.0001; CaPeak -5.6%, p<0.0001; CaLow +39.0% p<0.001; CaHigh -80.7%, p<0.001) and the inter-individual variation was higher compared to the adult population. The cortices appeared to be markedly less mineralized (CaMean -3.1%, p<0.0001) than cancellous bone due to higher amounts of low mineralized secondary bone. However, the cortical BMDD parameters showed a strong correlation (r=0.38 to 0.85, with p<0.001 to<0.0001) with cancellous BMDD parameters. In conclusion, this study provides evidence that BMDD parameters in growing healthy subjects are relatively constant and that these data can be used as normative references in pediatrics osteology. The larger inter-individual variability compared to adults is most likely related to alterations of the bone turnover rate during growth.
Occipitoatlantoaxial junction malformation and early onset senile ankylosing vertebral hyperostosis in a girl with MURCS association
Recent onset of head mobility limitations associated with significant stiffness along the vertebral column were the predominating symptomatology in a girl with MURCS association. Occipitoatlantoaxial junction malformation complex and vertebral hyperostosis have been identified. Three-dimensional computerized tomography (3-DCT) scan showed assimilation of the anterior arch of the atlas causing basilar invagination. She also had significant thoracic vertebral hyperostosis closely resembling senile ankylosing vertebral hyperostosis (Forestier disease). We report on what might be a novel constellation of spine maldevelopment in connection with MURCS association.
Am J of Med Genet Part A 149:470
Distinctive tomographic features of atlantoaxial dislocation in a boy with acromesomelic dysplasia du Pan syndrome
Distinctive tomographic features of atlantoaxial dislocation have been encountered in a child with du Pan syndrome. Three-dimensional computed tomography scan showed agenesis of the odontoid process associated with significant hypoplasia of the left lateral mass of the odontoid. Bidirectional fluorescent DNA sequencing has been used to identify mutations in the complete coding region (exon 1-2) of the cartilage-derived morphogenic protein 1 gene. No mutation was detected in the analysed region. We report what might be a novel variant of acromesomelic du Pan syndrome.
Clinical Dysmorphology 18:122
Fourier transform infrared analysis and bone
This is a review article summarizing the utilization of Fourier Transform Infrared Imaging to the analysis of bone. It describes the major outcomes of such analyses as well as the major contributions in understanding the role of material properties, and in particular mineral crystallites and collagen, in determining bone strength. Appreciating these helps us better define the pathophysiology of diseases such as osteoporosis and assist us in better comparing the various therapeutic protocols as well as the design of new, more targeted ones.
Osteoporos Int 20:1043
Significant traumatic atrophy of the spinal cord in connection with severe cervical vertebral body hypoplasia in a boy with Larsen syndrome: a case report and review of the literature
Introduction: Cervical kyphosis may be potentially the most serious and, indeed, a life-threatening manifestation of Larsen syndrome because of the impingement on the spinal cord at the apex of the kyphosis. Abnormalities of the spine, specifically cervicothoracic kyphosis requires specific attention and management.
Case presentation: We report on a 3-year-old boy who presented with full clinical and the radiographic features of Larsen syndrome. There was significant vertebral body hypoplasia of C5/7 combined with spina bifida occulta from C1/T2, resulting in congenital cervical instability and kyphosis.
Conclusion: Congenital or developmental cervical kyphosis is a serious orthopaedic abnormality, which is associated with several syndromic associations such as Larsen syndrome, diastrophic dysplasia, chondrodysplasia punctata, camptomelic dysplasia, and neurofibromatosis
Cases Journal 2:6729
Labordiagnostik in der Prävention, Differentialdiagnose und Verlaufskontrolle in der Osteoporose.
Osteoporose wird von der WHO zu den ökonomisch bedeutsamsten Erkrankungen des 21. Jahrhunderts gezählt. Abgesehen von Anamnese, klinischer Untersuchung und bildgebenden Verfahren sind Laboruntersuchungen wichtige Werkzeuge in der Diagnose, Therapieüberwachung und Verlaufskontrolle der Osteoporose. Man unterscheidet Basis-Laboruntersuchungen von weiterführenden Laboruntersuchungen. Das Basislabor dient zur Differentialdiagnose zwischen primären und sekundären Formen der Osteoporose. Ursachen der sekundären Formen der Osteoporose müssen unter anderem durch weiterführende Untersuchungen abgeklärt werden. Spezielle Biomarker des Knochenstoffwechsels werden hauptsächlich zur Therapieüberwachung und Verlaufsbeurteilung der Osteoporose genutzt.
J Lab Med 33:140
Vibrational spectroscopy in biomedical science: bone
Fourier transform infrared imaging (FTIR) and Raman Microspectroscopy are powerful tools for characterizing the distribution of different chemical moieties in heterogeneous materials. FTIR and Raman measurements have been adapted to assess the maturity of the mineral and the quality of the organic component (collagen and non-collagenous proteins) of the mineralized tissue in bone. Unique to the FTIRI analysis is the capability to provide the spatial distribution of two of the major collagen cross-links (pyridinoline, and dehydro-dihydroxylysinonorleucine) and through the study of normal and diseased bone, relate them to bone strength. These FTIR parameters have been validated based on analysis of model compounds. It is widely accepted that bone strength is determined by bone mass and bone quality. The latter is a multifactorial term encompassing the material and structural properties of bone, and one important aspect of the bone material properties is the organic matrix. The bone material properties can be defined by parameters of mineral and collagen, as determined by FTIR and Raman analysis. Considerably less attention has been directed at collagen, although there are several publications in the literature reporting altered collagen properties associated with fragile bone, in both animals and humans. Since bone is a heterogeneous tissue due to the remodeling process, microscopic areas may be carefully selected based on quantitative Backscattered Electron Imaging or histological staining, thus ensuring comparison of areas with similar metabolic activity and mineral content. In conclusion, FTIRI and Raman vibrational spectroscopy are proving to be powerful tools in bone-related medical research
Progress in Biomedical Optics and Imaging 10:7166 02
Antibody against mutated citrullinated vimentin: a new sensitive marker in the diagnosis of rheumatoid arthritis
The aim of this study was to determine the performance of antibodies against mutated citrullinated vimentin (anti-MCV) in comparison with antibodies to cyclic citrullinated peptides (anti-CCP) in patients with rheumatoid arthritis (RA). Serum levels of anti-MCV and anti-CCP were determined in 193 patients with RA and 332 controls, and sensitivity and specificity were calculated. In a separate analysis of 86 patients, the anti-MCV levels were compared to disease activity. Sensitivity of anti-MCV versus anti-CCP was 71.5 and 69.4%, specificity was 81.3 and 97.6%, respectively. The ROC curves showed higher specificity and an advantage of anti-CCP. In seronegative RA patients the sensitivity of anti-MCV was superior over anti-CCP. Anti-MCV positivities also occurred in systemic lupus erythematosus and Sjoegren's syndrome. In a subgroup of 86 RA patients we found a significant correlation between anti-MCV and disease activity. Anti-MCV appears to be an important marker for the diagnosis of RA, and correlates also with disease activity.
Rheumatol Int 29:1315
Austrian guidance for the pharmacological treatment of osteoporosis in postmenopausal women--update 2009
Osteoporosis is a systemic skeletal disease characterized by diminished bone mass and deterioration of bone microarchitecture, leading to increased fragility and subsequent increased fracture risk. Therapeutic measures therefore aim at reducing individual fracture risk. In Austria, the following drugs, all of which have been proven to reduce fracture risk, are currently registered for the treatment of postmenopausal osteoporosis: alendronate, risedronate, etidronate, ibandronate, raloxifene, teriparatide (1-34 PTH), 1-84 PTH, strontium ranelate and salmon calcitonin. Fluorides are still available, but their role in daily practice has become negligible. Currently, there is no evidence that a combination of two or more of these drugs could improve anti-fracture potency. However, treatment with PTH should be followed by the treatment with an anticatabolic drug such as bisphosphonates. Calcium and vitamin D constitute an important adjunct to any osteoporosis treatment.
Wien Med Wochenschr Suppl. 2009;(122):1-34
Spatial and temporal variations of mechanical properties and mineral content of the external callus during bone healing.
After bone fracture, various cellular activities lead to the formation of different tissue types, which form the basis for the process of secondary bone healing. Although these tissues have been quantified by histology, their material properties are not well understood. Thus, the aim of this study is to correlate the spatial and temporal variations in the mineral content and the nanoindentation modulus of the callus formed via intramembranous ossification over the course of bone healing. Midshaft tibial samples from a sheep osteotomy model at time points of 2, 3, 6 and 9 weeks were employed. PMMA embedded blocks were used for quantitative back scattered electron imaging and nanoindentation of the newly formed periosteal callus near the cortex. The resulting indentation modulus maps show the heterogeneity in the modulus in the selected regions of the callus. The indentation modulus of the embedded callus is about 6 GPa at the early stage. At later stages of mineralization, the average indentation modulus reaches 14 GPa. There is a slight decrease in average indentation modulus in regions distant to the cortex, probably due to remodelling of the peripheral callus. The spatial and temporal distribution of mineral content in the callus tissue also illustrates the ongoing remodelling process observed from histological analysis. Most interestingly the average indentation modulus, even at 9 weeks, remains as low as 13 GPa, which is roughly 60% of that for cortical sheep bone. The decreased indentation modulus in the callus compared to cortex is due to the lower average mineral content and may be perhaps also due to the properties of the organic matrix which might be different from normal bone.
Long-Term Marginal Zinc Supply Is Not Detrimental to the Skeleton of Aged Female Rats
In this experiment, we investigated the long-term effects of a marginal zinc (Zn) supply on bone metabolism in aged rats. Nine-mo-old female Fischer-344 rats were divided into 8 weight-matched groups of 8 rats each. All rats were adapted for 1 mo to restrictive feeding (7.5 g/d) of a purified diet containing 8 g/kg sodium phytate and 64 mg/kg Zn. Control rats were pair-fed throughout the experiment. During the 1-mo depletion phase, controls received the Zn-replete diet with 64 mg/kg Zn, whereas Zn-deficient rats were fed the same diet with 2.2 mg/kg Zn. The depletion phase was followed by a 3-mo marginal phase in which the rats fed the diet with 2.2 mg/kg Zn received an additional daily Zn supplement of 75 mg Zn/rat by gavage. In the following 2-mo repletion phase, a marginal group was switched to the Zn-replete diet, while the other groups were maintained on marginal Zn supply or on the Zn-replete diet. Zn depletion and marginal Zn reduced serum and bone Zn and serum alkaline phosphatase activity. Zn repletion normalized serum Zn. However, apart from subtle changes in bone mineralization density distribution, Zn deficiency was not associated with detrimental effects on bone mineral density,
turnover, architecture, or biomechanics relative to control rats at any time point. Our data suggest that Zn does not play an essential role in bone metabolism in aged rats and cast doubt on the hypthosis that Zn deficiency is a risk factor for osteoporosis.
J. Nutr. 139: 703–709
PTH(1-34) Replacement Therapy in a Child With Hypoparathyroidism Caused by a Sporadic Calcium Receptor Mutation
Autosomal dominant hypocalcemia (ADH) is an inherited form of hypoparathyroidism caused
by activating mutations in the calcium-sensing receptor (CaR). Treatment with PTH(1-34) may be superior to conventional therapy but is contraindicated in children, and long-term effects on the skeleton are unknown. The patient is a 20-yr-old female with ADH treated with PTH continuously since 6 yr and 2 mo of age. A bone biopsy was obtained for histomorphometry and quantitative backscattered electron imaging (qBEI). Her data were compared with one age-, sex-, and length of hypoparathyroidism–matched control not on PTH and two sex-matched ADH controls before and after 1 yr of PTH. The patient’s growth was normal. Hypercalciuria and hypermagnesuria persisted despite normal or subnormal serum calcium and magnesium levels.
Nephrocalcinosis, without evidence of impaired renal function, developed by 19 yr of age. Cancellous bone volume was dramatically elevated in the patient and in ADH controls after 1 yr of PTH. BMD distribution (BMDD) by qBEI of the patient and ADH controls was strikingly shifted toward lower mineralization compared with the non-ADH control. Moreover, the ADH controls exhibited a further reduction in mineralization after 1 yr of PTH. These findings imply a role for CaR in bone matrix mineralization. There were no fractures or osteosarcoma. In conclusion, long-term PTH replacement in a child with ADH was not unsafe, increased bone mass without negatively impacting mineralization, and improved serum mineral control but did
not prevent nephrocalcinosis. Additionally, this may be the first evidence of a role for CaR in human bone.
J Bone Miner Res 24:964–973
Combination of Nanoindentation and Quantitative Backscattered Electron Imaging Revealed Altered Bone Material Properties Associated with Femoral Neck Fragility
Osteoporotic fragility fractures were hypothesized to be related to changes in bone material properties and not solely to reduction in bone mass. We studied cortical bone from the superior and inferior sectors of whole femoral neck sections from five female osteoporotic hip fracture cases (74-92 years) and five nonfractured controls (75-88 years). The typical calcium content (Ca(Peak)) and the mineral particle thickness parameter (T) were mapped in large areas of the superior and inferior regions using quantitative backscattered electron imaging (qBEI) and scanning small-angle X-ray scattering, respectively. Additionally, indentation modulus (E) and hardness (H) (determined by nanoindentation) were compared at the local level to the mineral content (Ca(Ind)) at the indent positions (obtained from qBEI). Ca(Peak) (-2.2%, P = 0.002), Ca(Ind) (-1.8%, P = 0.048), E (-5.6%, P = 0.040), and H (-6.0%, P = 0.016) were significantly lower for the superior compared to the inferior region. Interestingly, Ca(Peak) as well as Ca(Ind) were also lower (-2.6%, P = 0.006, and -3.7%, P = 0.002, respectively) in fracture cases compared to controls, while E and H did not show any significant reduction. T values were in the normal range, independent of region (P = 0.181) or fracture status (P = 0.551). In conclusion, it appears that the observed femoral neck fragility is associated with a reduced mineral content, which was not accompanied by a reduction in stiffness and hardness of the bone material. This pilot study suggests that a stiffening process in the organic matrix component contributes to bone fragility independently of mineral content.
Calcif Tissue Int 85:335-343
Mineralization density distribution of postmenopausal osteoporotic bone is restored to normal after long-term alendronate treatment: qBEI and sSAXS data from the Fracture Intervention Trial Long-Term Extension (FLEX)
Long term treatment studies showed that the therapeutic effects of alendronate (ALN) weresustained over a 10 years treatment period. However, data on the effects on intrinsic bone material properties by long term reduction of bone turnover are still sparse. We analyzed transiliacal bone biopsies of a subgroup of 30 FLEX-participants (n=6 were treated 10 years with ALN at dose of 10mg/day, n=10 10 years with ALN at dose of 5mg/day and n=14 were treated 5 years with ALN plus further 5 years with placebo) by quantitative backscattered electron imaging (qBEI) and scanning small angle X-ray scattering (sSAXS) to determine the bone mineralization density distribution (BMDD) and the mineral particle thickness parameter T. BMDD data from these FLEX-participants were compared to those from a previously published healthy population (n=52). Compared to 5years ALN plus 5 years placebo 10 years ALN treatment (independent of the dose given) did not cause any difference in any of the BMDD-parameters: The weighted mean (CaMean), the typical calcium concentration (CaPeak), the heterogeneity of mineralization (CaWidth), the percentage of low mineralized bone areas (CaLow) and the portion of highly mineralized areas (CaHigh) were not different for the patients who continued ALN from those who stopped ALN after 5 years. Moreover, no significant differences for any of the BMDD-parameters between the FLEX participants and the healthy population could be observed. In none of the investigated cases, abnormally high mineralization or changes in mineral particle thickness were observed (CaHigh and T were both in the normal range). The findings of the present study support the recommendation that antiresorptive treatment with ALN should be maintained for 5 years. But even at longer treatment duration of up to 10 years no negative effects on the bone matrix
mineralization were observed.
J Bone Miner Res 25:48-55
Increased Matrix Mineralization in the Immature Femoral Head Following Ischemic Osteonecrosis
Traditionally, it is believed that structural failure of the ischemic epiphysis as well as changes in radiodensity seen in the early stage of Legg-Calve-Perthes disease are due to repair process. However, little is known if matrix properties are altered following ischemic injury of the juvenile femoral head. Purpose of this study was to determine the matrix mineralization density, an important determinant of material quality and strength, of the epiphysis in an experimental animal model of Perthes disease. Ten piglets were surgically induced with femoral head ischemia and euthanized at 4- and 8 weeks following surgery. Contralateral, unoperated femoral heads were used as controls. Bone and calcified cartilage mineralization density distribution parameters were determined using quantitative backscattered electron imaging (qBEI) in the epiphyseal calcified articular cartilage-, subchondral bone- and central trabecular bone region. Histological as well as radiographic assessment was also performed.
Gelatin-based Photopolymers for Bone Replacement Materials
Gelatin-based monomers were considered as suitable base component for the 3D structuring of potential bone replacement materials by stereolithographic techniques. Different methacrylate-based gelatin derivatives were prepared whereas a polyethylene glycol modified derivative GP4M turned out to have the highest tolerance towards other monomers. These are essential as they allow the tuning of the photoreactivity and the mechanical properties. Cell culture experiments with osteoblast- and endothelial-like cells confirmed negligible cytotoxicity of these monomers. Finally we were able to show the possibility of producing arbitrary cellular structures with these gelatin-containing formulations using stereolithography.
Journal of Polymer Science Part A: Polymer Chemistry accepted
Vinyl esters: Low cytotoxicity monomers for the fabrication of biocompatible 3D scaffolds by lithography based additive manufacturing technologies
Lithography based additive manufacturing technologies (AMT) like stereolithography or digital light processing have become appealing methods for the fabrication of 3D cellular scaffolds for tissue engineering and regenerative medicine. To circumvent the use of (meth)acrylate-based photopolymers, that suffer from skin irritation and sometimes cytotoxicity, new monomers based on vinyl esters were prepared. In-vitro cytotoxicity studies with osteoblast-like cells proofed that monomers based on vinyl esters are significantly less cytotoxic than (meth)acrylates. Photoreactivity was followed by Photo-Differential Scanning Calorimetry and the mechanical properties of the photocured materials were screened by nanoindentation. Conversion rates and indentation moduli between those of acrylate and methacrylate references could be observed. Furthermore osteoblast-like cells were successfully seeded onto polymer specimens. Finally, we were able to print a 3D test structure out of a vinyl ester-based formulation by µ-SLA with a layer thickness of 50 µm. For in-vivo testing of vinyl esters these 3D scaffolds were implanted into surgical defects of the distal femoral bone of adult New Zealand white rabbits. The obtained histological results approved the excellent biocompatibility of vinyl esters.
Journal of Polymer Science Part A: Polymer Chemistry accepted
Strontium is incorporated into mineral crystals only in newly formed bone during strontium ranelate treatment
Strontium ranelate has been shown to increase bone mass in postmenopausal osteoporosis patients and to reduce fracture risk. The aim of this study was to investigate the potential influence of strontium ranelate (Protelos®) treatment on the human bone tissue characteristics and quality at the micro- and nanostructural level. We investigated transiliac biopsies from patients treated for 36 months with strontium ranelate or placebo (n=5 per group) using synchrotron radiation with a microbeam, combining scanning small-angle scattering, X-ray diffraction and fluorescence spectroscopy (SAXS/XRD/XRF) for a detailed characterization of the mineral crystals within the collagenous bone matrix. A scanning procedure allowed the simultaneous determination of maps of the chemical composition together with thickness, length and lattice spacing of these mineral crystals within each of the 15 or 25 microns wide pixels in a thin bone section. The fluorescence results show that only bone packets or osteons formed during the strontium ranelate treatment contain significant amounts of strontium and that up to 0.5 out of 10 calcium atoms in the mineral crystals are replaced by strontium, as revealed by a corresponding shift in apatite lattice spacing. The thickness and length of the plate-shaped bone mineral crystals were not affected by the strontium ranelate treatment. As a consequence, there was no indication for a change in human bone tissue quality at the nanoscale after a 36-month treatment of postmenopausal osteoporotic women with strontium ranelate, except for a partial replacement of calcium by strontium ions in the hydroxyapatite crystals, only in newly formed bone.
J Bone Miner Res accepted
Bone material quality in transiliac bone biopsies of postmenopausal osteoporotic women after 3 years strontium ranelate treatment
Strontium ranelate (SrR) is a relatively new treatment for osteoporosis. In the present study, we investigated its potential impact on human bone material quality in transiliac bone biopsies from postmenopausal osteoporotic women treated 3 years with calcium and VitD plus either 2g SrR per day or placebo. Bone mineralization density distribution (BMDD), strontium (Sr) concentration, collagen cross-link ratio and indentation modulus were analyzed by quantitative backscattered electron imaging, electron-induced X-ray fluorescence analysis, synchrotron radiation induced micro X-ray fluorescence elemental mapping, Fourier transform infrared imaging, and nanoindentation, respectively. The BMDD of SrR-treated patients was shifted to higher atomic numbers (Zmean +1.5%, p<0.05 vs. placebo). We observed Sr being preferentially incorporated in bone packets formed during SrR-treatment up to 6% atom fraction [Sr/(Sr+Ca)] dependent on the SR serum levels of the individuals (correlation r=0.84, P=0.018). Collagen cross-link ratio was preserved in SR-treated bone. The indentation modulus was significantly decreased in younger versus older bone packets for both placebo (-20.5%, P<0.0001) and SrR-treated individuals (-24.3%, P<0.001), while no differences were found between the treatment groups. In conclusion, our findings indicate that after SrR treatment, Sr is heterogeneously distributed in bone and preferentially present in bone packets formed during treatment. The effect of SrR on the BMDD seems to be mainly due to the uptake of Sr and not by changes in bone calcium content. Taken together, these data provide evidence that the investigated bone quality determinants at tissue level were preserved in postmenopausal osteoporotic women after 3-year treatment with 2g SrR/day plus calcium/VitD.
J Bone Miner Res 25:891-900
Description of closed projects and published manuscripts of the year 2008
Determination of the elemental distribution in human joint bones by SR micro XRF
In humans the toxic trace element lead (Pb) mainly accumulates in the skeletal tissue where it resides for a long period. Although Pb is known to play a role in bone and cartilage diseases, the distribution of Pb in these tissues is mostly unknown. Therefore synchrotron-radiation -induced micro x-ray flouorescence analysis (SR µ-XRF) in various geometries was used to determine the distribution of Pb, Ca, Zn, and Sr at the cartilage-bone interface in human femoral heads and patellae. SR µ-XRF results were matched with backscattered electron (BE) images providing information on structural features of the tissue. Conventional SR µ-XRF at the HASYLAB beamline L showed that the Pb mostly accumulates in a zone of some micrometers around the transition between non-calcified and calcified cartilage. However, the relatively large sample thickness did not allow more precise conclusions. Exploiting the 3D capabilities of the confocal SR µ-XRF and SR microfluorescence tomography at ANKA Fluo-Topo beamline and HASILAB beamline L, the spatial resolution could be improved and a highly specific accumulation of Pb at the tidemark, the calcification front between non-calcified and calcified cartilage, was detected. It was found that Pb and Zn accumulation coincide at the tidemark. Since the tidemark plays an important role in osteoarthritis, the results may strengthen other authors' conclusions that Pb is associated with this joint disease. Although offering less spatial resolution when compared to micro-tomography, confocal SR µ-XRF is best suited for such studies. It facilitates the comparison of element maps with other imaging techniques like BE imaging.
X-Ray Spectroscopy 37:3-11
Dolicho-odontoid in a boy with pseudoachondroplasia
We report on a 9-year-old-boy with the clinical and radiographic diagnosis of pseudoachondroplasia. An antero-posterior open mouth radiogram, showed an unduly long odontoid and a 3 CT scan confirmed the presence of a long, bifid odontoid. This is the first clinical report describing a dolicho-odontoid in a boy with pseudoachondroplasia.
Eur J Orthop Surg Traumatol 18:297-301
Bone mineralization density distribution in health and disease
Human cortical and trabecular bones are formed by individual osteons and bone packets, respectively, which are produced at different time points during the (re)modeling cycle by the coupled activity of bone cells. This leads to a heterogeneously mineralized bone material with a characteristic bone mineralization density distribution (BMDD) reflecting bone turnover, mineralization kinetics and average bone matrix age. In contrast to BMD, which is an estimate of the total amount of mineral in a scanned area of whole bone, BMDD describes the local mineral content of the bone matrix throughout the sample. Moreover, the mineral content of the bone matrix is playing a pivotal role in tuning its stiffness, strength and toughness. BMDD of healthy individuals shows a remarkably small biological variance suggesting the existence of an evolutionary optimum with respect to its biomechanical performance. Hence, any deviations from normal BMDD due to either disease and/or treatment might be of significant biological and clinical relevance. The development of appropriate methods to sensitively measure the BMDD in bone biopsies led to numerous applications of BMDD in the evaluation of diagnosis and treatment of bone diseases, while advancing the understanding of the bone material, concomitantly. For example, transiliacal bone biopsies of postmenopausal osteoporotic women were found to have mostly lower mineralization densities than normal, which were partly associated by an increase of bone turnover, but also caused by calcium and Vit-D deficiency. Antiresorptive therapy causes an increase of degree and homogeneity of mineralization within three years of treatment, while normal mineralization levels are not exceeded. In contrast, anabolic therapy like PTH decreases the degree and homogeneity of matrix mineralization, at least transiently. Osteogenesis imperfecta is generally associated with increased matrix mineralization contributing to the brittleness of bone in this disease, though bone turnover is usually increased suggesting an alteration in the mineralization kinetics. Furthermore, BMDD measurements combined with other scanning techniques like nanoindentation, Fourier transform infrared spectroscopy and small angle X-ray scattering can provide important insights into the structure-function relation of the bone matrix, and ultimately a better prediction of fracture risk in diseases, and after treatment.
The effect of geometry on three-dimensional tissue growth
Tissue formation is determined by uncountable biochemical signals between cells; in addition, physical parameters have been shown to exhibit significant effects on the level of the single cell. Beyond the cell, however, there is still no quantitative understanding of how geometry affects tissue growth, which is of much significance for bone healing and tissue engineering. In this paper, it is shown that the local growth rate of tissue formed by osteoblasts is strongly influenced by the geometrical features of channels in an artificial three-dimensional matrix. Curvature-driven effects and mechanical forces within the tissue may explain the growth patterns as demonstrated by numerical simulation and confocal laser scanning microscopy. This implies that cells within the tissue surface are able to sense and react to radii of curvature much larger than the size of the cells themselves. This has important implications towards the understanding of bone remodelling and defect healing as well as towards scaffold design in bone tissue engineering.
J. R. Soc. Interface 5:1173-1180
A patient with Melorheostosis manifesting with features similar to tricho-dento-osseous syndrome: a case report.
Introduction: A case of melorheostosis in association with tricho-dento-osseous (TDO) syndrome has been encountered. Case presentation: The clinical and the radiographic manifestations of melorheostosis have been encountered in a 41-year-old man. Mutations in the 13 exons and flanking intronic regions of the LEMD3-gene have not been detected. His phenotypic features were consistent but not completely diagnostic for tricho-dento-osseous syndrome (TDO). We report what might be a novel syndromic association. Conclusion: Melorheostosis has not previously been reported to be a part of TDO and an extensive review of the literature suggests that the constellation of hair, tooth and bone abnormalities found in our patient either represents an unusual variant of tricho-dento-osseous syndrome or a new syndrome.
Journal of Medical Case Reports 2:51
Imatinib mesylate (IM)-induced growth inhibition is associated with production of spliced osteocalcin-mRNA in cell lines
It has been suggested that imatinib mesylate (IM) influences osteogenesis and bone turnover in treated patients. Here we show that the inhibitory effect of IM on cell multiplication is associated with an increased proportion of spliced osteocalcin (OCNs) in leukemia (HL-60) and osteosarcoma cells (MG-63, U-2 OS), despite a lower mRNA synthesis rate. In mouse osteoblastic MC3T3-E1 cells only OCNs is present, independently of treatment. As the stimulatory effect of IM on OCNs is also observed upon treatment with vitamin D, common regulatory processes may be considered.
Leukemia Research 32:437-443
Diffuse skull base/cervical fusion syndromes in two siblings with spondylocostal dysostosis syndrome: analysis via three dimensional computed tomography scanning
Study Design: A study on a pair of male sibs to reach for the etiological understanding of unusual skull base/spine maldevelopment. Objective: Previously, radiographs alone were used to formulate this diagnosis. Here, three-dimensional computed tomography (3D CT) studies further clarified the typical diagnostic findings associated with spondylocostal dysostosis (SCD). Interestingly, patients with SCD are at increased risk for diffuse skull base/cervical fusion syndromes and can result in severe neurologic deficits associated with any degree of trauma. Summary of Background Data: Classically SCD is defined as a skeletal dysplasia with clinical and radiologic manifestations, consisting of short neck and trunk, nonprogressive scoliosis and abnormalities of vertebral segmentation and of the ribs. Radiograms have been adopted as the only modality for the classification and prognostication of patients with SCD.
Methods: Detailed clinical and radiographic examinations were undertaken with emphasis on the significance of the 3D CT scanning. Results: We observed extensive fusion of the clivus with the cervical/entire spine, resulting in a remarkable solid, immobile, and fixed bony ankylosis of extremely serious outcome. Conclusion: Patients with spondylcostal dysostosis are predisposed to develop extensive skull-base-cervical spine fusion. The latter might lead to the development of a solid, immobile, and fixed bony ankylosis. In children/adults trivial injuries and/or high-energy trauma can lead to serious intracranial and spinal cord injury. Comprehensive orthopedic and neurosurgeons management must follow the recognition of these anomalies. To the best of our knowledge, no previous CT studies of the spine have been published in patients with SCD.
Evidence that abnormal high bone mineralization in growing children with osteogenesis imperfecta is not associated with specific collagen mutations
Osteogenesis imperfecta type I (OI-I) represents the mildest form of OI. The collagen I mutations underlying the disorder can be classified as quantitative mutations that lead to formation of a decreased amount of normal collagen or qualitative mutations where structurally aberrant collagen chains are generated. However, the phenotypic consequences of a particular mutation are not well understood. Transiliac bone biopsies from 19 young OI-I patients (age range 2.0-14.1 years) and 19 age-matched controls were used to assess bone histomorphometric parameters and bone mineralization density distribution, measured by quantitative backscattered electron imaging. Thirteen of the OI-I patients were affected by quantitative and six patients by qualitative mutations. Compared to age-matched controls, iliac bone samples in the OI group were smaller and had thinner cortices and less trabecular bone. Resorption parameters were similar between groups, whereas surface-based parameters of bone formation were considerably higher in OI patients than in controls with the exception of bone formation rate per osteoblast surface, which was reduced in OI. Backscattered electron imaging revealed a higher mean mineralization density (+7%, P < 0.001) in OI-I patients than in age-matched controls, which was accompanied by a reduced heterogeneity of mineralization (-13%, P < 0.001). However, the increase of mean degree of mineralization in OI did not exceed the average level of normal adult bone. No differences were found between the two mutation types. In summary, the tissue- and material-level abnormalities found in OI-I (low bone mass and increased mineral content of the matrix) seem to be independent of the collagen mutations.
Calcif Tissue Int 82:263-270
Lysyl oxidase (LOX) mRNA expression and genes of the differentiated osteoblastic phenotype are upregulated in human osteosarcoma cells by suramin
It is well known that suramin influences proliferation and differentiation of tumour cells. To study whether and how suramin effects osteosarcoma (OS) cells, proliferation, differentiation, LOX mRNA expression and telomerase activity (TA) was analysed in the human MG-63 and U-2 OS, and the rat UMR-106 OS cell lines. Data show that suramin inhibited proliferation in the human cell lines and upregulated alkaline phosphatase activity. TA was attenuated in the human cells while in UMR-106 it was not changed. In UMR-106 suramin had no influence on osteocalcin and LOX expression, in the human cells however, both genes were upregulated.
Cancer Letters 265:45-54
Collagen cross-linking influences osteoblastic differentiation
Osteoblasts synthesize collagen matrix, which itself regulates the differentiation of precursor cells into mature osteoblasts. They express lysyl oxidase (LOX), which is involved in the collagen cross-linking process. Lathyrogens, like ß-aminopropionitrile (ßAPN) inhibit the formation of a stable matrix. The aim of the present study was to investigate the influence of cross-linking on osteoblastic differentiation. MC3T3-E1 cells were seeded and treated without or with 400 µM ßAPN for one week. Thereafter living cells were removed and on this extracellular matrix (ECM), new MC3T3-E1 cells were seeded and cultured for one week, without ßAPN. RNA was isolated and expression of specific marker genes was determined by QRT-PCR. Changes in specific cross-links after ßAPN treatment were measured with Fourier-transform infrared spectroscopy (FTIR). The collagen matrix formed showed a significant reduction of two major cross-links of bone collagen, namely deH-DHLNL and pyr, compared to control cultures. Gene expression studies showed an increase of Collagen α1 (I) (COL1A1) to 150%. LOX and osteocalcin (OCN) mRNA expression was significantly downregulated to about 75%. When fresh MC3T3-E1 cells were seeded on this altered matrix without ßAPN, COL1A1 mRNA expression was upregulated (140%), OCN downregulated (60%), while LOX mRNA expression remained unaffected. These results indicate that ßAPN treatment not only disrupts collagen cross-link formation, but also affects osteoblastic activity and expression. In conclusion, the disrupted matrix produced in the presence of the lathyrogen influences, even in its absence, the expression of osteoblastic genes.
Calcif Tissue Int 82:392-400
Bone quality determined by Fourier Transform Infrared Imaging analysis in mild primary hyperparathyroidism
Mild primary hyperparathyroidism (PHPT) is characterized by asymptomatic hypercalcemia, most commonly in the absence of classical signs and symptoms. Hence, there is need to characterize this disorder with particular attention to the skeleton. We determined the ratio of pyr and deH-DHLNL collagen cross-links in 46 iliac crest bone biopsies from patients with PHPT (14 men, aged 28-68; 32 women, aged 26-74) by Fourier transform infrared imaging (FTIRI). The results were compared with previously reported collagen cross-links ratio determined in iliac crest biopsies from normal subjects. PHPT patients exhibited significantly lower pyr/deH-DHLNL collagen cross-links ratio compared to normal controls. Parathyroidectomy restored values to those comparable to normal controls. Moreover, the differences among PHPT subjects were gender-dependent with female PHPT patients having a statistically significant lower ratio compared to either male PHPT patients or normal controls. Comparison of the obtained outcomes with histomorphometry showed that the collagen cross-link ratio was strongly correlated with rate of bone formation, and mineralizing surface, in individual patients. This ratio was also correlated with bone mineralization density distribution (BMDD) parameters obtained in the same patients. The strongest correlations were with BMDD variables reflecting heterogeneity of mineralization and primary mineralization parameters. The results are consistent with the high turnover state manifested in PHPT patients. Reduced collagen cross-link ratio in patients with PHPT would be expected to reduce the stiffness of bone tissue. These observations provide a more complete assessment of bone material properties in this disorder.
J Clin Endocrinol Metab 93:3484-3489
Short-term effects of high dose zoledronic acid treatment on bone mineralization density distribution (BMDD) after orthotopic liver transplantation
Patients with “hepatic” bone disease exhibit increased fracture incidence. The effects on bone material properties, their changes due to orthotopic liver transplantation (OLT) as well as zolendronate (ZOL) treatment have not yet been investigated. We studied bone mineralization density distribution (BMDD) in paired transiliacal biopsies (at and 6 months after OLT) from patients (control CON n=18, treatment group ZOL n=21, the latter treated with iv ZOL at doses of 4 mg/month) for how bone at material level was affected by the "hepatic" disease in general, as well as by OLT and ZOL in particular. i) BMDD-parameters at baseline were reflecting disturbed bone matrix mineralization in “hepatic” bone disease combined with low turnover. Trabecular bone displayed a decrease in mean and most frequent calcium concentration (CaMean -2.9% and CaPeak -2.8%, respectively, both p<0.001), increased heterogeneity of mineralization (CaWidth +12.2%, p=0.01) and increased percentage of bone areas with low mineralization (CaLow +32.4%, p=0.02) compared to normal, however, no differences compared to cortical bone. ii) Six months after OLT, ZOL treated trabecular bone displayed reduced CaLow (-32.0%, p=0.047), cortical bone increased CaMean (+4.2%, p=0.009), CaPeak (+3.3%, p=0.040) and reduced CaLow (-55.7, p=0.038) compared to CON and increased CaMean compared to baseline (+1.9, p=0.032) without any signs of hyper- or defective mineralization. These changes as consequence of the antiresorptive action of ZOL visible already after 6 months result in beneficial effects on bone matrix mineralization, likely contributing to the significant decrease in fracture incidence observed in these patients 2 years post transplantation.
Calcif Tissue Int 83:167-175
Effect of teriparatide on early bone loss after kidney transplantation
Kidney transplantation is associated with bone loss and increased fracture risk. Prophylactic bone protective treatment, favourably with a biphosphonate, is therefore recommended. Since a large number of transplant recipients have adynamic renal bone disease anabolic therapy might be more effective. In a 6 months, double-blind, randomized, controlled trial 26 kidney transplant recipients were treated with 20ug teriparatide, or placebo, in addition to calcium and vitamin D. Femoral neck, lumbar spine and radial bone mineral density (BMD) was measured at transplantation and at 6 months. Paired bone biopsies for histomorphometric analysis were obtained in 6 patients of each group. Serologic bone markers were measured at transplantation, 3 and 6 months. 24/26 patients completed the study. Femoral neck BMD (g/cm2) was stable in the teriparatide group, but decreased significantly in the placebo group. Lumbar spine, radial BMD, and histomorphometric bone volume remained unchanged in teriparatide and placebo treated patients. Serologic bone markers decreased significantly after transplantation and did not differ between the groups. We conclude that teriparatide has only a marginal benefit in preventing early posttransplant bone loss in transplant recipients treated with calcium and vitamin D. Neither histomorphometry nor bone markers provide evidence for an improved bone turnover by teriparatide.
American Journal of Transplantation 8:1864-1870
Ball and socket ankle joint in connection with bilateral tarsal synostosis in a boy with congenital absence of the portal vein; a novel malformation complex
Introduction: Contracted valgus flat foot in the adolescent is frequently caused by tarsal synostosis or synchondrosis. These synostoses are prevalently symptomatic during adolescence, when by ossifying they block the subtalar joint in valgus. Careful and detailed examinations might reveal additional abnormalities. Case presentation: A 16-year-old boy of Austrian origin presented with contracted valgus foot associated with tarsal hypomobility and pain. Talonavicular synostosis with ball and socket ankle joint was detected via lateral radiographs and 3 DCT scan. Preoperative laboratory investigations revealed leucocytopenia, and thrombopenia. Computerised abdominal tomography showed portal vein atresia and portopulmonary hypertension. Conclusion: Clinical research is the corner stone to elucidate the aetiological understandings in patients with malformation complex. The latter is a critical task for the development of scientific bases for preventive strategies. Careful examination for these abnormalities should lead the clinician to earlier referral of patients for additional examination by a specialised medical team. This often enables more focused care for the individual and better characterisation/ documentation of the malformation complex. The association of tarsal synostosis and the previously unreported associated occurrences of congenital absence of the portal vein, portopulmonary hypertension, cardiomegaly and splenomegaly have been encountered. We stress that our present patient illustrates and supports the pathophysiological hypotheses that have previously proposed for the concurrent existence of absent portal vein, hepatic nodular hyperplasia and portopulmonary hypertension. Nevertheless, no previous single report signifies the existence of tarsal synostosis in connection with the above-mentioned abnormalities.
Cases Journal 1:76
Arthrogryposis multiplex congenital in a child manifesting phenotypic features resembling dysosteosclerosis/osteosclerosis malformation complex; 3DCT scan analysis of the skull base
Introduction: A boy presented with arthrogryposis multiplex congenita (AMC) associated with severe central nervous system dysfunction. The clinical history and the distinctive radiographic/tomographic features were consistent but not completely diagnostic for dysosteosclerosis. Case presentation: A 5-year-old boy from a consanguineous family in Austria was born with arthrogryposis multiplex congenita in connection with central nervous system dysfunction. Recently he was referred to the orthopaedic department for further clinical assessment. Radiographic documentation showed significant sclerosis and thickening at the skull base with further extension to involve the craniocervical junction. Spinal radiographs showed platyspondyly of the thoracic vertebral bodies associated with widening of the intervertebral spaces. Long bones were not sclerotic as usually seen in the classical dysosteosclerosis phenotype. It is highly likely that long-term immobilization because of arthrogryposis multiplex congenita was the main reason behind this. 3 DCT scans showed unprecedented hypertrophy of the clivus. The latter occupied the major space of the skull base.The overall radiographic and scanning images were compatible but not fully diagnostic with dysosteosclerosis/osteosclerosis malformation complex. Conclusion: The skull base malformation complex in patients with dysosteosclerosis/ osteosclerosis requires careful evaluation. 3DCT scanning of the skull base and the vertebrae could be useful tools for early recognition of the pathophysiological mechanism in patients with dysosteosclerosis/ osteosclerosis/multiple contractures spectrum Previously, radiographs only have assessed the skull base pathology in patients with dysosteosclerosis, here we further characterize the pathology via 3DCT scan. Our patient illustrates extensive sclerosis of the skull base, associated with extremely hypertrophied clivus. The latter occupied the whole space of the skull base and the craniocervical junction. We review the pertinent literature, discuss the differential diagnosis and suggest that our case was consistent but not fully compatible with dysosteosclerosis. We believe that our present patient represents either a novel type of dysosteosclerosis or a variant of osteosclerosis/ arthrogryposis spectrum from a consanguineous family in Austria.
Cases Journal 1:56
Achondroplasia manifesting as enchondromatosis and ossification of the spinal ligaments: a case report
Introduction: A girl presented with achondroplasia manifested as mild knee pain associated with stiffness of her back. A skeletal survey showed enchondroma-like metaphyseal dysplasia and ossification of the spinal ligaments. Magnetic resonance imaging of the spine further clarified the pathological composites. Case representation: A 7-year-old girl presented with the classical phenotypic features of achondroplasia. Radiographic documentation showed the co-existence of metaphyseal enchondromatosis and development of spinal bony ankylosis. Magnetic resonance imaging showed extensive ossification of the anterior and posterior spinal ligaments. Additional features revealed by magnetic resonance imaging included calcification of the peripheral vertebral bodies associated with anterior end-plate irregularities. Conclusion: Enchondromas are metabolically active and may continue to grow and evolve throughout the patient's lifetime; thus, progressive calcification over a period of years is not unusual. Ossification of the spinal ligaments has a specific site of predilection and often occurs in combination with senile ankylosing vertebral hyperostosis. Nevertheless, ossification of the spinal ligaments has been encountered in children with syndromic malformation complex. It is a multifactorial disease in which complex genetic and environmental factors interact, potentially leading to chronic pressure on the spinal cord and nerve roots with subsequent development of myeloradiculopathy. Our patient presented with a combination of achondroplasia, enchondroma-like metaphyseal dysplasia and calcification of the spinal ligaments. We suggest that the development of heterotopic bone formation along the spinal ligaments had occurred through an abnormal ossified enchondral mechanism. We postulate that ossification of the spinal ligaments and metaphyseal enchondromatous changes are related to each other and represent impaired terminal differentiation of chondrocytes in this particular case. Standard radiographic examination showed spinal bony ankylosis only. The pathological composites of the vertebrae have been clarified using scanning technology. Extensive spinal ligament ossification associated with calcification of the peripheral vertebral bodies and anterior end-plate irregularities were notable. We report what may be a novel spinal and extraspinal malformation complex in a girl with achondroplasia.
Journal of Medical Case Reports 2:263
Femoral-tibial-synostosis in a child with Roberts syndrome (Pseudothalidomide): a case report.
Background: Roberts syndrome (Pseudothalidomide) is a rare birth defect that causes severe bone malformation complex. The bones of the arms, and in some cases other appendages, may be extremely shortened and even absent. The fingers of the hands may be fused. An extreme case results in the absence of the upper bones of both the arms and legs so that the hands and feet appear attached directly to the body. This is called tetraphocomelia. Case presentation: We report on a two-year-old boy of Austrian origin who manifests a constellation of malformation complex include prenatal and postnatal growth retardation, craniofacial anomalies and defective development of all four extremities. The overall clinico-radiographic features were compatible with Roberts syndrome (Pseudothalidomide). Significant unilateral femoral-tibial synostosis was additional malformation. Conclusion: Associated malformations and symptoms may be the key factor in the differential diagnosis of neonatal malformation complex. Roberts syndrome may be genetically transmitted within families as an autosomal recessive trait or may be the result of spontaneous/sporadic changes in the gene. Because the signs of the disorder so closely mimic those caused by the ingestion of thalidomide, the term "pseudo-thalidomide" is frequently used. In this report we describe total femorotibial fusion in a child manifesting the phenotypic features consistent with Roberts syndrome from a healthy parents but first cousins in Austria. Aggressive medical intervention is of prime importance, as is forthright parental counselling when discussing the possible outcome for these patients.
Cases Journal 1:109
Progressive joint limitations as the first alarming signs in a boy with short - limbed dwarfism: A case report
Introduction: Contracture is a condition of abnormal shortening or shrinkage of a muscle, and or a tendon often with persistent flexion or distortion at a joint. Careful documentation of the kind of contractures encountered in different paediatric disorders is important in distinguishing a specific subtype. Achondroplasia has been considered as the most common short-limbed dwarfism syndrome, but there are a variety of other syndromes within this category, and other types of limb shortening. Case presentation: We report on a 5-year-old boy of Austrian origin who manifests progressive joint limitations in connection with dysplastic form of short-limbed dwarfism namely chondrodysplasia punctata-tibial-metacarpal- type. Progressive joint limitations of maximal intensity over the hip, and the ankle joints were the main presenting features. Conclusion: Osteochondrodysplasias involve abnormal bone or cartilage growth leading to skeletal maldevelopment, often short-limbed dwarfism. Diagnosis is by physical examination, radiographic documentation, and, in some cases, genetic testing. In patients with chondrodysplasia punctata, early life radiographic examination is fundamental, since resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after age one to three years seems to be characteristic.
Cases Journal 1:112
Persistent cloaca associated with a duplicated left leg: a novel disorganization-like syndrome.
Persistent cloaca, a malformation complex with urogenital sinuses associated with abdominal distension because of colonic and lower urinary tract obstruction. Our case with persistent cloaca associated with duplication of the left leg might represent a novel combination within the disorganisation-like syndrome.
Clinical Dysmorphology 17:137-139
Progressive noninfectious anterior vertebral fusion in a girl with axial mesodermal dysplasia spectrum.
We report a 7-year-old-girl who presented with the clinical criteria of the axial mesodermal dysplasia spectrum. Her parents were first cousins. Her facial dysmorphism was compatible with Goldenhar syndrome and in addition, she had anterior noninfectious vertebral fusions of the cervical and the thoracolumbar vertebrae, a congenital dermal sinus and a hypoplastic sacrum. The urogenital and the anal-recto regions were normal. To the best of our knowledge, this is the first clinical report of a child with axial mesodermal dysplasia in association with progressive noninfectious anterior vertebral fusion.
Clinical Dysmorphology 17:65-68
A hypoplastic atlas and long odontoid process in a girl manifesting phenotypic features resembling spondyloepimetaphyseal dysplasia joint laxity syndrome.
Phenotypic features consistent but not completely diagnostic for spondyloepimetaphyseal dysplasia joint laxity (SEMDJL) were encountered in a 7-year-old-girl. Additional tomographic features of a hypoplastic atlas (assimilation of the posterior arch of the atlas) and unduly long odontoid process were seen. We report what might be a novel type of SEMDJL.
Skeletal Radiology 37:469-473
Congenital contractures and distinctive phenotypic features consistent with Stuve-Wiedmann syndrome in a male infant
Introduction: Expressionless face associated with multiple contractures has been encountered in an infant. There is a wide range of misconception regarding the categorization of children with multiple contractures among different pediatric disciplines. The fundamental element in categorizing children with multiple contractures is "the etiological understanding". In the absence of concomitant neuromuscular disease, however, the search for other reasons is mandatory. Our present paper signifies the necessity of proper interpretations of unusual clinical and radiographic features. Case presentation: We describe a 3-months-old-infant presented with the phenotypic and the radiographic features consistent with the diagnosis of Stuve-Wiedemann syndrome. We report what might be the first clinical report of Stuve-Wiedemann syndrome from a consanguineous family in Austria. Conclusion: Congenital limitations of the hips in a newborn infant raise the possibility of " Congenital Hip Dislocation". As congenital hip dislocation is a dysplastic process. Here further knowledge by the pediatrician and the orthopaedic surgeon is needed. Our present patient appears to constitute a distinct pathological entity consistent with Stuve-Wiedemann syndrome (SWS). Superti-Furga et al, and Cormier-Daire et al, also suggest that Stuve-Wiedemann syndrome and Schwartz-Jampel syndrome type 2 are allelic conditions. We wish to stress that, given the rarity of syndromic malformation complex, our impression is that it is more common than it is reported.
Cases Journal 1:121
Vegetarian Diet Affects Genes of Oxidative Metabolism and Collagen Synthesis
Background/Aim: A vegetarian diet is known to prevent a series of diseases but may influence the balance of carbohydrate and fat metabolism as well as collagen synthesis. This study compares expression patterns of relevant genes in oral mucosa of omnivores and vegetarians. Methods: Quantitative reverse transcriptase polymerase chain reaction was applied for analysis of mRNA levels from carnitine transporter OCTN2, hepatic CPT1A and nonhepatic CPT1B isoforms of carnitine palmitoyltransferase and collagen (CCOL2A1) in oral mucosa. Results: Compared with volunteers with traditional eating habits, carbohydrate consumption was significantly higher (+22%) in vegetarians. This was associated with a significant stimulation of CPT1A (+50%) and OCTN2 (+10%) and a lowered collagen synthesis (–10%). Conclusion: These novel findings provide further insight into the association of a changed fat metabolism and reduced collagen synthesis in vegetarians, which could also play a role in the aging process.
Ann Nutrition Metab 53:29-32
Increased serum levels of cartilage oligomeric matrix protein in patients with psoriasis vulgaris: a marker for unknown peripheral joint involvement?
Background: Cartilage oligomeric matrix protein (COMP) is a parameter for the current extent of cartilage destruction. It has been shown that the release pattern of cartilage oligomeric matrix protein in serum reflects cartilage turnover. Objective: The aim of our study was to prove sCOMP as a marker for disease activity in patients with active psoriatic arthritis (PsA) in comparison to a control group only with psoriasis vulgaris (PV). Methods: Serum levels of COMP were measured in 64 patients with PsA and psoriasis vulgaris The control group consisted of a healthy population with PV from a dermatological outpatient clinic. ELISA-tests were used to detect sCOMP levels according to the manufacturers instructions. Results: In our 64 patients with PsA we found icreased sCOMP levels, which correlated significantly with inflammatory parameters and the number of swollen joints. Patients with active PsA had significantly higher sCOMP levels (p<0,0001) than the 39 patients with a low inflammatory status. In our control group wit PV we also found elevated sCOMP levels, which correlated significantly with the increased CRP levels in this group. The difference between the PsA and the PV group was not significant (p=0,092). Conclusion: In our study, sCOMP has been demonstrated as an indicator for disease activity in patients with PsA. Patients with active PsA showed significantly elevated sCOMP levels compared to the patients with low clinical and laboratory disease activity. The increased sCOMP levels in our control group with PV indicate that all patients with psoriatic lesions should be screened for additional joint involvement and should give rise to an exact joint examination.
Clinical and Experimental Rheumatology 26:1087-90
The effect of temporal changes in bone turnover on the bone mineralization density distribution: A computer simulation study
Introduction: The heterogeneous distribution of mineral content in trabecular bone reflects the continuous renewal of bone material in bone remodeling and the subsequent increase in mineral content in the newly formed bone packets. The bone mineralization density distribution (BMDD) is typically used to describe this non-uniform mineralization of the bone matrix. Materials and Methods: Our mathematical model describes changes of the BMDD of trabecular bone as a function of bone resorption and deposition rates, and the mineralization kinetics in a newly formed bone packet. Input parameters used in the simulations were taken from experimental studies. Results: The simulations of the time evolution of the BMDD after increase in bone turnover (onset of menopause) resulted in a shift of the BMDD towards lower values of the mineral content. Transiently there was a broadening of the BMDD configuration partly revealing two peaks, which points to a strongly heterogeneous distribution of the mineral. Conversely, when the remodeling rate was reduced (antiresorptive therapy) the BMDD shifted towards higher mineralization values. There was a transient narrowing of the distribution before broadening again to reach the new steady state. Results from this latter simulation are in good agreement with measurements of the BMDD of patients after 3 and 5 years treatment with risedronate. Conclusions: Based on available experimental data on bone remodeling, this model gives reliable predictions of changes in BMDD, an important factor of bone material quality. With the availability of medications with a known effect on bone turnover, this knowledge opens the possibility for therapeutic manipulation of the BMDD.
J Bone Miner Res accepted 07/08
Progressive contractures as the first alarming signs in a boy with Geleophysic dysplasia
Introduction: Contracture is a condition of abnormal shortening or shrinkage of a muscle, and or a tendon often with persistent flexion or distortion at a joint. Careful documentation of the kind of contractures encountered in different paediatric disorders is important in distinguishing a specific subtype. Achondroplasia has been considered as the most common short-limbed dwarfism syndrome, but there are a variety of other syndromes within this category, and other types of limb shortening.
Case presentation: We report on a 5-year-old boy of Austrian origin who manifests progressive joint limitations in connection with dysplastic form of short-limbed dwarfism namely chondrodysplasia punctata-tibial-metacarpal- type. Progressive joint limitations of maximal intensity over the hip, and the ankle joints were the main presenting features. Conclusion: Joint contractures are not uncommon impairments occur in association with a number of syndromic associations such as Chondrodysplasia punctata, Geleophysic dysplasia, Freeman-Sheldon syndrome, Stüve- Wiedemann syndrome and Schwartz-Jampel syndrome. Selected progressive neuromuscular disease conditions can also lead to such increased disabilities as worsening motor performance, decreased mobility, loss of skills and sometimes pain. Early recognition of affected children should allow for aggressive contractures control and expectant management of multiple associated problems.
Cases Journal accepted 7/08
Bone nanostructure and its relevance for mechanical performance, disease and treatment
The remarkable mechanical properties of bone are due to its hierarchical structure which is optimized at all levels of hierarchy. At the lowest level, bone is a nano-composite of collagen and mineral particles. The quality of this material is crucial for the mechanical performance of bone as a whole. This chapter reviews structure and composition of the bone material at the nano-scale and reports several examples on how it may be affected by disease or treatment.
Nanotechnology – Nanomedicine and nanobiotechnology (edited by V. Vogel), Wiley-VCH, Weinheim, Germany in press