Osteoporosis | EPFL Graph Search

Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone sterility, and consequent increase in fracture risk. It is the most common reason for a broken bone among the elderly. Bones that commonly break include the vertebrae in the spine, the bones of the forearm, and the hip. Until a broken bone occurs there are typically no symptoms. Bones may weaken to such a degree that a break may occur with minor stress or spontaneously. After the broken bone heals, the person may have chronic pain and a decreased ability to carry out normal activities. Osteoporosis may be due to lower-than-normal maximum bone mass and greater-than-normal bone loss. Bone loss increases after the menopause due to lower levels of estrogen, and after 'andropause' due to lower levels of testosterone. Osteoporosis may also occur due to a number of diseases or treatments, including alcoholism, anorexia, hyperthyroi

Differential Roles of MAPK Kinases MKK3 and MKK6 in Osteoclastogenesis and Bone Loss

Mario Michael Zaiss

Bone mass is maintained by osteoclasts that resorb bone and osteoblasts that promote matrix deposition and mineralization. Bone homeostasis is altered in chronic inflammation as well as in post-menopausal loss of estrogen, which favors osteoclast activity that leads to osteoporosis. The MAPK p38 alpha is a key regulator of bone loss and p38 inhibitors preserve bone mass by inhibiting osteoclastogenesis. p38 function is regulated by two upstream MAPK kinases, namely MKK3 and MKK6. The goal of this study was to assess the effect of MKK3- or MKK6-deficiency on osteoclastogenesis in vitro and on bone loss in ovariectomy-induced osteoporosis in mice. We demonstrated that MKK3 but not MKK6, regulates osteoclast differentiation from bone marrow cells in vitro. Expression of NFATc1, a master transcription factor in osteoclastogenesis, is decreased in cells lacking MKK3 but not MKK6. Expression of osteoclast-specific genes Cathepsin K, osteoclast-associated receptor and MMP9, was inhibited in MKK3-/- cells. The effect of MKK-deficiency on ovariectomy-induced bone loss was then evaluated in female WT, MKK3-/- and MKK6-/- mice by micro-CT analysis. Bone loss was partially inhibited in MKK3-/- as well as MKK6-/- mice, despite normal osteoclastogenesis in MKK6-/- cells. This correlated with the lower osteoclast numbers in the MKK-deficient ovariectomized mice. These studies suggest that MKK3 and MKK6 differentially regulate bone loss due to estrogen withdrawal. MKK3 directly mediates osteoclastogenesis while MKK6 likely contributes to pro-inflammatory cytokine production that promotes osteoclast formation.

Public Library of Science2014

Orthopedic implants used as drug delivery systems

Bastian Peter

Total Hip Replacement (THR) is today a routine procedure executed more than 800'000 times per year worldwide. THR gives generally satisfactory results, although the quality of outcome is inversely proportional to the age of the patient. In parallel, there is a trend to propose cementless THR to patients younger than 60 years. These patients have more demanding physical activity resulting in a significant increased failure rate of the implants. In particular for these patients, the desired service life of the implant should be extended. Proximal peri-implant bone loss is generally observed during the first two years following the implantation. This bone loss may lead to aseptic loosening, the major cause of THR failure. In order to control peri-implant bone remodeling and in particular the proximal bone loss, we developed the innovative concept of using the orthopedic implant as drug delivery system (DDS). The cementless stem of a hip implant would be coated with hydroxyapatite (HA) and bisphosphonate, a drug affecting bone resorption. The basic idea is to biologically reduce the initial peri-implant bone loss by decreasing the osteoclastic bone resorption activity. This approach could significantly increase the THR outcome. Pre-clinical tests were performed to numerically validate this new concept. An existing bone remodeling model was modified to take into account the bisphosphonate effect. The outcome of a THR was evaluated with different simulated bisphosphonate concentrations. Results of the simulations showed that the implant used as a drug delivery system would increase bone density around the implant and decrease, at the same time, the micromovements between the implant and the surrounding bone tissue. Therefore, the evolution towards peri-implant bone loss and fibrous tissue development at the bone-implant interface would be delayed, which could positively influence the THR outcome. Pre-clinical tests allowed us to verify that a partial proximal coating of the stem would result in a homogeneous bone remodeling, a situation biomechanically more favorable than the simulated situation obtained with a full coating of the stem. Despite a numerically observed positive concentration effect, it was noted that the decrease of peri-implant bone loss was most notably affected with the intermediate simulated bisphosphonate concentration. Based on these positive pre-clinical results, in vitro and in vivo experiments were performed to further validate the concept of orthopedic implant used as drug delivery system. As bisphosphonates were developed for systemic delivery, little information was available regarding the bisphosphonate concentrations which could be safely used for a local delivery application. It was especially important to quantify the bisphosphonate concentration osteoblasts could be exposed to without harmful effect for the bone formation process. We challenged osteoblasts from human and murine origins to different concentrations of the choosen bisphosphonate (Zoledronate from Novartis). As wear particles are inevitably present in the peri-implant bone, we also added titanium particles to quantify the eventual synergetic negative effect between Zoledronate and particles on osteoblast behavior. In this in vitro study, we showed that Zoledronate did not impair proliferation of human osteoblasts when used at concentrations lower or equal to 1 µM, while murine cells could be exposed to concentrations up to 10 µM. A concentration of 0.01% of titanium particles did not impair proliferation of either cell line. Zoledronate affected, through a chelation phenomenon, ALP activity of murine osteoblasts, whereas the presence of titanium particles strongly decreased the ALP activity of murine osteoblasts. We did not detect any synergic effect of Zoledronate and titanium particles on neither human and murine osteoblast behavior. Those results allowed us to conclude that 1 µM and 10 µM Zoledronate concentrations for human and murine respectively, could be used in the proposed drug delivery system. The basic idea behind the drug delivery system is that the bisphosphonate will stay around the implant where its effect on bone resorption is needed. Since the drug is directly brought into contact with the endosteal bone, it was necessary to study the bisphosphonate diffusion in bone. The in vitro measured Zoledronate diffusion profile in the bone showed that the bisphosphonate entered the bone and diffused from the endosteal bone towards the periosteal bone. The drug accumulated in the first millimeter of the endosteal bone. This meant that the Zoledronate would stay in the peri-implant bone and would not reach regions which are not influenced by the presence of the implant. Based on the in vitro results for Zoledronate concentrations effect on osteoblast and diffusion in bone, an in vivo experiment was designed to demonstrate the proof of concept of orthopedic implant used as drug delivery system. Several Zoledronate quantites were grafted to hydroxyapatite (HA) coatings of titanium implants. The implants were inserted in rat condyles for 3 weeks. Bone density, histomorphometric and biomechanical measurements were performed on the collected rat femurs. A concentration-dependent effect was observed on the peri-implant bone density and on different histomorphometric parameters. The Zoledronate coated implant positively influenced the structure of the trabecular bone. Biomechanical pull-out tests confirmed the higher peri-implant bone quality of Zoledronate coated implant. Interestingly, this in vivo study highlighted the existence of a window of Zoledronate coating concentration in which the mechanical fixation of the implant was increased. A similar result was suggested with the pre-clinical testing. The in vivo study allowed the demonstration of proof-of-concept for orthopedic implant used as drug delivery system to control peri-implant bone remodeling. The results obtained in this thesis might then open the way of an easy transformation of currently existing HA coated implants. By grafting bisphosphonate onto the implant HA coating, the peri-implant bone loss might be reduced which would increase the service life of a THR. This approach is especially interesting for patient younger than 60 years.

EPFL2004

Development of a Bisphosphonate Delivering Hydrogel for the Augmentation of Impaired Peri-Implant Bone

Ulrike Kettenberger

Osteoporosis is a major health problem in our aging society. This metabolic disease, which is characterized by a deterioration of the bone microarchitecture and a significant loss of bone mass, is affecting a rising number of mostly elderly patients. The main clinical consequences are typical fragility fractures resulting in severe pain, morbidity, and mortality for affected patients. Osteoporosis does not only cause fractures, but also complicates fracture treatment, as implants are difficult to anchor in the impaired bone structure. Therefore, many mechanical and pharmaceutical approaches have been developed over the last decades to target this issue and improve implant anchorage in osteoporotic bone. The overall goal of the present PhD thesis was the development of a bisphosphonate (BP) releasing hydrogel that can enhance implant fixation in osteoporotic bone. The project was divided into three major sections: the investigation of the BP effect on peri-implant bone, the development and testing of the drug delivering biomaterial, and the evaluation of its efficiency in terms of implant fixation improvement. An ovariectomized rat model of postmenopausal osteoporosis was utilized for the investigation of the spatio-temporal effect of locally released Zoledronate, the BP used in this study. The drug was delivered from a biodegradable hyaluronic acid (HyA) hydrogel matrix to the bone stock surrounding screws that were implanted in the femoral condyles of the rats. Static and dynamic bone histomorphometric parameters were monitored in four concentric bone layers around the screw with time-lapsed in vivo microCT scans. With this study, we were able to demonstrate a significant enhancement of early bone formation rate accompanied by an efficient inhibition of peri-implant bone resorption in a large range around the screw. In a second in vivo study, we incorporated Zoledronate-loaded hydroxyapatite nanoparticles in the HyA hydrogel resulting in an unexpected rapid mineralization of the hydrogel within 10 days after implantation. Histology performed 2 months after implantation revealed granule-shaped mineralized spots within the peri-implant bone serving as scaffolds for new bone formation. When using Zoledronate-loaded particles, we could demonstrate a strong inhibitory effect on both peri-implant bone resorption and mineralized hydrogel degradation. Finally, we used the in vivo microCT scans of the first animal study to create micro-finite element models for the analysis of the screw fixation time course. We were able to show that Zoledronate locally delivered from the hyaluronic acid hydrogel improved screw fixation significantly as soon as 17 days after implantation when compared to an untreated control group. This difference persisted until the end of the study at day 58. Taken together, the studies performed for the present PhD thesis demonstrated an excellent suitability of HyA hydrogels for the local delivery of BPs intended to improve implant fixation in impaired bone. A Zoledronate triggered enhancement of screw fixation occurred early and persisted over a prolonged period, an important aspect considering that osteosynthesis implants need a reliable bone anchorage from the time of implantation until complete fracture healing. Furthermore, it could be shown that an addition of hydroxyapatite particles to the HyA resulted in a rapid in vivo mineralization of the hydrogel, a promising feature for bone defect repair applications.

EPFL2014