Incidence and bone biopsy findings of atypical femoral fractures

Authors

Inari S. Tamminen, Tero Yli-Kyyny, Hanna Isaksson, Mikael J. Turunen, Xiaoyu Tong, Jukka S. Jurvelin, Heikki Kröger

Abstract

Bisphosphonates are widely used in the treatment of osteoporosis. It has been suggested that bisphosphonate treatment may be associated with atypical femoral fractures (AFFs), severely suppressed bone turnover rate, and decreased mineralization. We studied bone properties using bone quantitative histomorphometry and Fourier transform infrared spectroscopic imaging (FTIRI) on patients with AFFs. Further, the incidence of AFFs was estimated. Patient records of Kuopio University Hospital, Finland from January 2007 to June 2009 were reviewed to identify all patients who had sustained and had been operated for AFF (n = 8). The incidence of AFFs among patients on bisphosphonates was 0.61 fractures/1,000 patients per year, compared to 0.0067/1,000 per year among untreated patients. The patients that underwent bone biopsy (n = 4) were postmenopausal women (aged 55.5–81.1 years) who had been treated with bisphosphonates for over 4 years. Histomorphometry revealed low trabecular bone volume. Bone formation and resorption parameters tended to be low. Trabecular bone single labels were detected in one patient in the region of interest. In the extended label search, trabecular bone double labels were found in two patients. Based on FTIRI results, higher phosphate-to-amide I ratio and collagen maturity were found compared to normal samples. The heterogeneity of phosphate-to-amide I ratio was low. Overall incidence of atypical femoral fractures is low. The poor fracture resistance in some patients on long-term bisphosphonate-therapy could be explained by low bone formation, and changes in bone composition, i.e., higher degree of mineralization, increased collagen maturity, and decreased heterogeneity of the degree of mineralization.

Link to Article

http://dx.doi.org/10.1007/s00774-013-0448-7

A peptidomimetic antagonist of the alpha(v)beta3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo

Authors

V W Engleman, G A Nickols, F P Ross, M A Horton, D W Griggs, S L Settle, P G Ruminski and S L Teitelbaum

Abstract

Osteoclastic bone degradation requires intimacy between the matrix and the resorptive cell. While the precise role the integrin alpha(v)beta3 plays in the process is not yet understood, occupancy of the heterodimer by soluble ligand or by blocking antibody effectively inhibits bone resorption in vitro and in vivo, suggesting that alpha(v)beta3 blockade may prevent postmenopausal osteoporosis. Thus, we identified a synthetic chemical peptide mimetic, beta-[2-[[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-1-+ ++oxoethyl]amino-3-pyridinepropanoic acid, bistrifluoroacetate (SC56631) based upon the alpha(v)beta3 ligand, Arg-Gly-Asp (RGD), which recognizes the isolated integrin, and its relative, alpha(v)beta5, as effectively as does the natural peptide. The mimetic dampens osteoclastic bone resorption in vitro and in vivo. Most importantly, intravenous administration of the mimetic prevents the 55% loss of trabecular bone sustained by rats within 6 wk of oophorectomy. Histological examination of bones taken from SC56631-treated, oophorectomized animals also demonstrates the compound's bone sparing properties and its capacity to decrease osteoclast number. Thus, an RGD mimetic prevents the rapid bone loss that accompanies estrogen withdrawal.

Link to Article

http://dx.doi.org/10.1172/JCI119404

Development and characterization of murine models of medulloblastoma extraneural growth in bone

Authors

Jessica M. Grunda, Dezhi Wang, Gregory A. Clines

Abstract

Medulloblastoma is a malignant pediatric brain neoplasm with an unusual predilection for metastasis to the skeleton. The objective of this study was to generate and characterize murine models of medulloblastoma extraneural growth in bone as ‘discovery tools’ for the identification of unrecognized signal transduction pathways and factors driving metastatic bone disease. To this end, the human Daoy and D283 medulloblastoma cell lines were inoculated into the intratibial medullary space of athymic nude mice. Daoy injected mice developed a primarily osteolytic radiographic and histological phenotype. In contrast, both areas of osteolytic and osteosclerotic activity were evident in D283 inoculated bones. D283 and Daoy cell conditioned media increased in vitro osteoblast differentiation and is consistent with the enhanced bone turnover characteristic of bone metastases. Daoy cells also significantly increased bone marrow osteoclast formation, consistent with the robust in vivo osteolytic phenotype. A survey of secreted factors implicated in bone metastasis and expressed by D283 and Daoy was performed. High expression of the bone-homing factor, CXCR4, was observed in both Daoy and D283 tissues. Consistent with the skeletal phenotypes, Daoy cells, while secreting the osteoblastic factor ET-1, abundantly produced the osteolytic factors RANKL, PTHrP and TNFα. D283 cells produced high levels of both RANKL and ET-1. These newly described animal models of medulloblastoma bone metastasis are expected to serve as platforms to aid in the elucidation of novel bone metastasis signaling cascades and to test therapeutics that target both medulloblastoma metastasis and the primary tumor.

Link to Article

http://dx.doi.org/10.1007/s10585-013-9577-6

Preclinical Evaluation of a Novel Implant for Treatment of a Full-Thickness Distal Femoral Focal Cartilage Defect

Authors

Erik I. Waldorff, PhD, Blake J. Roessler, MD, Terri A. Zachos, DVM, PhD, Bruce S. Miller, MD, MS, Jonathan McHugh, MD, Steven A. Goldstein, PhD

Abstract

A novel, nonresorbable, monolithic composite structure ceramic, developed using a partially stabilized zirconia ceramic common to implantable devices, was used in a cementless weight-bearing articular implant to test the feasibility of replacing a region of degenerated or damaged articular cartilage in the knee as part of a preclinical study using male mongrel dogs lasting up to 24 weeks. Gross/histological cartilage observations showed no differences among control, 12-week and 24-week groups, while pull-out tests showed an increase in maximum pull-out load over time relative to controls. Hence, the use of a novel ceramic implant as a replacement for a focal cartilage defect leads to effective implant fixation within 12 weeks and does not cause significant degradation in opposing articular cartilage in the time frame evaluated.

Link to Article

http://dx.doi.org/10.1016/j.arth.2012.11.020

Differential stem- and progenitor-cell trafficking by prostaglandin E2

Authors

Jonathan Hoggatt, Khalid S. Mohammad, Pratibha Singh, Amber F. Hoggatt, Brahmananda R. Chitteti, Jennifer M. Speth, Peirong Hu, Bradley A. Poteat, Kayla N. Stilger, Francesca Ferraro, Lev Silberstein, Frankie K. Wong, Sherif S. Farag, Magdalena Czader, Ginger L. Milne, Richard M. Breyer, Carlos H. Serezani, David T. Scadden, Theresa A. Guise, Edward F. Srour & Louis M. Pelus

Abstract

To maintain lifelong production of blood cells, haematopoietic stem cells (HSCs) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSCs reside in several, perhaps overlapping, niches that produce regulatory molecules and signals necessary for homeostasis and for increased output after stress or injury. Despite considerable advances in the specific cellular or molecular mechanisms governing HSC–niche interactions, little is known about the regulatory function in the intact mammalian haematopoietic niche. Recently, we and others described a positive regulatory role for prostaglandin E2 (PGE2) on HSC function ex vivo. Here we show that inhibition of endogenous PGE2 by non-steroidal anti-inflammatory drug (NSAID) treatment in mice results in modest HSC egress from the bone marrow. Surprisingly, this was independent of the SDF-1–CXCR4 axis implicated in stem-cell migration. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin. Haematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in other species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced E-prostanoid 4 (EP4) receptor signalling. These results not only uncover unique regulatory roles for EP4 signalling in HSC retention in the niche, but also define a rapidly translatable strategy to enhance transplantation therapeutically.

Link to Article

http://dx.doi.org/10.1038/nature11929

Delayed Versus Immediate Reconstruction of Mandibular Segmental Defects Using Recombinant Human Bone Morphogenetic Protein 2/Absorbable Collagen Sponge

Authors

Khaled A. Hussein, Ibrahim E. Zakhary, Dana Hailat, Rami Elrefai, Mohamed Sharawy, Mohammed E. Elsalanty

Abstract

We randomized 11 dogs into 2 groups: immediate reconstruction (group 1, n = 6) and delayed reconstruction (group 2, n = 5). A 35-mm osteoperiosteal segmental defect was created on the left side of the mandible. Reconstruction with rhBMP2/ACS was carried out in the same setting in group 1 or at 4 weeks postoperatively in group 2. The contralateral side acted as an internal control. Animals were monitored both clinically and radiographically throughout the experiment. Twelve weeks after the application of rhBMP2/ACS, the quantity of bone formation was evaluated using regenerate mapping and histomorphometric analysis. Qualitative evaluation was performed based on bone mineral density and Vickers microhardness (μHV) testing. Postoperative seromas were observed in 83.3% of group 1 dogs only. Group 1 showed significantly larger physical dimensions than group 2 in most regenerate zones. Successful regeneration was achieved in 83.3% of group 1 dogs (discontinuity defect was seen in 1 of 6 dogs in group 1). Meanwhile, none of the 5 dogs in group 2 could be considered to have undergone successful regeneration (3 dogs had discontinuity defects, bony union occurred only in the basal third in the fourth dog, and the last dog showed union with only a shell of bone). The percent bone area and percent defect filling were significantly higher in group 1 than in group 2 (percent bone area, 52.4% ± 5.6% in group 1 and 36.6% ± 11.2% in group 2 [P = .02]; percent defect filling, 56.3% ± 5.5% in group 1 and 38.5% ± 10.8% in group 2 [P = .01]). Group 1 showed higher bone mineral density (0.7 ± 0.3 mg/cm3 in group 1 and 0.4 ± 0.1 mg/cm3 in group 2, P = .1). Finally, μHV was significantly higher in group 1 (20.3 ± 2.6 μHV) than in group 2 (13.2 ± 2.4 μHV) (P = .01). Delaying the application of rhBMP2/ACS for 4 weeks attenuated the quantity and quality of regenerated bone in mandibular segmental defects.

Link to Article

http://dx.doi.org/10.1016/j.joms.2012.12.018