Jochen G. Hofstaetter

Regulation of Adult Bone Mass by the Zinc Finger Adapter Protein Schnurri-3

Genetic mutations that disrupt osteoblast function can result in skeletal dysmorphogenesis or, more rarely, in increased postnatal bone formation. Here we show that Schnurri-3 (Shn3), a mammalian homolog of the Drosophila zinc finger adapter protein Shn, is an essential regulator of adult bone formation. Mice lacking Shn3 display adult-onset osteosclerosis with increased bone mass due to augmented osteoblast activity. Shn3 was found to control protein levels of Runx2, the principal transcriptional regulator of osteoblast differentiation, by promoting its degradation through recruitment of the E3 ubiquitin ligase WWP1 to Runx2. By this means, Runx2-mediated extracellular matrix mineralization was antagonized, revealing an essential role for Shn3 as a central regulator of postnatal bone mass.

Effects of 3- and 5-Year Treatment With Risedronate on Bone Mineralization Density Distribution in Triple Biopsies of the Iliac Crest in Postmenopausal Women

Long‐term effects of risedronate on bone mineralization density distribution in triple transiliac crest biopsies of osteoporotic women were evaluated. In this double‐blinded study, 3‐ and 5‐year treatment with risedronate increased the degree and homogeneity of mineralization without producing hypermineralization. These changes at the material level of bone could contribute to risedronates antifracture efficacy.

Spatial distribution of the trace elements zinc, strontium and lead in human bone tissue.

Trace elements are chemical elements in minute quantities, which are known to accumulate in the bone. Cortical and trabecular bones consist of bone structural units (BSUs) such as osteons and bone packets of different mineral content and are separated by cement lines. Previous studies investigating trace elements in bone lacked resolution and therefore very little is known about the local concentration of zinc (Zn), strontium (Sr) and lead (Pb) in BSUs of human bone. We used synchrotron radiation induced micro X-ray fluorescence analysis (SR μ-XRF) in combination with quantitative backscattered electron imaging (qBEI) to determine the distribution and accumulation of Zn, Sr, and Pb in human bone tissue. Fourteen human bone samples (10 femoral necks and 4 femoral heads) from individuals with osteoporotic femoral neck fractures as well as from healthy individuals were analyzed. Fluorescence intensity maps were matched with BE images and correlated with calcium (Ca) content. We found that Zn and Pb had significantly increased levels in the cement lines of all samples compared to the surrounding mineralized bone matrix. Pb and Sr levels were found to be correlated with the degree of mineralization. Interestingly, Zn intensities had no correlation with Ca levels. We have shown for the first time that there is a differential accumulation of the trace elements Zn, Pb and Sr in BSUs of human bone indicating different mechanisms of accumulation.

Total ankle arthroplasty versus ankle arthrodesis. Comparison of sports, recreational activities and functional outcome

PurposeAnkle arthrodesis (AAD) and total ankle replacement (TAR) are the major surgical treatment options for severe ankle arthritis. There is an ongoing discussion in the orthopaedic community whether ankle arthrodesis or ankle fusion should be the treatment of choice for end stage osteoarthritis. The purpose of this study was to compare the participation in sports and recreational activities in patients who underwent either AAD or TAR for end-stage osteoarthritis of the ankle.MethodsA total of 41 patients (21 ankle arthrodesis /20 TAR) were examined at 34.5 (SD18.0) months after surgery. At follow-up, pre- and postoperative participation in sports and recreational activities has been assessed. Activity levels were determined using the ankle activity score according to Halasi et al. and the University of California at Los Angeles (UCLA) activity scale. Clinical and functional outcome was assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score. The percentage of patients participating in sports and recreational activities, UCLA score and AOFAS score were compared between both treatment groups.ResultsIn the AAD group 86% were active in sports preoperatively and in the TAR group this number was 76%. Postoperatively in both groups 76% were active in sports (AAD, p = 0.08). The UCLA score was 7.0 (± 1.9) in the AAD group and 6.8 (± 1.8) in the TAR group (p = 0.78). The AOFAS score reached 75.6 (± 14) in the AAD group and 75.6 (± 16) in the TAR group (p = 0.97). The ankle activity score decrease was statistically significant for both groups (p = 0.047).ConclusionsOur study revealed no significant difference between the groups concerning activity levels, participation in sports activities, UCLA and AOFAS score. After AAD the number of patients participating in sports decreased. However, this change was not statistically significant.

Intermediate-term Results of the Ludloff Osteotomy in One Hundred and Eleven Feet

BACKGROUND The modified Ludloff proximal first metatarsal osteotomy is indicated for the surgical correction of moderate-to-severe hallux valgus deformity associated with metatarsus primus varus. We report the intermediate-term results of this procedure. METHODS Ninety-nine patients (111 feet) with a mean age of fifty-six years underwent a modified Ludloff proximal first metatarsal osteotomy and a distal soft-tissue procedure at two institutions for the treatment of a moderate-to-severe hallux valgus deformity. The American Orthopaedic Foot and Ankle Society score and weight-bearing radiographs of the foot were assessed preoperatively and after a mean duration of follow-up of thirty-four months. Clinical and radiographic outcome was also compared between younger and older patients, with the arbitrarily chosen age of sixty years dividing the two groups. RESULTS The mean American Orthopaedic Foot and Ankle Society score improved significantly (p < 0.0001) from 53 points preoperatively to 88 points at the time of the most recent follow-up. The mean American Orthopaedic Foot and Ankle Society score for patients who were sixty years of age or less was significantly higher than that for patients who were more than sixty years of age (91 compared with 83 points; p = 0.0057). The mean hallux valgus angle decreased significantly from 35 degrees preoperatively to 9 degrees at the time of the most recent follow-up (p < 0.0001), and the mean intermetatarsal angle decreased significantly from 17 degrees to 8 degrees (p < 0.0001). All osteotomy sites united without dorsiflexion malunion but with a mean first metatarsal shortening of 2.2 mm. CONCLUSIONS To our knowledge, the present report describes the largest cohort of patients undergoing a modified Ludloff osteotomy for the correction of hallux valgus deformity that has been reported in the literature. Our intermediate-term results demonstrate that the procedure achieves significant correction of moderate-to-severe hallux valgus deformity, significant reduction in forefoot pain, and significant improvement in functional outcome. Patients with an age of sixty years or less appear to have a more favorable outcome.

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.

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-Calvé-Perthes disease is due to the repair process. However, little is known if matrix properties are altered following ischemic injury of the juvenile femoral head. The purpose of this study was to determine the matrix mineralization density, an important determinant of material quality and strength, of the proximal femoral 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. In the necrotic calcified epiphyseal cartilage matrix, a significant increase in the mean degree of mineralization (CaMean: +24%, p<0.0001) as well as the homogeneity of mineralization (CaWidth: -21%, p<0.05) and a significantly reduced amount of low mineralized matrix (CaLow: -49%, p<0.0001) were already present at 4 weeks post-ischemia induction. Similar changes, but more moderate, were also seen in the subchondral bone region. In contrast, in the necrotic central trabecular region, significant changes in matrix mineralization were found at 8 weeks (CaMean: +4%, p<0.05; CaWidth: -22%, p<0.05; CaLow: -8%, p<0.05) but not at 4 weeks post-ischemia induction. Our findings indicate that the process of matrix mineralization continues in necrotic calcified articular cartilage and bone following femoral head ischemia, which leads to a higher and more homogenous mineralized tissue matrix altering its intrinsic material properties. This may also explain the increased radiodensity seen in the early stage of Perthes disease prior to the initiation of the repair process.

The effects of alendronate in the treatment of experimental osteonecrosis of the hip in adult rabbits

OBJECTIVE Characterize the effects of alendronate (ALN) on the repair process of the osteonecrotic femoral head as well as the development of secondary osteoarthritis in the ipsilateral hip in an established experimental model of osteonecrosis. METHODS Osteonecrosis of the femoral head was induced surgically in 60 adult, male New Zealand white rabbits. Animals were randomized in two placebo- (saline) and two treatment-groups (ALN 150 microg/kg/day S.C., 3x per wk) and were euthanized at 6 and 12 months post-operatively. Contralateral hip was used as control. Micro-Quantitative-CT (microQCT) analysis as well as histological assessment was performed in the femoral head and the acetabulum. Mankin Score was used to assess cartilage degeneration in the acetabulum. RESULTS Repair in the osteonecrotic femoral head in the placebo group led to a significantly increased bone volume fraction (BVF) and volumetric bone mineral density (vBMD) in the trabecular region and to an increase in porosity in the cortical and subchondral region when compared to the normal femoral head on the contralateral side. ALN treatment significantly further increased BVF and vBMD in the trabecular region, and significantly reduced porosity and increased vBMD in the necrotic subchondral and cortical bone when compared to placebo. ALN led to a significant increase in vBMD in the subchondral region of the osteoarthritic acetabulum as well as to a significant reduction in articular cartilage degeneration. CONCLUSION Inhibition of bone resorption by ALN treatment during repair of the osteonecrotic femoral head significantly increased bone mass in the trabecular region of the femoral head, inhibited subchondral resorption and reduced cartilage degeneration in the acetabulum.

Sodium MR Imaging of Achilles Tendinopathy at 7 T: Preliminary Results

PURPOSE To investigate the feasibility of sodium magnetic resonance (MR) imaging in the diagnosis of Achilles tendinopathy. MATERIALS AND METHODS Institutional review board approval and written informed consent were obtained. Twenty healthy volunteers and eight patients with Achilles tendinopathy were examined by using a 7-T whole-body MR imager with a 15-channel sodium knee coil. The sodium signal-to-noise ratio (SNR) from each region, as well as from the whole Achilles tendon, was compared between patients and healthy control subjects. The changes in SNR were assessed with a two-tailed unpaired t test in three regions of the Achilles tendon: the insertion area, the middle portion, and the muscle-tendon junction. P values less than .05 were considered to indicate a statistically significant difference. To validate a relationship between the sodium SNR and the glycosaminoglycan content in tendon, five cadaver ankles were examined with MR imaging and immunohistologically. The Pearson correlation coefficient between sodium SNR and glycosaminoglycan content was calculated. RESULTS Significant differences (P < .05) in the mean sodium SNR of healthy control subjects (mean SNR, 4.9 ± 2.1 [standard deviation]) and patients with chronic Achilles tendinopathy (mean SNR, 9.3 ± 2.3) were observed. Similar results were found at the insertion (mean SNR in control subjects, 6.7 ± 2.3; mean SNR in patients, 12.3 ± 4.5; P < .05) and the midportion (mean SNR in control subjects, 5.1 ± 1.9; mean SNR in patients, 9.4 ± 3.0; P < .05) of the Achilles tendon. At the muscle-tendon junction, the sodium SNR difference between control subjects and patients was small but still bellow the significance level (P = .0137). The increase in sodium SNR was observed in all regions independently of the location of morphologic findings. The Pearson correlation coefficient between sodium SNR and glycosaminoglycan content was 0.71. CONCLUSION Sodium MR imaging may allow detection of the proteoglycan content increase in Achilles tendinopathy and thus identify the biochemical changes in the early stages of tendinopathy.

Differential accumulation of lead and zinc in double-tidemarks of articular cartilage

INTRODUCTION Long-term exposure to increased lead (Pb) concentrations is associated with several chronic diseases. The divalent cation zinc (Zn) is essential for numerous enzymes. In a recent study we found remarkably elevated concentrations of Pb and Zn in the tidemark (TM), which is the mineralization front of human articular cartilage. OBJECTIVE Duplication or multiplication of TMs occurs with advancing age or degeneration. We hypothesized that trace elements accumulate in TMs as a function of time. Thus, in cases of double TMs, the deep (older) TM should contain higher Pb and Zn concentrations than the superficial (younger) TM. DESIGN Undecalcified tissue from articular cartilage and subchondral bone of femoral heads and patellae was examined by synchrotron radiation induced confocal micro X-ray fluorescence analysis and by quantitative backscattered electron imaging to determine the local distribution of Ca, Zn, and Pb in this tissue. RESULTS The evaluation of X-ray fluorescence intensities in double TMs revealed in average a 2.6-fold higher Pb level in the deep TM compared to the superficial TM while Zn concentrations were similar. Pb and Zn contents were significantly enhanced in the deep TM (Pb: 35-fold, Zn: five-fold) and in the superficial TM (Pb: 12-fold, Zn: five-fold) compared to the bone level. CONCLUSION For the first time a differential accumulation of Pb and Zn is documented in regions with double TMs revealing various timescales for the accumulation of these elements. Increased amounts of Pb are present in the TMs (up to the 62-fold of the bone level) featuring a potential source of internal Pb release if the TM region is destroyed.