Despite total hip replacement (THR) gives generally satisfactory results, the quality of outcome in young patients is markedly decreased compared to the average THR outcome. For this population, pharmacological treatment with bisphosphonate would be beneficial to decrease the peri-implant osteolysis. However, as this population does not necessarily suffer from osteoporosis, a nonsystemic treatment would be preferable. Zoledronate was then grafted to hydroxyapatite (HA) coating of titanium implants. The implants were inserted in rat condyles with various zoledronate concentrations. A positive concentration-dependent effect was observed on the peri-implant bone density and on different histomorphometric parameters. Importantly for the outcome of the implants, the mechanical fixation was increased by the local presence of zoledronate.The obtained results open the way of an easy transformation of currently existing HA-coated implants by grafting bisphosphonate onto the coating in order to increase their service life in the patients. D 2004 Elsevier Inc. All rights reserved.

Abstract:Patients with osteoporosis and joint disabilities represent a constant growing and challenging population to be treated in the musculoskeletal clinical field. Especially in the case of total hip arthroplasty, new solutions should be developed to compensate for the double negative factors, peri-implant osteolysis, and osteoporotic bone loss, affecting the quality of implant outcome. The goal of this study was then to establish a proof of concept for orthopedic implant used as Zoledronate delivery in osteoporotic rats, and in particular, to verify if this approach could increase the initial implant stability. Twenty-five female 6-month-old Wistar rats were ovariectomized 6 weeks before the implantation to induce osteoporosis. The animals were randomly separated in five groups representing the different Zoledronate concentrations in the HA coating: 0, 0.2, 2.1, 8.5, and 16 g/implant. Histomorphometric measures and peri-implant bone volume fraction were assessed and mechanical stability tests were performed. Bone volume fraction and biomechanical results clearly illustrate the positive effect of Zoledronate coated implants in the osteoporotic rats. A remarkable result was to show the existence of a window of Zoledronate content (0.2 to 8.5 g/implant) in which the mechanical fixation of the implant increased. We were able to establish the proof of concept for orthopedic implants used as a drug delivery system in osteoporotic rats. The local bisphosphonate delivery from a calcium phosphate coating allowed increase of the mechanical fixation of an orthopedic implant. This study shows that orthopedic implants containing bisphosphonates could be beneficial for osteoporotic patients in need of a total joint replacement.

A hydraulic calcium phosphate cement made of beta-tricalcium phosphate [beta-Ca3(PO4)2], monocalcium phosphate monohydrate [Ca(H2PO4)2-H2O], and water was used as a delivery system for the antibiotic gentamicin sulfate (GS). GS, added as powder or as aqueous solution, was very beneficial to the physicochemical properties of the cement. The setting time increased from 2 to 4.5 min with 3% (w/w) GS and then slowly decreased to 3.75 min with 16% (w/w) GS. The tensile strength increased from 0.4 to 1.6 MPa with 16% (w/w) GS. These effects were attributed to the presence of sulfate ions in GS. The release of GS from the cement was measured in a pH 7.4 phosphate-buffered saline solution at 37 degrees C by USP paddle method. Factors such as cement porosity, GS content and presence of sulfate ions or polymeric additives were investigated. The amount of GS released was roughly proportional to the square root of time up to approximately 50% release. Afterwards, the release rate markedly slowed down to zero. In all but two cement formulations, the total dose of GS was released within 7 days, indicating that no irreversible binding occurred between the cement paste and the antibiotic. When small amounts of hydroxypropylcellulose or poly(acrylic acid) were added to the cement, the maximum fraction released was a few percent lower than the total GS dose, suggesting some binding between the polymer and GS. The GS release rate was strongly influenced by the presence of sulfate ions in the cement paste and by the cement porosity. The higher the sulfate ion content of the cement paste, the lowe the GS release rate. This influence was attributed to the finer cement micro-structure induced by the presence of sulfate ions. Furthermore, when the initial cement porosity was increased from 38 to 69%, the release rate almost tripled (0.16 to 0.45 h-1/2). Finally, the biological activity of GS in the cement was maintained, as measured by assaying the release medium.

We envision the use of human fetal bone cells for engineered regeneration of adult skeletal tissue. A description of their cellular function is then necessary. To our knowledge, there is no description of human primary fetal bone cells treated with differentiation factors. The characterization of fetal bone cells is particularly important as the pattern of secreted proteins from osteoblasts has been shown to change during aging. In the first part of this work, human primary fetal bone cells were compared to adult bone cells and mesenchymal stem cells for their ability to proliferate and to differentiate into osteoblasts in vitro. Cell proliferation, gene expression of bone markers, alkaline phosphatase (ALP) activity, and mineralization were analyzed during a time-course study. In the second part of this paper, bone fetal cells behavior exposed to osteogenic factors is further detailed. The doubling time of fetal bone cells was comparable to mesenchymal stem cells but significantly shorter than for adult bone cells. Gene expression of cbfa-1, ALP, a1 chain of type I collagen, and osteocalcin were upregulated in fetal bone cells after 12 days of treatment, with higher inductions than for adult and mesenchymal stem cells. The increase of ALP enzymatic activity was stronger for fetal than for adult bone cells reaching a maximum at day 10, but lower than for mesenchymal stem cells. Importantly, the mineralization process of bone fetal cells started earlier than adult bone and mesenchymal stem cells. Proliferation of fetal and adult bone cells was increased by dexamethasone, whereas 1a,25-dihydroxyvitamin D 3 did not show any proliferative effect. Mineralization studies clearly demonstrated the presence of calcium deposits in the extracellular matrix of fetal bone cells. Nodule formation and calcification were strongly increased by the differentiation treatment, especially by dexamethasone. This study shows for the first time that human primary fetal bone cells could be of great interest for bone research, due to their fast growth rate and their ability to differentiate into mature osteoblasts. They represent an interesting and promising potential for therapeutic use in bone tissue engineering.

We report two unrelated patients with a multisystem disease involving liver, eye, immune system, connective tissue, and bone, caused by biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene. Both presented as infants with recurrent episodes triggered by fever with vomiting, dehydration, and elevated transaminases. They had frequent infections, hypogammaglobulinemia, reduced natural killer cells, and the Pelger-Huët anomaly of their granulocytes. Their facial features were similar with a pointed chin and proptosis; loose skin and reduced subcutaneous fat gave them a progeroid appearance. Skeletal features included short stature, slender bones, epiphyseal dysplasia with multiple phalangeal pseudo-epiphyses, and small C1-C2 vertebrae causing cervical instability and myelopathy. Retinal dystrophy and optic atrophy were present in one patient. NBAS is a component of the synthaxin-18 complex and is involved in nonsense-mediated mRNA decay control. Putative loss-of-function mutations in NBAS are already known to cause disease in humans. A specific founder mutation has been associated with short stature, optic nerve atrophy and Pelger-Huët anomaly of granulocytes (SOPH) in the Siberian Yakut population. A more recent report associates NBAS mutations with recurrent acute liver failure in infancy in a group of patients of European descent. Our observations indicate that the phenotypic spectrum of NBAS deficiency is wider than previously known and includes skeletal, hepatic, metabolic, and immunologic aspects. Early recognition of the skeletal phenotype is important for preventive management of cervical instability.