Local alendronate increases fixation of implants inserted with bone compaction: 12-week canine study.

Bone compaction has been shown to increase initial implant fixation. Furthermore, bone compaction creates a peri-implant zone of autograft that exerts osteoconductive properties. We have previously shown that locally applied bisphosphonate (alendronate) at 4-week observation can preserve the autograft generated by bone compaction. We now investigate whether the increased amount of autograft, seen at 4 weeks, can increase implant osseointegration and biomechanical fixation. Porous-coated titanium implants were bilaterally inserted with bone compaction into the proximal part of tibia of 10 dogs. On the right side, local bisphosphonate was injected into the bone cavity prior to bone compaction immediately prior to implant insertion. On the left side, saline was used as control. Observation period was 12 weeks. Locally applied bisphosphonate significantly increased biomechanical implant fixation (approximately twofold), bone-to-implant contact (1.2-fold), and peri-implant bone volume fraction (2.3-fold). This study indicates that local alendronate treatment can increase early implant osseointegration and biomechanical fixation of implants inserted by use of bone compaction. Long term effects remain unknown.     

Local bisphosphonate treatment increases fixation of hydroxyapatite‐coated implants inserted with bone compaction

It has been shown that fixation of primary cementless joint replacement can independently be enhanced by either: (1) use of hydroxyapatite (HA) coated implants, (2) compaction of the peri‐implant bone, or (3) local application of bisphosphonate. We investigated whether the combined effect of HA coating and bone compaction can be further enhanced with the use of local bisphosphonate treatment. HA‐coated implants were bilaterally inserted into the proximal tibiae of 10 dogs. On one side local bisphosphonate was applied prior to bone compaction. Saline was used as control on the contralateral side. Implants were evaluated with histomorphometry and biomechanical push‐out test. We found that bisphosphonate increased the peri‐implant bone volume fraction (1.3‐fold), maximum shear strength (2.1‐fold), and maximum shear stiffness (2.7‐fold). No significant difference was found in bone‐to‐implant contact or total energy absorption. This study indicates that local alendronate treatment can further improve the fixation of porous‐coated implants that have also undergone HA‐surface coating and peri‐implant bone compaction. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:189–194, 2009     

Osseointegration: the slow delivery of BMP-2 enhances osteoinductivity

Although the placement of dental and orthopedic implants is now generally a safe, reliable and successful undertaking, the functional outcome is less assured in patients whose bone-healing capacity is compromised. To enhance peri-implant osteogenesis in these individuals, BMP-2 could be locally administered. However, neither a free suspension nor an implant-adsorbed depot of the agent is capable of triggering sustained bone formation. We hypothesize that this end could be achieved by incorporating BMP-2 into the three-dimensional crystalline latticework of a bone-mineral like, calcium-phosphate implant coating, where from it would be liberated gradually - as the inorganic layer undergoes osteoclast-mediated degradation - not rapidly, as from an implant-adsorbed (two-dimensional) depot. To test this postulate, we compared the osteoinductive efficacies of implant coatings bearing either an incorporated, an adorbed, or an incorporated and an adsorbed depot of BMP-2 at a maxillary site in miniature pigs. The implants were retrieved 1, 2 and 3 weeks after surgery for the histomorphometric analysis of bone formation within a defined 'osteoinductive' space. At each juncture, the volume of newly-formed bone within the osteoinductive space was greatest around implants that bore a coating-incorporated depot of BMP-2, peak osteogenic activity being attained during the first week and sustained thereafter. In the other groups, the temporal course of bone formation was variable, and the peak levels were not sustained. The findings of this study confirm our hypothesis: they demonstrate that we now have at our disposal a means of efficaciously augmenting and expediting peri-implant bone formation. Clinically, this possibility would render the process of implant placement a safer and a more reliable undertaking in patients whose bone-healing capacity is compromised, and would also permit a curtailment of the postoperative recovery period by a forestallment of the mechanical-loading phase.     

Toxic acute tubular necrosis following treatment with zoledronate (Zometa)

BACKGROUND: Renal failure and toxic acute tubular necrosis (ATN) may be seen following exposure to a variety of therapeutic agents. Zoledronate (Zometa) is a new, highly potent bisphosphonate used in the treatment of hypercalcemia of malignancy. We report the first clinical-pathologic study of nephrotoxicity associated with this agent. METHODS: A cohort of six patients (four males and two females) with a mean age of 69.2 years received bisphosphonate therapy for multiple myeloma (five patients) or Paget's disease (one patient). In all patients, zoledronate was administered at a dose of 4 mg intravenously monthly, infused over at least 15 minutes, and the duration of therapy was mean 4.7 months (range, 3 to 9 months). RESULTS: All patients developed renal failure with a rise in serum creatinine from a mean baseline level of 1.4 mg/dL to 3.4 mg/dL. Renal biopsy revealed toxic ATN, characterized by tubular cell degeneration, loss of brush border, and apoptosis. Immunohistochemical staining revealed a marked increase in cell cycle-engaged cells (Ki-67 positive) and derangement in tubular Na+,K+-ATPase expression. Importantly, although all patients had been treated with pamidronate prior to zoledronate, no biopsy exhibited the characteristic pattern of collapsing focal segmental glomerulosclerosis observed in pamidronate nephrotoxicity. Following renal biopsy, treatment with zoledronate was discontinued and all six patients had a subsequent improvement in renal function (mean final serum creatinine, 2.3 mg/dL at 1 to 4 months of follow-up). CONCLUSION: The close temporal relationship between zoledronate administration and the onset of renal failure and the partial recovery of renal function following drug withdrawal strongly implicate this important and widely used agent in the development of toxic ATN.     

Bone Mass Gains After One Denosumab Injection Followed by Zoledronate

Denosumab discontinuation can lead to bone loss despite subsequent bisphosphonate therapy. This bone loss is more severe in patients treated with denosumab for longer than 3 years. We aimed to evaluate the bone mass changes after only a single denosumab injection followed by zoledronate administration. We screened all of our patients who received a single denosumab injection and who were included in the osteoporosis register from the Swiss Society of Rheumatology between August 1, 2010, and January 31, 2022. This case series assessed the outcome of patients who were consecutively treated with one denosumab injection followed by a single infusion of zoledronate 6 months later. Bone mineral density (BMD) and bone turnover markers (BTM) changes were analysed before therapy and 18 months later. Percentage BMD changes and T-scores were compared with those of registered patients who received 2.5 years of denosumab treatment and one subsequent infusion of zoledronate. Thirty-two patients (31 female, 1 male) received a single denosumab injection and one zoledronate infusion 6 months later. BTM decreased significantly in this period (p = 0.035). Percentage BMD changes from baseline to 1 year after zoledronate treatment were 7.6% [IQR 3.2, 9.4] at the lumbar spine, 3.5% [1.8, 5.9] at the total hip and 4.6% [1.3, 6.0] at the femoral neck. In contrast, percentage changes from baseline in 110 patients with 2.5 years of denosumab treatment and one zoledronate infusion were 5.6% [3.0, 9.1], 2.3% [0.2, 4.9] and 2.3% [?0.9, 4.7], respectively. Differences between the 2 groups were significant at the lumbar spine (p = 0.014), total hip (p = 0.010) and femoral neck (p = 0.010).A single denosumab injection followed by zoledronate led to a remarkable gain of BMD at the lumbar spine and hip within a short time. This observation could help to identify a new short treatment sequence for patients with osteoporosis.     

Persistence with intravenous zoledronate in elderly patients with osteoporosis

Summary

The present study evaluates the proportion of patients who had re-infusion of intravenous zoledronate after first administration and identifies the factors that contribute to discontinuation.

Introduction

In terms of persistence, annual administration of zoledronate seems to overcome a shortcoming of oral bisphosphonate. However, little information is available concerning persistence with intravenous zoledronate for osteoporosis in a usual care setting. The aim of this study was to assess the persistence of intravenous zoledronate after first administration and to identify the factors that contribute to its discontinuation.

Methods

A questionnaire survey concerning the second administration of zoledronate was performed on 259 patients, who had been administered with first intravenous zoledronate injection between January 2009 and December 2009, when they visit for second injection. The questionnaire asked whether patients were administered a second zoledronate injection or not, and non-persistent patients were asked why they declined the second infusion.

Results

One hundred and ninety-two patients revisited our outpatient clinic a year after first visit, and 94 patients (36.3%, 94/259) agreed to a second injection. Of the 136 patients that completed the questionnaire, 47 refused second administration and requested a change to oral bisphosphonate. Thirty-nine of the 47 patients (83%) stated that post-infusion syndrome was the reason why they refused the second administration.

Conclusion

Although the effects of annual intravenous zoledronate are guaranteed to last for a year, this study shows that only a third of patients agree to second administration. The factors associated with discontinuation were male gender, adverse effects (especially post-infusion syndrome) and under-explanation of intravenous drug. These findings should be of concern to clinicians and indicate that patients should be informed before the administration.     

Local delivery of zoledronate from a poly (D,L‐lactide)—Coating increases fixation of press‐fit implants

Early secure fixation of total joint replacements is crucial for long‐term survival. Antiresorptive agents such as bisphosphonates have been shown to increase implant fixation. We investigated whether local delivery of zoledronate from poly‐D, L‐lactide (PDLLA)‐coated implants could improve implant fixation and osseointegration. Experimental titanium implants were bilaterally inserted press‐fit into the proximal tibiae of 10 dogs. On one side the implant was coated with PDLLA containing zoledronate. The contralateral implant was uncoated and used as control. Observation period was 12 weeks. Implant fixation was evaluated with histomorphometry and biomechanical push‐out test. We found an approximately twofold increase in all biomechanical parameters when comparing data from the zoledronate group with their respective controls. Histomorphometry showed increased amount of preserved bone and increased bone formation around the zoledronate implants. This study indicates that local delivery of zoledronate from a PDDLA coating has the potential to increase implant fixation. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:65–71, 2016.     

Local delivery of zoledronate from a poly (d,l‐lactide)‐coating increases fixation of hydroxy‐coated implants

Initial secure implant fixation predicts long‐term survival. Bisphosphonates are anti‐resorptive agents. They have been shown to increase implant fixation. We investigated whether local delivery of zoledronate from a poly‐d ,l ‐lactide (PDLLA)‐coating could improve fixation and osseointegration of hydroxy‐apatite coated implants. Cylindrical hydroxy‐apatite coated implants were bilaterally inserted press‐fit into the proximal tibiae of 10 dogs. On one side the implant was coated with PDLLA containing zoledronate. The PDLLA coating was applied upon the hydroxy‐apatite coating. We used the contralateral implant as control. This implant was not coated with a poly‐d ,l ‐lactide. Observation period was 12 weeks. We evaluated implant fixation with histomorphometry and biomechanical push‐out test. Zoledronate resulted in an approximately threefold increase in all biomechanical parameters when comparing data with their respective controls. We found that zoledronate increased preservation of old lamellar bone and increased formation of new woven bone. This study indicates that local delivery of zoledronate from a PDDLA coating has the potential to increase implant fixation. Studies investigating different doses of zoledronate and longer follow‐up are needed. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:974–979, 2017.

     

The bisphosphonate zoledronate decreases type II collagen breakdown in patients with Paget's disease of bone

Bisphosphonates have been suggested to be partially chondroprotective in animal models of arthritis. The aim of this study was to assess the short-term effect of the bisphosphonate zoledronate on type II collagen degradation in patients with Paget's disease of bone. Twenty-six patients with active Paget's disease who were a part of a double-blind, placebo-controlled, randomized study comparing the effects of several doses of a single injection of zoledronate, a potent bisphosphonate, were studied. Type II collagen destruction was assessed by urinary levels of type II collagen C-telopeptide (CTX-II) using a new immunoassay. Bone resorption was assessed by measuring the urinary excretion of nonisomerized type I collagen C-telopeptide (alpha CTX-I). Biochemical markers were measured at baseline and 5, 10, 30, and 60 days after injection. At baseline, no significant increase of CTX-II was observed in patients with Paget's disease compared with a group of 27 gender-and age-matched controls, in contrast to the ninefold (p < 0.0001) increase of urinary alpha CTX-I. After a single intravenous injection of zoledronate (200 or 400 microg), urinary CTX-II transiently decreased by a median of 25% 5 days after the injection of zoledronate (p = 0.0023 vs. placebo), then increased to pretreatment levels after 10 days. In contrast, urinary alpha CTX-I decreased within 5 days with a maximal decrease of 51% at day 10 (p < 0.001 vs. baseline and placebo), and levels remained suppressed during the 2 months of the study. Zoledronate not only reduces bone turnover but also directly decreases type II collagen degradation in patients with Paget's disease, suggesting that bisphosphonates may have chondroprotective effects in humans. Measurement of type II collagen breakdown by a new urinary biochemical marker may be useful for in vivo assessment of the effects of drugs that potentially inhibit cartilage destruction.     

Expression of interleukin 1-beta, transforming growth factor beta-1, and vascular endothelial growth factor in soft tissue over the implant before uncovering.

BACKGROUND: Overexpression of inflammatory cytokines interleukin 1-beta (IL-1beta), transforming growth factor beta-1 (TGF-beta1), and vascular endothelial growth factor (VEGF) may cause healing impairment following implant insertion, jeopardizing success especially in patients previously irradiated. Limited data is available regarding expression pattern of inflammatory cytokines in peri-implant soft tissue caused by the surgical intervention itself. STUDY DESIGN: This study examined 21 patients receiving dental implants. Biopsies of peri-implant tissue were harvested at re-entry 4 months after initial surgery. Eight patients underwent probing of untreated mucosa. Three groups were created (group 1: regular peri-implant mucosa; group 2: patients with irradiated peri-implant mucosa, radiation treatment due to oral squamous cell cancer; group 3: control). Immunohistochemical staining was performed for TGFss1, IL-1ss, and VEGF. RESULTS: Following the placement of dental implants (group 1 vs group 3) a significant increase (P > .05) in TGF-beta1, IL-1beta, and VEGF expression in the peri-implant mucosa was demonstrated. No alteration of this distinct pattern was found for previously irradiated tissue (group 1 vs. group 2). CONCLUSIONS: The study highlights the fundamental involvement of TGF-beta1, IL-1beta, and VEGF during the regeneration of peri-implant soft tissue structures. The use of extended interim solutions may be one clinical implication of these prolonged tissue remodeling processes.     

Outcomes of placing dental implants in patients taking oral bisphosphonates: a review of 115 cases.

PURPOSE: In recent years, numerous cases of bisphosphonate-associated osteonecrosis of the jaw have been reported involving both intravenous and oral therapy regimens. The majority of these cases have involved intravenous bisphosphonates. Subsequently, drug manufacturers and the US Food and Drug Administration issued warnings about possible bisphosphonate-associated osteonecrosis of the jaw. The American Dental Association and the American Association of Oral and Maxillofacial Surgeons assembled expert panels to formulate treatment guidelines. Both panels differentiated between patients receiving bisphosphonates intravenously and those receiving the drugs orally. However, the recommendations were based on limited data, especially with regard to patients taking oral bisphosphonates. We wanted to ascertain the extent to which bisphosphonate-associated necrosis of the jaw has occurred in our dental implant patients. We also wanted to determine whether there was any indication that the bisphosphonate therapy affected the overall success of the implants as defined by Albrektsson and Zarb. PATIENTS AND METHODS: We identified 1,319 female patients over the age of 40 who had received dental implants at Montefiore Medical Center between January 1998 and December 2006. A survey about bisphosphonate therapy was mailed to all 1,319 patients. Responses were received from 458 patients of whom 115 reported that they had taken oral bisphosphonates. None had received intravenous bisphosphonates. All 115 patients were contacted and informed about the risk of bisphosphonate-associated osteonecrosis of the jaw. Seventy-two patients returned to the clinic for follow-up clinical and radiological evaluation. RESULTS: A total of 468 implants were placed in the 115 patients who reported that they had received oral bisphosphonate therapy. There is no evidence of bisphosphonate-associated osteonecrosis of the jaw in any of the patients evaluated in the clinic and those contacted by phone or e-mail reported no symptoms. Of the 468 implants, all but 2 integrated fully and meet criteria for establishing implant success. Implant success rates were comparable for patients receiving oral bisphosphonate therapy and those not receiving oral bisphosphonate therapy. CONCLUSIONS: Guidelines for treatment of dental patients receiving intravenous bisphosphonate treatments should be different than for patients taking the oral formulations of these medications. In this study, oral bisphosphonate therapy did not appear to significantly affect implant success. Implant surgery on patients receiving bisphosphonate therapy did not result in bisphosphonate-associated osteonecrosis of the jaw. Nevertheless, sufficient evidence exists to suggest that all patients undergoing implant placement should be questioned about bisphosphonate therapy including the drug taken, the dosage, and length of treatment prior to surgery. For patients having a history of oral bisphosphonate treatment exceeding 3 years and those having concomitant treatment with prednisone, additional testing and alternate treatment options should be considered.     

A Single Infusion of Zoledronate in Postmenopausal Women Following Denosumab Discontinuation Results in Partial Conservation of Bone Mass Gains

Discontinuation of denosumab is associated with a rapid return of bone mineral density (BMD) to baseline and an increased risk of multiple vertebral fractures. No subsequent treatment regimen has yet been established for preventing either loss of BMD or multiple vertebral fractures after denosumab discontinuation. The aim of this 8-year observational study was to investigate the effect of a single zoledronate infusion, administered 6 months after the last denosumab injection, on fracture occurrence and loss of BMD. We report on 120 women with postmenopausal osteoporosis who were treated with 60 mg denosumab every 6 months for 2 to 5 years (mean duration 3 years) and then 5 mg zoledronate 6 months after the last denosumab injection. All patients were evaluated clinically, by dual-energy X-ray absorptiometry (DXA) and vertebral fracture assessment (VFA), before the first and after the last denosumab injection and at 2.5 years (median) after denosumab discontinuation. During this off-treatment period, 3 vertebral fractures (1.1 per 100 patient-years) and 4 nonvertebral fractures (1.5 per 100 patient-years) occurred. No patients developed multiple vertebral fractures. Sixty-six percent (confidence interval [CI] 57% to 75%) of BMD gained with denosumab was retained at the lumbar spine and 49% (CI 31% to 67%) at the total hip. There was no significant difference in the decrease of BMD between patients with BMD gains of >9% versus <9% while treated with denosumab. Previous antiresorptive treatment or prevalent fractures had no impact on the decrease of BMD, and all bone loss occurred within the first 18 months after zoledronate infusion. In conclusion, a single infusion of 5 mg zoledronate after a 2- to 5-year denosumab treatment cycle retained more than half of the gained BMD and was not associated with multiple vertebral fractures, as reported in patients who discontinued denosumab without subsequent bisphosphonate treatment. © 2020 American Society for Bone and Mineral Research.     

A dose-finding study of zoledronate in hypercalcemic cancer patients.

Zoledronate is a new heterocyclic imidazole bisphosphonate that is the most potent bisphosphonate administered in humans because it is 100-850 times more potent than pamidronate, according to in vitro or animal models of bone resorption. We conducted an open-label, dose-finding, single-dose phase I study in tumor-induced hypercalcemia (TIH), which has been similarly used as a model to determine the active doses of other bisphosphonates. The primary objective was to determine, with a dose escalation schedule, two nontoxic dose levels of zoledronate able to induce normocalcemia in at least 80% of patients with TIH after rehydration (corrected Ca for albumin levels >/=2.75 mmol/l). Based on estimates of potency, the starting dose was 0.002 mg/kg, and further tested doses were 0. 005, 0.01, 0.02, and 0.04 mg/kg. To obtain a more precise estimate of the response rate, we treated 10 more patients at the highest of the two effective dose levels. The median infusion time of zoledronate was 30 minutes. Thirty out of the 33 treated patients were evaluable for efficacy. Thirty percent of the patients had breast cancer and 54% had metastatic bone involvement. For all groups combined, mean Ca levels at baseline was 3.0 mmol/l. The two effective dose levels were 0.02 mg/kg and 0.04 mg/kg. Five out of five patients became normocalcemic after 0.02 mg of zoledronate/kg and 14 out of 15 after 0.04 mg of zoledronate/kg. The success rate of the latter dose was thus 93% (95% confidence interval [CI] 68-100%). At this dose, the first day of normocalcemia was day 2 or 3 for all but one patient. The duration of normocalcemia for the two effective doses could be assessed in nine patients; seven patients remained normocalcemic throughout the trial (32-39 days). The fall in serum Ca was accompanied by a marked fall in fasting urinary Ca excretion. Zoledronate was well tolerated: 7 out of 33 patients developed transient hypophosphatemia, and 3 developed transient hypocalcemia. The only clinically detectable side effect was an increase in body temperature occurring in 10 (30%) patients. In summary, very low doses of zoledronate (0.02 mg/kg and 0.04 mg/kg, i. e., 1.2 mg and 2.4 mg for a 60-kg individual, respectively) administered by a short-time infusion effectively treated patients with TIH. The fall in serum Ca was rapid, and normocalcemia was often maintained for several weeks. Zoledronate was well tolerated. Future trials will determine whether prolonged treatment with this potent compound can have greater effects on the skeletal morbidity rate in patients with tumor bone disease than can be achieved with currently available bisphosphonates.     

High dosage treatment of nitrogen-containing bisphosphonate ibandronate is required for osseointegration of cementless metal implants

Background There is evidence that application of a bisphosphonate can improve fixation of cementless metal implants by enhancing the extent of osseointegration, but the required dose regimen is still under discussion. The current preclinical study was designed to determine the optimal treatment dose of the nitrogen-containing bisphosphonate ibandronate to improve osseointegration of cementless metal implants. Methods The study was conducted in 52 female Sprague-Dawley rats in which uncoated and hydroxyapatite-coated titanium implants were surgically inserted into the medullary canal of each femur. The animals were randomly assigned to receive subcutaneous treatment with ibandronate 1 μg/kg body weight (osteoporosis dose) or 25 μg/kg (tumor dose) per day or saline solution for control. Results Histomorphometric evaluation revealed a significant enhanced extent of osseointegrated implant surface in the high-dose treatment group for both implants compared to the low-dose group and the control group. No significant differences were observed between the two implants in any group. Conclusions The results of the present study indicate that improved osseointegration of hydroxyapatite-coated and uncoated titanium implants is dose-dependent and requires high-dose application of bisphosphonate ibandronate equivalent to that needed to treat patients with tumor disease. Lower doses equivalent to those for treatment of osteoporosis showed no beneficial effect.     

Assessing the dog as a model for human total hip replacement. Analysis of 38 canine cemented femoral components retrieved at post-mortem

Post-mortem retrieval of canine, cemented femoral components was analysed to assess the performance of these implants in the dog as a model for human total hip replacement (THR). Mechanical testing and radiological analysis were performed to determine the stability of the implant and the quality of the cement. Thirty-eight implants from 29 dogs were retrieved after time intervals ranging from 0.67 to 11.67 years. The incidence of aseptic loosening was 63.2%, much higher than in human patients (6% in post-mortem studies). Failure of the femoral implants began with debonding at the cement-metal interface, similar to that in implants in man. The incidence of aseptic loosening was much lower in bilateral than in unilateral implants. Significant differences were observed for three different designs of implant. While the dog remains the animal model of choice for THR, results from this study provide insight into interspecies differences in the performance of implants. For example, the performance of THR in dogs should be compared with that in young rather than in elderly human patients.     

Displaced femoral neck fracture: comparison of primary total hip replacement with secondary replacement after failed internal fixation: a 2-year follow-up of 84 patients

INTRODUCTION: Recent randomized controlled trials have shown that for the active and lucid elderly patient with a displaced femoral neck fracture, a primary total hip replacement (THR) is superior to internal fixation (IF) regarding the need for secondary surgery, hip function and health-related quality of life (HRQoL). Despite the high failure rate for IF, the method is still recommended for this patient cohort by some authors. One argument is that if IF fails, there is always the possibility of performing a secondary salvage THR. The main aim of our study was to determine whether a primary THR, as compared to a secondary THR after failed IF, gives a better outcome after 2 years. METHODS: We compared outcome for 43 patients with a primary THR to the outcome for 41 patients who were treated with a secondary THR after failed IF. All patients (mean age 80 years) were lucid and had a displaced femoral neck fracture. Hip function (Charnley score) and health-related quality of life (HRQoL, EQ5D) were assessed 2 years after the THR procedure. RESULTS: Hip function was better in the primary THR group: the mean Charnley score was 15/18 as compared to 13/18 in the secondary THR group (p < 0.001). The patients with failed IF who later underwent a secondary THR experienced a more pronounced decrease in HRQoL (EQ-5D index score) during the first year of treatment compared to patients in the primary THR group, with a difference of 0.25 in the EQ-5D index score at the 4-month follow-up (p = 0.02). INTERPRETATION: We found that a secondary THR after failed IF results in inferior hip function compared to a primary THR for a displaced femoral neck fracture in the active and lucid elderly patient. Moreover, the patients with failed IF had to undergo at least one re-operation and experienced a significant reduction in HRQoL before the salvage THR.     

Cytotoxic effect of clodronate and zoledronate on the chondrosarcoma cell lines HTB-94 and CAL-78

The wide surgical tumour resection is the only effective treatment in chondrosarcoma. However, a major problem remains the high rate of local recurrences and metastases due to the lack of adjuvant therapies. In this study the cytotoxic effect of the bisphosphonate clodronate (0.1–1000 μM) and zoledronate (0.1–1000 μM) in different concentrations on two chondrosarcoma cell lines (HTB-94 and CAL-78) has been investigated. After an incubation period of 48, 72 and 96 hours the chondrosarcoma cell viability was measured as the MTT-proliferation rate. In concentrations of >1 μm zoledronate the cell activity was reduced by up to 95% for the CAL-78 cells. Further, zoledronate has been more effective in lower concentrations than clodronate in the reduction of cell viability for both cell lines. However, clodronate showed significant cytotoxic effects in high concentrations and after longer incubation periods. Further research is necessary, but in the light of these results bisphosphonates may also play a role in the treatment of chondrosarcomas.     

Jaw avascular osteonecrosis after treatment of multiple myeloma with zoledronate.

PURPOSE: Multiple myeloma, the second most common haematopoietic cancer, which represents the collection of plasma-cell neoplasms that invariably becomes fatal when self-renewing myeloma cells begin unrestrained proliferation. The major clinical manifestation of multiple myeloma is related to the loss of bone through osteolysis. This can lead to pathologic fractures, spinal cord compression, hypercalcaemia, and pain. It is also a major cause of morbidity and mortality in these patients, who frequently require radiation therapy, surgery and analgesic medications. Bisphosphonates are specific inhibitors of osteoclastic activity, and are currently used to prevent bone complications and to treat malignant hypercalcaemia in patients with multiple myeloma, or bone metastases from breast and prostate cancers. Hence, osteonecrosis of the mandible has been reported in three patients from Centro Hospitalar de Vila Nova de Gaia (CHVNG) with multiple myeloma treated for over 18-48 months with intravenous zoledronate, commonly prescribed for multiple myeloma therapy. Although, this report alerts clinicians about the potential complication of bone necrosis in patients receiving bisphosphonate therapy, many questions remain concerning the underlying pathogenesis of this process. PATIENTS AND METHODS: The medical and dental records of three patients with multiple myeloma, who were treated in CHVNG in the past 4 years, were reviewed. These three patients presented exposed bone and osteonecrosis of the mandible, and shared one common clinical feature: all of them were treated with bisphosphonate zoledronate, administered intravenously for long periods. Sequential orthopantomograms (OPGs) and histological evaluation have been analysed from the biopsies of the non healing dental extraction sites of these patients. RESULTS: After a routine dental extraction, these patients developed avascular osteonecrosis of the mandible and secondary bone infection with Actinomyces israelii (actinomycotic osteomyelitis), with no evidence of metastatic disease evaluated by biopsy. In these three described clinical cases, surgical debridment without flap elevation, intensive antibiotherapy and the suspension of the zoledronate treatment allowed a partial recovery of the patients. The purpose of this clinical report is to point out that patients suffering from multiple myeloma can develop bone osteonecrosis induced by treatment with bisphosphonates. Research to determine the mechanism of this dental phenomenon is needed to fully validate and substantiate the possible link between bisphosphonate treatment of multiple myeloma or other cancer diseases and avascular osteonecrosis of the jaws. Until then, clinicians involved in the care of patients at risk should consider this possible complication.     

Prevention of strain‐related osteopenia in aseptic loosening of hip prostheses using perioperative bisphosphonate

The hypothesis tested in this study was that perioperative administration of the bisphosphonate zoledronate will reduce strain protection‐related calcar osteopenia and maintain functional integration of the femoral component in an ovine hemiarthroplasty model. Twelve sheep received a unilateral cemented hemiarthroplasty where six animals were given nine intravenous infusions of zoledronate (10 µg/kg) pre‐, peri‐, and postsurgery over 8 months. Control animals received physiological saline only. Implants remained in vivo for 9 months. Ground reaction force (GRF) was used to assess functional loading of the implanted limb, bone mineral density (BMD) was quantified using dual energy X‐ray absorptiometry (DEXA). Cortical bone area, thickness, and viable osteocytes were assessed histologically. No significant differences in GRF data between groups was identified. Results demonstrated a significant drop in BMD values in the control group (9.7%) when compared with the bisphosphonate‐treated group (3.2%) (p = 0.0159). Histological results showed that cortical area, thickness, and the percentage of lacunae with viable osteocytes was significantly greater in the bisphosphonate‐treated group when compared with control (p = 0.002, p = 0.001, p = 0.003, respectively). The administration of zoledronate reduced cortical osteopenia in the calcar region of the proximal femur and this therapy could be used as a preventive measure to combat strain protection osteopenia and its contribution to associated aseptic loosening in total hip replacement surgery. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:693–703, 2008     

Total hip replacement in younger patientsSurvival rate after avascular necrosis of the femoral head

Background?A high risk of loosening has been reported in replacements performed because of avascular necrosis.Patients and methods?To study cementless total hip replacement (THR) in younger patients with avascular necrosis (AVN), we analyzed retrospectively the outcome in 129 cases: 46 Mittelmeier monobloc ceramic hips (22 cases with AVN), and 83 Zweymüller total hip systems (35 cases with AVN) clinically and radiographically.Results?At follow-up, 17 Mittelmeier prostheses (10 AVN) and 4 Zweymüller prostheses (none with AVN) had been revised. The diagnosis did not affect the implant survival, but the Zweymüller THR fared better than the Mittelmeier system. The main reason for revision of Mittelmeier implants was aseptic loosening, 3 of 4 Zweymüller revisions were necessary due to polyethylene wear. This difference was confirmed by the radiographic evaluation of the still intact implants: Zweymüller THR showed better values for signs of osseointegration, radiolucent lines around the implants and migration, but more acetabular wear. None of these differences was affected by the AVN diagnosis.Interpretation?We could not confirm that AVN is a risk factor in total hip replacement.