Local Delivery Of Bisphosphonates Research Articles

Chitosan modified with lanthanum ions as implantable hydrogel for local delivery of bisphosphonates

Osteoporosis is a disease that affects many people around the world. One group of drugs used to treat it are bisphosphonates. However, they have poor bioavailability and many side effects. Therefore, research around the world is focused on developing bisphosphonate delivery systems. In this paper, we would like to present the design of a hydrogel material with chitosan matrix modified with lanthanum, that could serve as an implantable hydrogel capable of sustained and slow release of Zoledronate. Various research techniques were used to characterize the materials, and the swelling ratio and water solubility were also tested. The conducted research proved that the prepared hydrogel is capable of the long-term release of the Zoledronate. Thanks to this, the prepared material can be successfully used as an implantable hydrogel or a coating on titanium implants for the local delivery of drugs.

A sustained release of alendronate from an injectable tetra-PEG hydrogel for efficient bone repair.

Significant efforts on construction of smart drug delivery for developing minimally invasive gelling system to prolong local delivery of bisphosphonates are considered as promising perspectives for the bone-related diseases, which provide the hydrogels with unique bioactivities for bone repair in clinic. Herein, we have constructed an alendronate (ALN)-conjoined injectable tetra-PEG hydrogel with excellent biocompatibility, uniform network, and favorable mechanical properties in one-pot strategy. In views of the quick ammonolysis reaction between N-hydroxysuccinimide (NHS)-ester of tetra-PEG-SG and amine groups of tetra-PEG-NH2 polymer and ALN molecules, the uniform networks were formed within seconds along with the easy injection, favorable biocompatibility and mechanical properties for hydrogel scaffolds. On account of the simultaneous physical encapsulation and chemical linkage of the ALN within the hydrogels, the ALN-conjoined tetra-PEG hydrogel exhibited a sustained drug release delivery that could persistently and effectively facilitate viability, growth, proliferation, and osteogenesis differentiation of stem cells, thereby allowing the consequent adaptation of hydrogels into the bone defects with irregular shapes, which endowed the ALN-conjoined tetra-PEG hydrogel with depot formulation capacity for governing the on-demand release of ALN drugs. Consequently, the findings imply that these drug-based tetra-PEG hydrogels mediate optimal release of therapeutic cargoes and effective promotion of in situ bone regeneration, which will be broadly utilized as therapeutic scaffolds in tissue engineering and regenerative medicine.

Alendronate-functionalized double network hydrogel scaffolds for effective osteogenesis.

Development of artificial bone substitutes mimicking the extracellular matrix is a promising strategy for bone repair and regeneration. In views of the actual requirement of biomechanics, biodegradability, and bioactivity, herein, a double-network (DN) hydrogel was constructed by interspersing a methacrylated gelatin (GelMA) network into alendronate (ALN)-modified oxidized alginate (OSA) network via Schiff base reaction and photo-crosslinking process to promote in situ bone regeneration. This GelMA@OSA-ALN DN hydrogel possessed favorable network and pores, good biocompatibility, and enhanced biomechanics. Notably, the introduction of Schiff base furnished the ND hydrogel scaffold with pH-responsive biodegradation and sustained ALN drug release delivery, which could provide effective bioactivity, upregulate osteogenesis-related genes, and promote the cell viability, growth, proliferation, and osteogenesis differentiation for bone regeneration. Therefore, we provide a new insight to develop functional DN hydrogel scaffold toward governing the on-demand drug release and achieving the stem cell therapy, which will be developed into the minimally invasive gelling system to prolong local delivery of bisphosphonates for the bone-related diseases.

Pamidronate-Encapsulated Electrospun Polycaprolactone-Based Composite Scaffolds for Osteoporotic Bone Defect Repair.

Bone fractures associated with osteoporosis are a major concern all over the world especially among the elderly population and postmenopausal women. Bisphosphonates (BPs) are widely used clinically for both treatment and prevention of osteoporosis despite their poor oral bioavailability and undesired side effects. Local delivery of BPs from polymeric scaffolds can improve the efficacy and overcome the undesirable side effects associated with oral bisphosphonate therapy. The aim of the present study is to explore the effectiveness of pamidronate (PDS) encapsulated electrospun polycaprolactone/polycaprolactone-polyethyleneglycol-polycaprolactone/nanohydroxyapatite (PCH) scaffolds in healing critical-size calvarial defects in an osteoporotic rat animal model. Prior to implantation studies, the effect of PDS on the fiber architecture, mechanical properties, and in vitro degradation behavior was evaluated. The in vitro release of PDS from PCH scaffolds in phosphate buffer saline (PBS) at 37 °C was monitored for a period of 21 days. An osteoporotic animal model was successfully developed in Wistar rats by bilateral ovariectomy. Results of micro CT (computed tomography) and blood serum analysis confirmed the osteoporotic model induction in rats. Critical-size calvarial defects of 8 mm size were created in osteoporotic rats, and the in vivo osteogenic efficacy of PCH-PDS scaffolds was evaluated by micro CT, histology, and histomorphometry. Micro CT analysis showed improved osseous tissue integration with the use of PDS-loaded PCH scaffolds after 12 week post implantation. Histology, density measurement using micro CT, and histomorphometry further substantiate that PCH-PDS scaffolds have the potential to be used for the repair of osteoporotic bone defects. Our findings revealed that incorporation of PDS onto PCH scaffolds provides a promising biomaterial that could be used for regenerating osteoporosis-related fractures.

The influence of local delivery of bisphosphonate on osseointegration of dental implants.

Data sourcesThe databases searched were the Cochrane Library, PubMed/Medline, Embase, ISI Web of Knowledge, Scopus and SIGLE OpenGrey. Databases were searched with no restriction on year of publication or language.Study selectionRandomised controlled clinical trials (RCTs), prospective and retrospective studies, case-control studies and case series studies in humans were included. The test group received implants with the local delivery of bisphosphonates, controls received implants only. Studies involving patients with metabolic bone diseases or undergoing systemic medications for bone bio-modulation or immunosuppression or with relevant pathologies were excluded.Data extraction and synthesisThree authors independently selected studies with disagreements being resolved by discussion. Study quality was assessed by two reviewers using the Newcastle-Ottawa scale (NOS).ResultsThree articles published between 2010 and 2013 met the selection criteria. Sample size ranged from five to 39. Mean age was 52.6 to 66. Efficacy was assessed using radiographic analysis, implant stability quotient (ISQ) and histological assessment. Despite methodological differences, all articles reported positive results for osseointegration when a local bisphosphonate was used, either on the implant surface or direct application of a pharmacologically active compound at the surgical site or in the form of a gel directly at the surgical site. Greater implant stability, better implant survival rates and reduced peri-implant bone loss were recorded in the test groups compared with controls. As well as formation of lamellar bone trabeculae in intimate contact with the implants.ConclusionsThe local use of a bisphosphonate appears to favour the osseointegration of titanium implants in humans.

Spray-congealed solid lipid microparticles as a new tool for the controlled release of bisphosphonates from a calcium phosphate bone cement

The aim of this work was to develop an innovative drug delivery system potentially useful for the local delivery of Bisphosphonates to bone tissue. We propose the use of Solid Lipid Microparticles (MPs), up to now mainly used for oral and topical drug delivery, as carrier for bisphosphonates due to the favourable biocompatibility and lower toxicity of the lipids compared with many polymers. The delivery platform consisted of a biomimetic α-tricalcium phosphate-gelatin cement (CPC) enriched with alendronate loaded MPs (MPs-AL) produced by the spray congealing technology. Alendronate direct addition to cement composition is limited since Alendronate is able to sequester calcium from calcium phosphates, thus preventing the setting of the cements. At variance, this approach permitted to load a relatively high amount of the drug on the CPC and allowed the controlled release of the highly water soluble alendronate. A Design of Experiment (DoE) was employed for the screening of the effects of the formulation variables related to the presence of unloaded microparticle (MPs) on the cement most important mechanical properties. Then, MPs loaded with 10% w/w of alendronate were produced using five different carriers (Stearic Acid, Stearilic Alcohol, Cutina HR, Tristearin and Precirol ATO5). All MPs-AL exhibited a spherical shape, encapsulation efficiency higher than 90% and prevalent particle size ranging from 100 to 150μm. Solid state characterization (DSC, HSM and X-ray powder diffraction) demonstrated that encapsulation of alendronate into MPs did not alter its crystal structure. MPs-AL addition to the cement provoked a modest lengthening of the setting times and of the hardening reaction leading to the complete transformation of α-tricalcium phosphate into calcium-deficient hydroxyapatite, without significantly affect the cement mechanical properties. Moreover, the results of in vitro AL release study performed on cements enriched with MPs-AL showed that the system allows a controlled release of the drug over time.

Measurement of Ototoxicity Following Intracochlear Bisphosphonate Delivery.

Assessing the maximum safe dose for local bisphosphonate delivery to the cochlea enables efficient delivery without ototoxicity. Otosclerosis is a disease of abnormal bone metabolism affecting the otic capsule, which can cause conductive hearing loss. Larger otosclerotic lesions involving the cochlear endosteum and spiral ligament can result in sensorineural hearing loss. Bisphosphonates are used to treat patients with metabolic bone diseases, including otosclerosis. Local delivery is the most efficient way of delivery to the cochlea while avoiding systemic side effects. To attain intracochlear bisphosphonate delivery without ototoxicity, the maximum safe dose of bisphosphonates requires definition. In the present study, we tested increasing concentrations of zoledronate, a third-generation bisphosphonate in an intracochlear delivery system. We measured ototoxicity by monitoring distortion product otoacoustic emissions and compound action potentials. Artificial perilymph and increasing molar concentrations of zoledronate were administered to the cochlea in guinea pigs via a cochleostomy. Hearing was measured at multiple time points. A fluorescently labeled zoledronate derivative (6-FAM-ZOL) was coadministered as an internal control for drug delivery. Specimens embedded in the resin blocks were ground to a mid-modiolar section and fluorescent photomicrographs were taken. No significant shift in hearing was observed in animals treated either with artificial perilymph or with 4% of the human systemic zoledronate dose. However, compound action potentials thresholds increased during infusion of 8% of the human systemic zoledronate dose, improved 4 hours later, and then increased again 4 weeks later. Using fluorescent photomicrography, intracochlear bisphosphonate delivery up to the apical cochlear turn was confirmed by visualizing 6-FAM-ZOL. These findings provide reference values for intracochlear bisphosphonate delivery in the treatment of cochlear otosclerosis and describe a useful method for tracking cochlear drug delivery.

Non-Ototoxic Local Delivery of Bisphosphonate to the Mammalian Cochlea

Non-Ototoxic Local Delivery of Bisphosphonate to the Mammalian Cochlea

INHIBITION OF AORTIC VALVE CALCIFICATION IN AN EXPERIMENTAL MODEL OF AORTIC VALVE STENOSIS

Local delivery of bisphosphonates has been proven to inhibit calcification of the arterial wall in an experimental model of atherosclerosis. The aim of the present study was to evaluate the anticalcific action of bisphosphonates on the aortic valve in an experimental model of aortic stenosis.

Non-Ototoxic Local Delivery of Bisphosphonate to the Mammalian Cochlea.

Local delivery of bisphosphonates results in superior localization of these compounds for the treatment of cochlear otosclerosis, without ototoxicity. Otosclerosis is a common disorder of abnormal bone remodeling within the human otic capsule. It is a frequent cause of conductive hearing loss from stapes fixation. Large lesions that penetrate the cochlear endosteum and injure the spiral ligament result in sensorineural hearing loss. Nitrogen-containing bisphosphonates (e.g., zoledronate) are potent inhibitors of bone remodeling with proven efficacy in the treatment of metabolic bone diseases, including otosclerosis. Local delivery to the cochlea may allow for improved drug targeting, higher local concentrations, and the avoidance of systemic complications. In this study, we use a fluorescently labeled bisphosphonate compound (6-FAM-ZOL) to determine drug localization and concentration within the otic capsule. Various methods for delivery are compared. Ototoxicity is evaluated by auditory brainstem responses and distortion product otoacoustic emissions. 6-FAM-ZOL was administered to guinea pigs via intraperitoneal injection, placement of alginate beads onto the round window membrane, or microfluidic pump infusion via a cochleostomy. Hearing was evaluated. Specimens were embedded into resin blocks, ground to a mid-modiolar section, and quantitatively imaged using fluorescence microscopy. There was a dose-dependent increase in fluorescent signal after systemic 6-FAM-ZOL treatment. Local delivery via the round window membrane or a cochleostomy increased delivery efficiency. No significant ototoxicity was observed after either systemic or local 6-FAM-ZOL delivery. These findings establish important preclinical parameters for the treatment of cochlear otosclerosis in humans.

Time course of bone screw fixation following a local delivery of Zoledronate in a rat femoral model – A micro-finite element analysis

A good fixation of osteosynthesis implants is crucial for a successful bone healing but often difficult to achieve in osteoporotic patients. One possible solution to this issue is the local delivery of bisphosphonates in direct proximity to the implants, A critical aspect of this method, that has not yet been well investigated, is the time course of the implant fixation following the drug release. Usual destructive mechanical tests require large numbers of animals to produce meaningful results. Therefore, a micro-finite element (microFE) approach was chosen to analyze implant fixation. In vivo micro computed tomography (microCT) scans were obtained, first weekly and later bi-weekly, after implantation of polymeric screws in the femoral condyles of ovariectomized rats. In one half of the animals, Zoledronate was released from a hydrogel matrix directly in the peri-implant bone stock, the other animals were implanted only with screws as control. The time course of the implant fixation was investigated with linear elastic microFE models that were created based on in vivo microCT scans. The numerical models were validated against experimental pullout-tests measurements in an additional cadaver study. The microFE analysis revealed a significant increase in force at yield of the Zoledronate treated group compared to the control group. The force of the treated group was 28% higher after 17 days of screw implantation, 42% higher after 31 days. The significant difference persisted until the end of the in vivo study at day 58 (p<0.01). The early onset and prolonged duration of the implant anchorage improvement that was found in this study indicates the great potential of Zoledronate-loaded hydrogel for an enhancement of osteosynthesis implant fixation in impaired bone.

Calcium Phosphate/Etidronate Disodium Biocement: Etidronate, Retarder or Accelerator

Bisphosphonate release from calcium phosphate cement has been investigated. We hypothesized that local delivery of bisphosphonate from the calcium phosphate cement improves the mechanical properties. Different samples with different concentration of Etidronate disodium have been made and analyzed. We observed a dual behavior from Etidronate in retarding and accelerating the setting of calcium phosphate cement in low and high concentration respectively. After soaking samples in simulated body fluid, an optimum concentration of Etidronate disodium was added to the calcium phosphate paste in order to achieve the best mechanical properties. Scanning electron microscopy (SEM) showed the formation of hydroxyapatite crystals. X-ray diffraction (XRD) analysis was used to

Effect of Local vs. Systemic Bisphosphonate Delivery on Dental Implant Fixation in a Model of Osteonecrosis of the Jaw

Locally applied bisphosphonates may improve the fixation of metal implants in bone. However, systemic bisphosphonate treatment is associated with a risk of osteonecrosis of the jaw (ONJ). We hypothesized that local delivery of bisphosphonate from the implant surface improves the fixation of dental implants without complications in a setting where systemic treatment induces ONJ. Forty rats were randomly allocated to 4 groups of 10. All groups received a titanium implant inserted in an extraction socket. Group I received the implants only. Group II received dexamethasone (0.5 mg/kg). Group III received dexamethasone as above plus alendronate (200 µg/kg). Group IV received zoledronate-coated implants and dexamethasone as above. The animals were sacrificed 2 weeks after tooth extraction. All 10 animals with systemic alendronate treatment developed large ONJ-like changes, while all with local treatment were completely healed. Implant removal torque was higher for the bisphosphonate-coated implants compared with the other groups (p < 0.03 for each comparison). Micro-computed tomography of the maxilla showed more bone loss in the systemic alendronate group compared with groups receiving local treatment (p = 0.001). Local bisphosphonate treatment appears to improve implant fixation in a setting where systemic treatment caused ONJ.

EFFECT OF ALENDRONATE-CONTAINING COATINGS ON OSTEOINTEGRATION INTO POROUS TANTALUM IN A CORTICAL BONE MODEL

Hip replacement is extensively performed in hips with serious damages. The clinical outcomes of hip implants remain to be improved. Local delivery of bisphosphonates may improve implant fixation by positively affecting local bone modeling. In this study, two alendronate-containing coatings were prepared on porous tantalum by electrolytic deposition. Calcium phosphate coating was deposited and adsorbed with alendronate; the resulting coating had a low drug dose and slow release rate. Solid calcium alendronate coating was also deposited on tantalum; the resulting coating had high drug dose and faster release rate. The effects of the two coatings on new bone formation and implant fixation were studied in the rabbit tibial cortex. Four weeks after implantation, the implants with adsorbed alendronate showed the highest total new bone formation and mechanical fixation, whereas the implants with solid drug coating showed slightly lower fixation and total new bone formation than control bare implants. The improvement by the alendronate-adsorbed calcium phosphate coating provides potentials of enhancing early fixation of porous implants. The solid drug coating warranted further studies to exploit its high drug dose for inhibiting future osteolysis.

In vivo assessment of local effects after application of bone screws delivering bisphosphonates into a compromised cancellous bone site

Background The primary stability of cancellous screw is difficult to obtain in bone of compromised quality and failure of screw fixation is common. To overcome this problem, it is proposed to locally deliver bisphosphonate from the screw. An in vivo validation of the increase in fixation of the cancellous screw is then needed in compromised bone. Methods In this study, we used an overdrilling procedure, which enables consistent modeling of reduced screw stability comparable to compromised cancellous bone. Forty eight adult NZW rabbits were used in this study and all animals underwent bilateral femur implantation. One leg was implanted with the screw containing the bisphosphonate (biocoated group) while the other was used as control (control group) with the screw only. Mechanical testing and micro-CT imaging were used to assess the effect of local drug delivery of Zoledronate on screws fixation at 5 time points. Findings At the early time points (1, 5, and 10 days), no significant difference could be seen between the biocoated and control groups. At 6 weeks, the bone volume fraction was significantly higher in the trabecular region of the biocoated group. However, this increase did not have a significant effect on the pull-out force. At the last time point, 11 weeks, both the bone volume fraction and the pull-out force were significantly higher in the biocoated group. Interpretation The results of this study suggest that, in compromised bone, local delivery of bisphosphonate enhances the stability of bone screws.

Combined effects of zoledronate and mechanical stimulation on bone adaptation in an axially loaded mouse tibia

Background Local bisphosphonate delivery may be a solution to prevent periprosthetic bone loss and improve orthopedic implants fixation. In load-bearing implants, periprosthetic bone is exposed to high mechanical demands, which in normal conditions induce an adaptation of bone. In this specific mechanical situation, the modulation of the bone response by bisphosphonate remains uncertain. Methods We assessed the combined effects of zoledronate and mechanical loading on bone adaptation using an in-vivo axial compression model of the mouse tibia and injections of zoledronate. Bone structure was quantified with in-vivo μCT before and after the period of stimulation and the mechanical properties of the tibias were evaluated with 3 point-bending tests after sacrifice. Findings Axial loading induced a localized increase of cortical thickness and bone area. Zoledronate increased cortical thickness, bone perimeter, and bone area. At the most loaded site of the tibia, the combined effect of zoledronate and mechanical stimulation was significantly smaller than the sum of the individual effects measured at the same site in the control groups. Interpretations The results of this study suggested that a negative interaction between zoledronate and mechanical loading might exist at high level of strain.

Could local delivery of bisphosphonates be a new therapeutic choice for hemangiomas?

Hemangiomas are endothelial neoplasms that affected about 8-12% of one-year-old children. Their life cycle is characterized by a rapid endothelial proliferation phase, followed by a slow involution phase. About 10% of the hemangiomas will cause functional complications or psychological concern requiring active treatments. Current therapy methods, such as intra-lesional or systemic administration of corticosteroids, systemic interferon treatment, or surgery, are diverse but uncertainty. To date, the etiology of hemangiomas is still controversial. However, general consensus on the importance of the endothelial cells leads hemangioma pathogenesis to angiogenesis. Thus, local delivery of anti-angiogenic agents may be of great interest for the treatment of hemangiomas. Bisphosphonates are potent in inhibiting osteoclast activity and promoting apoptosis, which are widely used for the treatment of osteoporosis and osteolysis diseases with minor adverse side effects. In addition to its anti-osteolytic effect, bisphosphonates are currently shown to be capable of anti-angiogenesis and induction of apoptosis in tumor cells. Experimental evidences demonstrated that bisphosphonates can inhibit capillary tube formation and vessel sprouting by impairing endothelial proliferation and migration, as well as reducing the serum fibroblast growth factor-2 and vascular endothelial growth factor. Moreover, it is not impossible to deliver bisphosphonates to local lesion by a new local drug delivery system (DDS), which employed the biocompatible calcium phosphate as the drug carriers for clinical use. This local drug delivery system is a suitable carrier for loading and releasing of bioactive bisphosphonates. Therefore, we hypothesis that local deliver of bisphosphonates by fine calcium phosphate particles may be a potential treatment of hemangiomas. By employing proper calcium phosphate particles, bioactive bisphosphonates will be gradually released and exert their anti-angiogenesis effect, destructing rapid proliferation of epithelial cells and promoting the involution of hemangiomas without systematic adverse side effects.

Controlled Release of Alendronate from Polymeric Films

Bisphosphonate drugs alter the balance of bone resorption and formation, leading to a net increase in bone density. Therefore, these drugs are commonly used to treat osteoporosis or as an adjunct to cancer chemotherapy. Local delivery of bisphosphonates, such as alendronate, from polymeric films has the potential to improve efficacy and decrease side-effects common to oral bisphosphonate therapy. Alendronate was effectively encapsulated in film formulations composed of poly(lactic-co-glycolic acid) (PLGA) blended with poly(DL-lactic acid)-block-methoxy poly(ethylene glycol) (diblock co-polymer) and the films were characterized for elasticity, swelling, thermal and drug-release properties. Increasing the proportion of diblock co-polymer in the formulation decreased the glass transition temperature of PLGA, allowing for improved handling via increases in film elasticity. Immersion in aqueous media caused a rapid stiffening and swelling of the films. The inclusion of diblock co-polymer increased the rate of drug release from the films over a 3-week period. Drug-loaded polymeric films containing 0.25% alendronate increased osteoblast viability after 4 days compared to polymer alone. After 5 weeks, there was a significant increase in alkaline phosphatase activity and calcium nodule formation in osteoblasts grown on films containing 1.25% alendronate in 5% diblock co-polymer in PLGA.

Targeted Local Delivery of Bisphosphonate from Orthopaedic Implants

Two methods of loading bisphosphonate (BP) into hydroxylapatite (HA) coatings on crystalline TiO2 surfaces were investigated to improve bone ingrowth to implant surfaces. In the study the BP pamidronate was used. Ti-plates coated with crystalline TiO2 were soaked in phosphate buffer saline (PBS) for 7 days at 40° C and thereafter soaked in solutions of BP, 0.5 mg/ml for 15 or 60 minutes (fast loading method). In the second method BP was dissolved into PBS in different concentrations before immersion of the discs for 7 days (co-precipitation method). Surface and bulk were analysed using electron spectroscopy for chemical analysis, scanning electron microscope and x-ray diffraction. Release of BP was studied using alternating ionic current method. It was shown that fast loading by soaking in a BP solution for 15 minutes was sufficient to load BP into a HA coating. Co-precipitation showed that a thin layer of calcium phosphate crystals containing BP can be deposited directly onto a crystalline TiO2 surface.

Implants delivering bisphosphonate locally increase periprosthetic bone density in an osteoporotic sheep model. A pilot study

It is a clinical challenge to obtain a sufficient orthopaedic implant fixation in weak osteoporotic bone. When the primary implant fixation is poor, micromotions occur at the bone-implant interface, activating osteoclasts, which leads to implant loosening. Bisphosphonate can be used to prevent the osteoclastic response, but when administered systemically its bioavailability is low and the time it takes for the drug to reach the periprosthetic bone may be a limiting factor. Recent data has shown that delivering bisphosphonate locally from the implant surface could be an interesting solution. Local bisphosphonate delivery increased periprosthetic bone density, which leads to a stronger implant fixation, as demonstrated in rats by the increased implant pullout force. The aim of the present study was to verify the positive effect on periprosthetic bone remodelling of local bisphosphonate delivery in an osteoporotic sheep model. Four implants coated with zoledronate and two control implants were inserted in the femoral condyle of ovariectomized sheep for 4 weeks. The bone at the implant surface was 50% higher in the zoledronate-group compared to control group. This effect was significant up to a distance of 400mum from the implant surface. The presented results are similar to what was observed in the osteoporotic rat model, which suggest that the concept of releasing zoledronate locally from the implant to increase the implant fixation is not species specific. The results of this trial study support the claim that local zoledronate could increase the fixation of an implant in weak bone.