Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling

Vienna, Austria

Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling

Vienna, Austria
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Repp F.,Max Planck Institute of Colloids and Interfaces | Kollmannsberger P.,Max Planck Institute of Colloids and Interfaces | Kollmannsberger P.,ETH Zurich | Roschger A.,Max Planck Institute of Colloids and Interfaces | And 7 more authors.
Bone Reports | Year: 2017

Osteocytes interconnect with each other forming an intricate cell network within the mineralized bone matrix. One important function of the osteocyte network is the mechano-regulation of bone remodeling, where a possible mechanism includes the fluid flow through the porosity housing the cell network - the osteocyte lacuno-canalicular network (OLCN). In our study the OLCN in human osteons was three-dimensionally imaged with the aim to obtain a quantitative description of the canalicular density and spatial variations of this quantity within osteons. The topology of the OLCN was determined by first staining the bone samples with rhodamine, then imaging the OLCN with confocal laser scanning microscopy and finally using image analysis to obtain a skeletonized version of the network for further analysis. In total 49 osteons were studied from the femoral cortical bone of four different middle-aged healthy women. The mean canalicular density given as length of the canaliculi in a unit volume was 0.074 ± 0.015 μm/μm3 (corresponding to 74 km/cm3). No correlation was found between the canalicular density and neither the size of the osteon nor the volume fraction occupied by osteocyte lacunae. Within osteons the canalicular density varied substantially with larger regions without any network. On average the canalicular density decreases when moving from the Haversian canal outwards towards the cement line. We hypothesize that a decrease in accessible canaliculi with tissue age as a result of micropetrosis can reduce the local mechanosensitivity of the bone. Systematic future studies on age- and disease-related changes on the topology of the OLCN have to demonstrate the diagnostic potential of the presented characterization method. © 2017 The Authors


Gamsjaeger S.,Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling | Robins S.P.,Rowett Institute of Nutrition and Health | Tatakis D.N.,Ohio State University | Klaushofer K.,Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling | And 2 more authors.
Calcified Tissue International | Year: 2017

Intermolecular cross-linking of bone collagen is intimately related to the way collagen molecules are arranged in a fibril, imparts certain mechanical properties to the fibril, and may be involved in the initiation of mineralization. Raman microspectroscopy allows the analysis of minimally processed bone blocks and provides simultaneous information on both the mineral and organic matrix (mainly type I collagen) components, with a spatial resolution of ~1 μm. The aim of the present study was to validate Raman spectroscopic parameters describing one of the major mineralizing type I trivalent cross-links, namely pyridinoline (PYD). To achieve this, a series of collagen cross-linked peptides with known PYD content (as determined by HPLC analysis), human bone, porcine skin, predentin and dentin animal model tissues were analyzed by Raman microspectroscopy. The results of the present study confirm that it is feasible to monitor PYD trivalent collagen cross-links by Raman spectroscopic analysis in mineralized tissues, exclusively through a Raman band ~1660 wavenumbers. This allows determination of the relative PYD content in undecalcified bone tissues with a spatial resolution of ~1 μm, thus enabling correlations with histologic and histomorphometric parameters. © 2017 Springer Science+Business Media New York


PubMed | University of Auckland, Middlemore Hospital, Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling, Auckland City Hospital and Osaka Medical Center for Maternal and Child Health
Type: Case Reports | Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | Year: 2015

Hypophosphatasia is an inborn error of metabolism caused by mutations in the ALPL gene. It is characterized by low serum alkaline phosphatase (ALP) activity and defective mineralization of bone, but the phenotype varies greatly in severity depending on the degree of residual enzyme activity. We describe a man with compound heterozygous mutations in ALPL, but no previous bone disease, who suffered numerous disabling fractures after he developed progressive renal failure (for which he eventually needed dialysis treatment) and was prescribed alendronate treatment. A bone biopsy showed marked osteomalacia with low osteoblast numbers and greatly elevated pyrophosphate concentrations at mineralizing surfaces. In vitro testing showed that one mutation, T117H, produced an ALP protein with almost no enzyme activity; the second, G438S, produced a protein with normal activity, but its activity was inhibited by raising the media phosphate concentration, suggesting that phosphate retention (attributable to uremia) could have contributed to the phenotypic change, although a pathogenic effect of bisphosphonate treatment is also likely. Alendronate treatment was discontinued and, while a suitable kidney donor was sought, the patient was treated for 6 months with teriparatide, which significantly reduced the osteomalacia. Eighteen months after successful renal transplantation, the patient was free of symptoms and the scintigraphic bone lesions had resolved. A third bone biopsy showed marked hyperosteoidosis but with plentiful new bone formation and a normal bone formation rate. This case illustrates how pharmacological (bisphosphonate treatment) and physiologic (renal failure) changes in the environment can dramatically affect the phenotype of a genetic disorder.


Misof B.M.,Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling | Dempster D.W.,Helen Hayes Hospital | Dempster D.W.,Columbia University | Zhou H.,Helen Hayes Hospital | And 12 more authors.
Calcified Tissue International | Year: 2014

Bone mineralization density distribution (BMDD) is an important determinant of bone mechanical properties. The most available skeletal site for access to the BMDD is the iliac crest. Compared to cancellous bone much less information on BMDD is available for cortical bone. Hence, we analyzed complete transiliac crest bone biopsy samples from premenopausal women (n = 73) aged 25–48 years, clinically classified as healthy, by quantitative backscattered electron imaging for cortical (Ct.) and cancellous (Cn.) BMDD. The Ct.BMDD was characterized by the arithmetic mean of the BMDD of the cortical plates. We found correlations between Ct. and Cn. BMDD variables with correlation coefficients r between 0.42 and 0.73 (all p < 0.001). Additionally to this synchronous behavior of cortical and cancellous compartments, we found that the heterogeneity of mineralization densities (Ct.CaWidth), as well as the cortical porosity (Ct.Po) was larger for a lower average degree of mineralization (Ct.CaMean). Moreover, Ct.Po correlated negatively with the percentage of highly mineralized bone areas (Ct.CaHigh) and positively with the percentage of lowly mineralized bone areas (Ct.CaLow). In conclusion, the correlation of cortical with cancellous BMDD in the iliac crest of the study cohort suggests coordinated regulation of bone turnover between both bone compartments. Only in a few cases, there was a difference in the degree of mineralization of >1wt % between both cortices suggesting a possible modeling situation. This normative dataset of healthy premenopausal women will provide a reference standard by which disease- and treatment-specific effects can be assessed at the level of cortical bone BMDD. © 2014, Springer Science+Business Media New York.


Kerschnitzki M.,Max Planck Institute of Colloids and Interfaces | Wagermaier W.,Max Planck Institute of Colloids and Interfaces | Liu Y.,Max Planck Institute of Colloids and Interfaces | Roschger P.,Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling | And 3 more authors.
Cells Tissues Organs | Year: 2011

The mechanical properties of bone are known to depend on its structure at all length scales. In large animals, such as sheep, cortical bone grows very quickly and it is known that this occurs in 2 stages whereby a poorly ordered (mostly woven) bone structure is initially deposited and later augmented and partially replaced by parallel fibered and lamellar bone with much improved mechanical properties, often called primary osteons. Most interestingly, a similar sequence of events has also recently been observed during callus formation in a sheep osteotomy model. This has prompted the idea that fast intramembranous bone formation requires an intermediate step where bone with a lower degree of collagen orientation is deposited first as a substrate for osteoblasts to coordinate the synthesis of lamellar tissue. Since some osteoblasts become embedded in the mineralizing collagen matrix which they synthesize, the resulting osteocyte network is a direct image of the location of osteoblasts during bone formation. Using 3-dimensional imaging of osteocyte networks as well as tissue characterization by polarized light microscopy and backscattered electron imaging, we revisit the structure of growing plexiform (fibrolamellar) bone and callus in sheep. We show that bone deposited initially is based on osteocytes without spatial correlation and encased in poorly ordered matrix. Bone deposited on top of this has lamellar collagen orientation as well as a layered arrangement of osteocytes, both parallel to the surfaces of the initial tissue. This supports the hypothesis that the initial bone constitutes an endogenous scaffold for the subsequent deposition of parallel fibered and lamellar bone. Copyright © 2011 S. Karger AG, Basel.


Fratzl-Zelman N.,Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling | Schmidt I.,Max Planck Institute of Colloids and Interfaces | Roschger P.,Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling | Roschger A.,Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling | And 6 more authors.
Bone | Year: 2015

Osteogenesis imperfecta (OI) is a heterogeneous group of inheritable connective tissue disorders characterized by mutation in genes involved in collagen synthesis and leading to increased bone fragility, low bone mass, impaired bone material properties and abnormally high bone matrix mineralization. Recessive OI type VI is caused by mutation in SERPINF1 leading to a loss-of-function of pigment epithelium-derived factor (PEDF) a collagen-binding protein with potent antiangiogenic activity. Affected patients develop a severe OI phenotype with a striking histological characteristic, rare in other OI types, of an excess of osteoid tissue and prolonged mineralization lag time.To get insights into matrix mineralization, we evaluated biopsies from 9 affected children by quantitative and by high-resolution backscattered electron imaging and assessed bone mineralization density distribution. Thickness, shape and arrangement of mineral particles were measured in a subset of 4 patients by synchrotron small angle X-ray scattering.Typical calcium content in the bone matrix was found to be increased compared to controls, even exceeding values found previously in OI patients with collagen-gene mutations. A main characteristic however, is the coexistence of this highly mineralized bone matrix with seams showing abnormally low mineral content. Atypical collagen fibril organization was found in the perilacunar region of young osteocytes, suggesting a disturbance in the early steps of mineralization. These observations are consistent with the presence of a heterogeneous population of mineral particles with unusual size, shape and arrangement, especially in the region with lower mineral content. The majority of the particles in the highly mineralized bone areas were less disorganized, but smaller and more densely packed than in controls and in previously measured OI patients.These data suggest that the lack of PEDF impairs a proper osteoblast-osteocyte transition and consequently affects the early steps of mineralization, downstream collagen assembly making OI type VI different from "classical" OI with mutations in collagen-type I encoding genes, despite the typical hypermineralization of the bone matrix. © 2014 Elsevier Inc.


Misof B.M.,Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling | Paschalis E.P.,Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling | Blouin S.,Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling | Fratzl-Zelman N.,Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling | And 2 more authors.
Journal of Bone and Mineral Research | Year: 2010

Anabolic treatment with teriparatide of postmenopausal osteoporotic patients previously treated with bisphosphonates is a new therapeutic approach. However, its effects on the bone mineralization density distribution (BMDD) are unknown. We studied paired transiliac bone biopsy samples taken before and after 1 year of treatment with recombinant human parathyroid hormone peptide 1-34 (teriparatide) from 16 osteoporotic women treated with either alendronate (priorALN) or risedronate (priorRIS) for at least 2 years and subsequently treated for 12 months with teriparatide. Cancellous (Cn.) and cortical (Ct.) BMDD values were measured using quantitative backscattered electron imaging. At baseline, BMDD values of priorALN and priorRIS women were similar and within the normal range. One year of teriparatide treatment caused significant effects on the BMDD. Analyzing changes from baseline for each bisphosphonate group separately, priorALN patients revealed increases in the portion of low mineralized bone areas (Cn.CaLow +25.9%, Ct.CaLow +62.0%, both p<.05) and Ct. heterogeneity of mineralization (Ct.CaWidth +22.8%, p<.001). PriorRIS patients showed increased mineralization heterogeneity (Cn.CaWidth +14.8%, p<.05, and Ct.CaWidth +15.8%, p<.001). Analysis of the influence of the prior bisphosphonate treatment showed that the BMDD response to 1 year of teriparatide treatment did not depend on the type of prior bisphosphonate. In consequence, priorALN and priorRIS groups were combined. The pooled groups revealed increased Cn.Ca Width and Ct.CaWidth (+10.7%, p<.01, and +19.6%, p<.001, respectively) as well as increased Cn.CaLow and Ct.Ca Low (+18.2%, p<.05, and +36.6%, p<.01, respectively). In summary, our findings indicate a significant effect of teriparatide on BMDD when administered subsequent to a bisphosphonate in agreement with teriparatide's anabolic action. ©2010 American Society for Bone and Mineral Research.


PubMed | Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling
Type: Journal Article | Journal: Calcified tissue international | Year: 2014

Bone mineralization density distribution (BMDD) is an important determinant of bone mechanical properties. The most available skeletal site for access to the BMDD is the iliac crest. Compared to cancellous bone much less information on BMDD is available for cortical bone. Hence, we analyzed complete transiliac crest bone biopsy samples from premenopausal women (n = 73) aged 25-48 years, clinically classified as healthy, by quantitative backscattered electron imaging for cortical (Ct.) and cancellous (Cn.) BMDD. The Ct.BMDD was characterized by the arithmetic mean of the BMDD of the cortical plates. We found correlations between Ct. and Cn. BMDD variables with correlation coefficients r between 0.42 and 0.73 (all p < 0.001). Additionally to this synchronous behavior of cortical and cancellous compartments, we found that the heterogeneity of mineralization densities (Ct.Ca(Width)), as well as the cortical porosity (Ct.Po) was larger for a lower average degree of mineralization (Ct.Ca(Mean)). Moreover, Ct.Po correlated negatively with the percentage of highly mineralized bone areas (Ct.Ca(High)) and positively with the percentage of lowly mineralized bone areas (Ct.Ca(Low)). In conclusion, the correlation of cortical with cancellous BMDD in the iliac crest of the study cohort suggests coordinated regulation of bone turnover between both bone compartments. Only in a few cases, there was a difference in the degree of mineralization of >1wt % between both cortices suggesting a possible modeling situation. This normative dataset of healthy premenopausal women will provide a reference standard by which disease- and treatment-specific effects can be assessed at the level of cortical bone BMDD.


PubMed | Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling
Type: Journal Article | Journal: Journal of orthopaedic research : official publication of the Orthopaedic Research Society | Year: 2012

Little is known whether trabecular bone matrix mineralization is altered at the site of osteoporotic vertebral fractures. Bone mineralization density distribution (BMDD) was assessed in trabecular bone of acute, single-level compression fractures of the spine at various stages of fracture repair using quantitative backscattered electron imaging (qBEI). The grading of the repair stage was performed by histological methods. From 20 patients, who underwent either kyphoplasty (n=18) or vertebroplasty (n=2), a vertebral bone biopsy was taken prior to cement augmentation. Six patients took bisphosphonates (BP) prior to fracture. Three study groups were formed: N1=early-, N2=late-healing and B=BP treatment at late healing stage. In general, all groups had an altered BMDD when compared to historical normative reference data. Mean matrix mineralization (CaMean) was significantly (p<0.001) lower in all groups (N1: -5%, N2: -16%, and B2: -16%). In N2, CaMean was -13.1% (p<0.001) lower than N1. At this stage, deposition of new bone matrix and/or formation of woven bone are seen, which also explains the more heterogeneous matrix mineralization (CaWidth). Moreover, BP treatment (B2) led to a significant reduction in CaWidth (-28.5%, p<0.001), when compared to N2. Bone tissue from vertebrae with acute compression fractures reveals a large variation in matrix mineralization depending on the stage of repair. Bisphosphonate treatment does affect the mineralization pattern of tissue repair. The low mineralization values found in early stage of repair suggest that altered bone material properties may play a role in the occurrence of fragility fractures of the spine.


PubMed | Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of and Trauma Center Meidling
Type: Journal Article | Journal: Calcified tissue international | Year: 2011

The pathogenesis of primary osteoporosis in younger individuals is still elusive. An important determinant of the biomechanical competence of bone is its material quality. In this retrospective study we evaluated bone material quality based on quantitative backscattered electron imaging to assess bone mineralization density distribution (BMDD) in bone biopsies of 25 male patients (aged 18-61 years) who sustained fragility fractures but were otherwise healthy. BMDD of cancellous bone was compared with previously established adult reference data. Complementary information was obtained by bone histomorphometry. The histomorphometric results showed a paucity of osteoblasts and osteoclasts on the bone surface in the majority of patients. BMDD revealed a significant shift to lower mineralization densities for cancellous bone values: CaMean (weighted mean Ca content, -5.9%), CaPeak (mode of the BMDD, -5.6%), and CaHigh (portion of fully mineralized bone, -76.8%) were decreased compared to normative reference; CaWidth (heterogeneity in mineralization, +18.5%) and CaLow (portion of low mineralized bone, +68.8; all P < 0.001) were significantly increased. The shift toward lower mineral content in the bone matrix in combination with reduced indices of bone formation and bone resorption suggests an inherent mineralization defect leading to undermineralized bone matrix, which might contribute to the susceptibility to fragility fractures of the patients. The alteration in bone material might be related to osteoblastic dysfunction and seems fundamentally different from that in high bone turnover osteoporosis with a negative bone balance.

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