Intravenous injection of leconotide, an omega conotoxin : synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain

Objective.  Leconotide (CVID, AM336, CNSB004) is an omega conopeptide similar to ziconotide, which blocks voltage sensitive calcium channels. However, unlike ziconotide, which must be administered intrathecally, leconotide can be given intravenously because it is less toxic. This study investigated the antihyperalgesic potency of leconotide given intravenously alone and in combinations with morphine-administered intraperitoneally, in a rat model of bone cancer pain. Design.  Syngeneic rat prostate cancer cells AT3B-1 were injected into one tibia of male Wistar rats. The tumor expanded within the bone causing hyperalgesia to heat applied to the ipsilateral hind paw. Measurements were made of the maximum dose (MD) of morphine and leconotide given alone and in combinations that caused no effect in an open-field activity monitor, rotarod, and blood pressure and heart rate measurements. Paw withdrawal thresholds from noxious heat were measured. Dose response curves for morphine (0.312–5.0 mg/kg intraperitoneal) and leconotide (0.002–200 µg/kg intravenous) given alone were plotted and responses compared with those caused by morphine and leconotide in combinations. Results.  Leconotide caused minimal antihyperalgesic effects when administered alone. Morphine given alone intraperitoneally caused dose-related antihyperalgesic effects (ED50 = 2.40 ± 1.24 mg/kg), which were increased by coadministration of leconotide 20 µg/kg (morphine ED50 = 0.16 ± 1.30 mg/kg); 0.2 µg/kg (morphine ED50 = 0.39 ± 1.27 mg/kg); and 0.02 µg/kg (morphine ED50 = 1.24 ± 1.30 mg/kg). Conclusions.  Leconotide caused a significant increase in reversal by morphine of the bone cancer-induced hyperalgesia without increasing the side effect profile of either drug. Clinical Implication.  Translation into clinical practice of the method of analgesia described here will improve the quantity and quality of analgesia in patients with bone metastases. The use of an ordinary parenteral route for administration of the calcium channel blocker (leconotide) at low dose opens up the technique to large numbers of patients who could not have an intrathecal catheter for drug administration. Furthermore, the potentiating synergistic effect with morphine on hyperalgesia without increased side effects will lead to greater analgesia with improved quality of life.

Are bone-anchored prostheses about to revolutionise the world of prosthetics?

Individuals with limb amputation fitted with conventional socket-suspended prostheses often experience socket related discomfort leading to a significant decrease in quality of life. Most of these concerns can be overcome by surgical techniques enabling bone-anchored prostheses. In this case, the prosthesis is attached directly to the residual skeleton through a percutaneous implant. The primary aim of this study is to present the current advances in these surgical techniques worldwide with a strong focus on the developments in Australia. The secondary aim is to provide an overview of the possible critical changes that may occurred in the world of prosthetic following these developments in bone-anchored prostheses.

Is there a bone-nail specific entry point? automated fit quantification of tibial nail designs during the insertion for six different nail entry points

Intramedullary nailing is the standard fixation method for displaced diaphyseal fractures of tibia. Selection of the correct nail insertion point is important for axial alignment of bone fragments and to avoid iatrogenic fractures. However, the standard entry point (SEP) may not always optimise the bone-nail fit due to geometric variations of bones. This study aimed to investigate the optimal entry for a given bone-nail pair using the fit quantification software tool previously developed by the authors. The misfit was quantified for 20 bones with two nail designs (ETN and ETN-Proximal Bend) related to the SEP and 5 entry points which were 5 mm and 10 mm away from the SEP. The SEP was the optimal entry point for 50% of the bones used. For the remaining bones, the optimal entry point was located 5 mm away from the SEP, which improved the overall fit by 40% on average. However, entry points 10 mm away from the SEP doubled the misfit. The optimised bone-nail fit can be achieved through the SEP and within the range of a 5 mm radius, except posteriorly. The study results suggest that the optimal entry point should be selected by considering the fit during insertion and not only at the final position.

One step closer into the design of fall protective device for individuals fitted with a bone-anchored prosthesis

The consequences of falls are often dreadful for individuals with lower limb amputation using bone-anchored prosthesis.[1-5] Typically, the impact on the fixation is responsible for bending the intercutaneous piece that could lead to a complete breakage over time. .[3, 5-8] The surgical replacement of this piece is possible but complex and expensive. Clearly, there is a need for solid data enabling an evidence-based design of protective devices limiting impact forces and torsion applied during a fall. The impact on the fixation during an actual fall is obviously difficult to record during a scientific experiment.[6, 8-13] Consequently, Schwartze and colleagues opted for one of the next best options science has to offer: simulation with an able-bodied participant. They recorded body movements and knee impacts on the floor while mimicking several plausible falling scenarios. Then, they calculated the forces and moments that would be applied at four levels along the femur corresponding to amputation heights.[6, 8-11, 14-25] The overall forces applied during the falls were similar regardless of the amputation height indicating that the impact forces were simply translated along the femur. As expected, they showed that overall moments generally increased with amputation height due to changes in lever arm. This work demonstrates that devices preventing only against force overload do not require considering amputation height while those protecting against bending moments should. Another significant contribution is to provide, for the time, the magnitude of the impact load during different falls. This loading range is crucial to the overall design and, more precisely, the triggering threshold of protective devices. Unfortunately, the analysis of only a single able-bodied participant replicating falls limits greatly the generalisation of the findings. Nonetheless, this case study is an important milestone contributing to a better understanding of load impact during a fall. This new knowledge will improve the treatment, the safe ambulation and, ultimately, the quality of life of individuals fitted with bone-anchored prosthesis.

Bone-anchored prosthesis: Evidence that “gains” overcome the “pain”

Most of socket related discomforts leading to a significant decrease in quality of life of individuals with limb amputation can be overcome by surgical techniques enabling bone-anchored prostheses. To date, the OPRA two-stage procedure (i.e., S1, S2) is the most acknowledged treatment. However, surgical implantations of osseointegrated fixations are developing at an unprecedented pace worldwide.[1-18] Clearly, this option is becoming accessible to a wide range of individuals with limb amputations. The team led by Dr Rickard Branemark has published a number of landmark articles each focusing on a particular aspect (e.g., health related quality of life, functional outcomes, bone remodelling, infection rate). [1-3, 19-32] However, evidences presented in this prospective study are remarkable. Functional outcome, health-related quality of life and complications were considered concurrently for a large population (i.e., 51 participants) over an extended period of time (i.e., up to year follow up). Therefore, the “gain” and “pain” of the whole procedure were truly contrasted for the first time. The results confirmed that OPRA surgical and rehabilitation procedures improved significantly prosthetic use, mobility, global situation and fewer problems. Furthermore, the authors reported 47 episodes of infections for 63% (32) participants between post-op S1 and two years follow up. A total of 87% (41) were superficial infections recorded for 28 participants between post-op S2 and two years follow up, while 13% (6) were deep infections occurring for 4 participants during post-op S1 and S2. As expected, post-op S2 phase was the most prone to both infections. More importantly, the vast majority of infections were effectively treated with oral antibiotics. Clearly, this study provided definitive evidence that the benefits of OPRA fixation overcome complications. This article is also establishing reporting standards and benchmark data for future studies focusing on bone-anchored prostheses.

Development of a method to assess the quality of ankle joint reduction in 3D

This project developed a quantitative method for determining the quality of the surgical alignment of the bone fragments after an ankle fracture. The research examined the feasibility of utilising MRI-based bone models versus the gold standard CT-based bone models in order to reduce the amount of ionising radiation the patient is exposed to. In doing so, the thesis reports that there is potential for MRI to be used instead of CT depending on the scanning parameters used to obtain the medical images, the distance of the implant relative to the joint surface, and the implant material.

Rehabilitation of individuals with bone-anchored prosthesis: State-of-the-art and challenges

Individuals with limb amputation fitted with conventional socket-suspended prostheses often experience socket-related discomfort leading to a significant decrease in quality of life. Bone-anchored prostheses are increasingly acknowledged as viable alternative method of attachment of artificial limb. In this case, the prosthesis is attached directly to the residual skeleton through a percutaneous fixation. To date, a few osseointegration fixations are commercially available. Several devices are at different stages of development particularly in Europe and the US.[1-15] Clearly, surgical procedures are currently blooming worldwide. Indeed, Australia and Queensland in particular have one of the fastest growing populations. Previous studies involving either screw-type implants or press-fit fixations for bone-anchorage have focused on fragmented biomechanics aspects as well as the clinical benefits and safety of the procedure. However, very few publications have synthetized this information and provided an overview of the current developments in bone-anchored prostheses worldwide, let alone in Australia. The purposes of the presentation will be: 1. To provide an overview of the state-of-art developments in bone-anchored prostheses with as strong emphasis on the design of fixations, treatment, benefits, risks as well as future opportunities and challenges, 2. To present the current international developments of procedures for bone-anchored prostheses in terms of numbers of centers, number of cases and typical case-mix, 3. To highlight the current role Australia is playing as a leader worldwide in terms of growing population, broadest range of case-mix, choices of fixations, development of reimbursement schemes, unique clinical outcome registry for evidence-based practice, cutting-edge research, consumer demand and general public interest.

Cost-effectiveness of bone-anchored prosthesis: the Queensland experience

Individuals with limb amputation fitted with conventional socket-suspended prostheses often experience socket-related discomfort leading to a significant decrease in quality of life. Bone-anchored prostheses are increasingly acknowledged as viable alternative method of attachment of artificial limb. In this case, the prosthesis is attached directly to the residual skeleton through a percutaneous fixation. To date, a few osseointegration fixations are commercially available. Several devices are at different stages of development particularly in Europe and the US. [1-15] Clearly, surgical procedures are currently blooming worldwide. Indeed, Australia and Queensland, in particular, have one of the fastest growing populations. Previous studies involving either screw-type implants or press-fit fixations for bone-anchorage have focused on biomechanics aspects as well as the clinical benefits and safety of the procedure. In principle, bone-anchored prostheses should eliminate lifetime expenses associated with sockets and, consequently, potentially alleviate the financial burden of amputation for governmental organizations. Unfortunately, publications focusing on cost-effectiveness are sparse. In fact, only one study published by Haggstrom et al (2012), reported that “despite significantly fewer visits for prosthetic service the annual mean costs for osseointegrated prostheses were comparable with socket-suspended prostheses”. Consequently, governmental organizations such as Queensland Artificial Limb Services (QALS) are facing a number of challenges while adjusting financial assistance schemes that should be fair and equitable to their clients fitted with bone-anchored prostheses. Clearly, more scientific evidence extracted from governmental databases is needed to further consolidate the analyses of financial burden associated with both methods of attachment (i.e., conventional sockets prostheses, bone-anchored prostheses). The purpose of the presentation will be to share the current outcomes of a cost-analysis study lead by QALS. The specific objectives will be: • To outline methodological avenues to assess the cost-effectiveness of bone-anchored prostheses compared to conventional sockets prostheses, • To highlight the potential obstacles and limitations in cost-effectiveness analyses of bone-anchored prostheses, • To present cohort results of a cost-effectiveness (QALY vs cost) including the determination of fair Incremental cost-effectiveness Ratios (ICER) as well as cost-benefit analysis focusing on the comparing costs and key outcome indicators (e.g., QTFA, TUG, 6MWT, activities of daily living) over QALS funding cycles for both methods of attachment.

Transcutaneous bone-anchoring prosthesis with knee replacement: A novel treatment for amputees

Background Over the last two decades, Transcutaneous Bone-Anchored Prosthesis (TCBAP) has proven to be an effective alternative for prosthetic attachment for amputees, particularly for individuals unable to wear a socket. [1-17] However, the load transmitted through a typical TCBAP to the residual tibia and knee joint can be unbearable for transtibial amputees with knee arthritis. Aim A. To describe the surgical procedure combining TKR with TCBAP for the first time; and B. To present preliminary data on potential risks and benefits with assessment of clinical and functional outcomes at follow up Method We used a TCBAP connected to the tibial base plate of a Total Knee Replacement (TKR) prosthesis enabling the tibial residuum and the knee joint to act as weight sharing structures by transferring the load directly to the femur. We performed a standard hinged TKR connected to a custom made TCBAP at the first stage followed by creating a skin implant interface as a second stage. We retrospectively reviewed four cases of trans-tibial amputations presenting with knee joint arthritis. Patients were assessed clinically and functionally including standard measures of health-related quality of life, amputee mobility predictor tool, ambulation tests and actual activity level. Progress was monitored for 6-24 months. Results Clinical outcomes including adverse events show no major complications but one case of superficial infection. Functional outcomes improved for all participants as early as 6 months follow up. Discussion & Conclusion TKR and TCBAP were combined for the first time in this proof-of-concept case series. The preliminary outcomes indicated that this procedure is potentially a safe and effective alternative for this patient group despite the theoretical increase in risk of ascending infection through the skin-implant interface to the external environment. We suggest larger comparative series to further validate these results.

Transcutaneous bone-anchoring prosthesis with hip replacement: A novel treatment for amputees

Background Over the last two decades, Transcutaneous Bone-Anchored Prosthesis (TCBAP) has proven to be an effective alternative for prosthetic attachment for above knee amputees, particularly for individuals suffering from socket interface related complications. [1-17] Amputees with a very short femoral residuum (<15 cm) are at a considerable higher risk for these complications as well as high risk of implant failure, if they underwent a typical TCBAP due to the relatively small bony-implant contact leading to a need of a novel technique. Aim A. To describe the surgical procedure combining THR with TCBAP for the first time; and B. To present preliminary data on potential risks and benefits with assessment of clinical and functional outcomes at follow up Method We used a TCBAP connected to the stem of a Total Hip Replacement (THR) prosthesis enabling the femoral residuum and the hip joint to act as weight sharing structures by transferring the load directly to the pelvis. We performed a tri-polar THR connected to a custom made TCBAP at the first stage followed by creating a skin implant interface as a second stage. We retrospectively reviewed three cases of transfemoral amputations presenting with extremely short femoral residuum. Patients were assessed clinically and functionally including standard measures of health-related quality of life, amputee mobility predictor tool, ambulation tests and actual activity level. Progress was monitored for 6-24 months. Results Clinical outcomes including adverse events show no major complications. Functional outcomes improved for all participants as early as 6 months follow up. All cases were wheelchair bound preoperatively (K0 – AMPRO) improved to walking with One stick (K3 – AMPRO) at 3 months follow up. Discussion & Conclusion THR and TCBAP were combined for the first time in this proof-of-concept case series. The preliminary outcomes indicated that this procedure is potentially a safe and effective alternative despite the theoretical increase in risk of ascending infection through the skin-implant interface to the external environment for this patient group. We suggest larger comparative series to further validate these results.

Bone-anchored prosthesis: Current developments worldwide and challenges

Background Individuals with limb amputation fitted with conventional socket-suspended prostheses often experience socket related discomfort leading to a significant decrease in quality of life. Most of these concerns can be overcome by surgical techniques enabling bone-anchored prostheses. In this case, the prosthesis is attached directly to the residual skeleton through a percutaneous implant (e.g., screw type fixation, press-fit implant).[46, 48, 51, 52, 77, 78] The aim of this study is to present the current advances in these surgical techniques worldwide with a strong focus on the current challenges. Methods The current advances will be extracted from a systematic literature review including approximately 40 articles. The outcomes measured will include the estimation of the population worldwide as well as the complications (e.g., infection, loosening, fractures, and breakage) and the benefits (e.g., functional outcomes, health-related quality of life).[5-19, 51-53, 55, 57, 58, 62, 73, 79] Results The population of individuals fitted with a bone-anchored prosthesis is approximately 550 worldwide. Publications focusing on infection are sparse. However, the rate of superficial infection is estimated at 20%. Deep infection occurs rarely. Loosening and peri-prosthetic fractures are fairly uncommon. Breakage of implant parts occurs regularly mainly due to fall. All studies reported a significant improvement in functional level and overall quality of life. Conclusions Several commercial implants are in developments in Europe and US. The number of procedures is consistently growing worldwide. This technique might be primary way to fit a prosthesis to young and active amputees by 2025.

Bone-anchored prosthesis: Current developments worldwide and challenges

Background Individuals with limb amputation fitted with conventional socket-suspended prostheses often experience socket related discomfort leading to a significant decrease in quality of life. Most of these concerns can be overcome by surgical techniques enabling bone-anchored prostheses. In this case, the prosthesis is attached directly to the residual skeleton through a percutaneous implant (e.g., screw type fixation, press-fit implant).[46, 48, 51, 52, 77, 78] The aim of this study is to present the current advances in these surgical techniques worldwide with a strong focus on the current challenges. Methods The current advances will be extracted from a systematic literature review including approximately 40 articles. The outcomes measured will include the estimation of the population worldwide as well as the complications (e.g., infection, loosening, fractures, and breakage) and the benefits (e.g., functional outcomes, health-related quality of life).[5-19, 51-53, 55, 57, 58, 62, 73, 79] Results The population of individuals fitted with a bone-anchored prosthesis is approximately 550 worldwide. Publications focusing on infection are sparse. However, the rate of superficial infection is estimated at 20%. Deep infection occurs rarely. Loosening and peri-prosthetic fractures are fairly uncommon. Breakage of implant parts occurs regularly mainly due to fall. All studies reported a significant improvement in functional level and overall quality of life. Conclusions Several commercial implants are in developments in Europe and US. The number of procedures is consistently growing worldwide. This technique might be primary way to fit a prosthesis to young and active amputees by 2025.

Cost effectiveness of bone density measurements

Objective. To assess the cost-effectiveness of bone density screening programmes for osteoporosis. Study design. Using published and locally available data regarding fracture rates and treatment costs, the overall costs per fracture prevented, cost per quality of life year (QALY) saved and cost per year of life gained were estimated for different bone density screening and osteoporosis treatment programmes. Main outcome measures. Cost per fracture prevented, cost per QALY saved, and cost per year of life gained. Results. In women over the age of 50 years, the costs per fracture prevented of treating all women with hormone replacement therapy, or treating only if osteoporosis is demonstrated on bone density screening were £32,594 or £23,867 respectively. For alendronate therapy for the same groups, the costs were £171,067 and £14,067 respectively. Once the background rate of treatment with alendronate reaches 18%, bone density screening becomes cost-saving. Costs estimates per QALY saved ranged from £1,514 to £39,076 for osteoporosis treatment with alendronate following bone density screening. Conclusions. For relatively expensive medications such as alendronate, treatment programmes with prior bone density screening are far more cost effective than those without, and in some circumstances become cost-saving. Costs per QALY of life saved and per year of life gained for osteoporosis treatment with prior bone density screening compare favourably with treatment of hypertension and hypercholesterolemia.

Exercise improves quality of life in ADT-treated prostate cancer: Systematic review of RCTs

Men receiving androgen deprivation therapy (ADT) for prostate cancer (PCa) are likely to develop metabolic conditions such as diabetes, cardiovascular disease, abdominal obesity and osteoporosis. Other treatment-related side effects adversely influence quality of life (QoL) including vasomotor distress, depression, anxiety, mood swings, poor sleep quality and compromised sexual function. The objective of this study was to systematically review the nature and effects of dietary and exercise interventions on QoL, androgen deprivation symptoms and metabolic risk factors in men with PCa undergoing ADT. An electronic search of CINAHL, CENTRAL, Medline, PsychINFO and reference lists was performed to identify peer-reviewed articles published between January 2004 and December, 2014 in English. Eligible study designs included randomised controlled trials with pre- and post-intervention data. Data extraction and assessment of methodological quality with the Cochrane approach was conducted by two independent reviewers. Seven exercise studies were identified. Exercise significantly improved QoL, but showed no effect on metabolic risk factors (weight, waist circumference, lean or fat mass, blood pressure, lipid profile). Two dietary studies were identified, both of which tested soy supplements. Soy supplementation did not improve any outcomes. No dietary counselling studies were identified. No studies evaluated androgen-deficiency symptoms (libido, erectile function, sleep quality, mood swings, depression, anxiety, bone mineral density). Evidence from RCTs indicates that exercise enhances health- and disease-specific QoL in men with PCa undergoing ADT. Further studies are required to evaluate the effect of exercise and dietary interventions on QoL, androgen deprivation symptoms and metabolic risk factors in this cohort.

The development of a component to improve the loading safety of bone-anchored prostheses

Use of socket prostheses Currently, for individuals with limb loss, the conventional method of attaching a prosthetic limb relies on a socket that fits over the residual limb. However, there are a number of issues concerning the use of a socket (e.g., blisters, irritation, and discomfort) that result in dissatisfaction with socket prostheses, and these lead ultimately a significant decrease in quality of life. Bone-anchored prosthesis Alternatively, the concept of attaching artificial limbs directly to the skeletal system has been developed (bone anchored prostheses), as it alleviates many of the issues surrounding the conventional socket interface.Bone anchored prostheses rely on two critical components: the implant, and the percutaneous abutment or adapter, which forms the connection for the external prosthetic system (Figure 1). To date, an implant that screws into the long bone of the residual limb has been the most common intervention. However, more recently, press-fit implants have been introduced and their use is increasing. Several other devices are currently at various stages of development, particularly in Europe and the United States. Benefits of bone-anchored prostheses Several key studies have demonstrated that bone-anchored prostheses have major clinical benefits when compared to socket prostheses (e.g., quality of life, prosthetic use, body image, hip range of motion, sitting comfort, ease of donning and doffing, osseoperception (proprioception), walking ability) and acceptable safety, in terms of implant stability and infection. Additionally, this method of attachment allows amputees to participate in a wide range of daily activities for a substantially longer duration. Overall, the system has demonstrated a significant enhancement to quality of life. Challenges of direct skeletal attachment However, due to the direct skeletal attachment, serious injury and damage can occur through excessive loading events such as during a fall (e.g., component damage, peri-prosthetic fracture, hip dislocation, and femoral head fracture). These incidents are costly (e.g., replacement of components) and could require further surgical interventions. Currently, these risks are limiting the acceptance of bone-anchored technology and the substantial improvement to quality of life that this treatment offers. An in-depth investigation into these risks highlighted a clear need to re-design and improve the componentry in the system (Figure 2), to improve the overall safety during excessive loading events. Aim and purposes The ultimate aim of this doctoral research is to improve the loading safety of bone-anchored prostheses, to reduce the incidence of injury and damage through the design of load restricting components, enabling individuals fitted with the system to partake in everyday activities, with increased security and self-assurance. The safety component will be designed to release or ‘fail’ external to the limb, in a way that protects the internal bone-implant interface, thus removing the need for restorative surgery and potential damage to the bone. This requires detailed knowledge of the loads typically experienced by the limb and an understanding of potential overload situations that might occur. Hence, a comprehensive review of the loading literature surrounding bone anchored prostheses will be conducted as part of this project, with the potential for additional experimental studies of the loads during normal activities to fill in gaps in the literature. This information will be pivotal in determining the specifications for the properties of the safety component, and the bone-implant system. The project will follow the Stanford Biodesign process for the development of the safety component.