Emerging evidence has linked the long-term use of alendronate (fosamax) with subtrochanteric insufficiency fractures. However, findings to date have been anecdotal. The aims of this study were to determine the incidence of subtrochanteric insufficiency fractures and identify whether they were more prevalent following the introduction of alendronate in Australia. All patients that presented between January 2007 and February 2009 with low- energy subtrochanteric fracture were identified. Similar data were collected between January 1995 and February 1997 as this was immediately prior to introduction of alendronate in Australia. The radiographs were examined for failure due to pre- existing insufficiency fracture. Characteristic findings were a transverse fracture line on the tension side of the femur with lateral cortical thickening immediately adjacent to the fracture. Relevant details from the history were recorded. We also separately identified all patients that presented between 2007 and 2009 with a proximal femoral fracture and determined the proportion taking alendronate. One hundred and seventeen patients with low-energy subtrochanteric fracture were included. Seventy-nine patients presented between 2007 and 2009 and 38 presented between 1995 and 1997. Forty-one of the 79 (52%) patients were identified as having radiograph findings suggestive of underlying insufficiency fracture, whilst none were identified prior to the introduction of alendronate. Of the 41 patients with subtrochanteric insufficiency fracture, 40 (98%) had been taking alendronate and one had been taking risedronate. Twenty-nine of the 41 (71%) complained of prodromal pain in the affected femur. Eighteen of the 41 (44%) demonstrated subtrochanteric insufficiency changes on the contralateral side and 9 of 41 (22%) sustained spontaneous non-traumatic fracture during activities of daily living. Of the 38 patients without insufficiency changes, 12 (32%) had been taking alendronate. Alendronate use was therefore strongly suggestive of insufficiency fracture (sensitivity = 98%, specificity = 84%, PPV = 77%, NPV = 99%, LR+ = 6). The mean duration of alendronate use in those with insufficiency fracture was 7.1 years (95% CI, 6.6-7.6 years). The mean duration in those without was 3.2 years (95% CI, 2.6-3.8 years, P<0.0001). Three hundred and ninety eight patients presented with a low-energy proximal femur fracture between 2007 and 2009. Of these, only 52 (13%, P<0.0001) were taking alendronate. This is the largest study in the literature on subtrochanteric insufficiency fractures and alendronate therapy. Confirming recent reports, alendronate use was strongly suggestive of subtrochanteric insufficiency fracture. Our findings provide the most compelling evidence to date of the potential long-term sequelae of alendronate but more research is needed before definitive conclusions can be made

Introduction. In osteonecrosis of the femoral head (ONFH), progression of collapse is influenced by a repair reaction, especially bone resorptive activity, around the necrotic bone. Alendronate is a potent inhibitor of bone resorption by inhibiting osteoclast activity. We performed a clinical study to test if systemic alendronate treatment would prevent the development of collapse in patients with ONFH. Methods. Thirty-three hips in 22 ONFH patients with initial ARCO Stage 1 to 3 were included. Fourteen patients (20 hips) received daily administration of oral alendronate 5mg/day (alendronate group) and 8 patients (13 hips) did not receive alendronate administration (Control group). Baseline investigations included anteroposterior and lateral plain radiographs, T1-weighted magnetic resonance imaging (MRI), and biochemical markers (urinary NTX and serum BAP). Examination of the biochemical markers were repeated at 3, 6, and 12 months, and MRI imaging was repeated at 12 months. At 3 years, clinical symptoms and findings on plain radiographs were compared between the 2 groups. Advancement of ARCO stages or increase of collapse by more than 2 mm were considered as development of collapse. Results. At baseline, there were no significant differences regarding patients' age, distribution of gender, etiology, ARCO radiographic stage, and extent of necrosis between the 2 groups. In the alendronate group, there was an early decrease of osteoclast activity (NTX) and osteoblastic activity (BAP) at 3 months, with significantly larger decrease in NTX (43%) than BAP (21%) at 12 months. At 3 years, development of collapse was observed in 7 hips (54%) of the Control group, and in 3 hips (15%) of the alendronate group. Hip pain was noted in 9 hips (69%) of the Control group, and in 6 hips (30%) of the alendronate group. There was a significant difference oncollapse development and occurrence of hip pain between the two groups (p<0.05). Signal change around the necrotic region on serial MRI images during the first 1 year was observed in 54 % of the Control group, and only 11% of the alendronate group. Conclusion. Alendronate therapy decreased biochemical markers, especially osteoclast activity, after an early period from start of administration. Several clinical studies have shown promising short-term results for prevention of collapse in ONFH by administration of bisphosphonates. The present study showed a significant preventing effect of collapse development by administration of alendronate which was maintained for 3 years of treatment. Low incidence of signal change on serial MRI images may also reflect decrease of repair activity in the alendronate group. Further studies with longer follow-up, larger numbers of patients, and randomized administration of the drug among patients are required., However, alendronate administration may become one of the effective conservative treatments which might obviate the need for osteotomy or replacement surgery in some populations of ONFH patients

Alendronate is a potent inhibitor of bone resorptive activity, and has been shown to prevent and restore periprosthetic osteolysis in experimental models. A preliminary study was conducted to examine clinical usefulness of a lendronate treatment. Twenty-five patients (27 hips) with radiological evidence of osteolysis after cemented total hip arthroplasty were included. Of these, 14 patients (15 hips) were administered 5 mg of alendronate daily (alendronate group), and 11 patients (12 hips) did not receive alendronate treatment (control group). The subjects were followed up for 12 months, using radiological examinations and biochemical markers. The radiological analysis was evaluated blindly by 2 joint arthroplasty experts, each with more than 10 years of experience, without knowledge of alendronate administration. In the alendronate group, average serum bone alkaline phosphatase and urinary excretion of the N-telopep-tide of type I collagen values decreased from the baseline values after administration of alendronate, to 71% and 76% of baseline at the 3-month examination, and 57% and 62% at the 1-year examination, respectively. In the control group, expansion of osteolysis was found in 5 hips (42%) and no hip showed restoration of osteolysis. In the alendronate group, expansion of osteolysiswas found in 2 hips (13%), and restoration of osteolysis was found in 5 hips (33%). There was a statistically significant difference in ratio of hips with osteolysis restoration between the 2 groups (p< 0.05). In the alendronate group, there was no significant difference in age, average linear wear rate of polyethylene, and the biochemical markers, between the hips with and without diminishment of osteolysis. Conclusions: The present results indicate that clinicala-lendronate treatment can prevent and restore periprosthetic osteolysis, which is generally thought to require surgical intervention. These findings warrant further study of the effects of duration and dose of alendronate treatment, component materials, and component fixation methods

Introduction: Alendronate is a well known inhibitor of osteoclastic activity and is used for the treatment of various metabolic bone diseases. Recent studies indicate that alendronate may have additional effect on osteoblastic activity. In this study, we evaluated the effect of alendronate on the osteogenic differentiation of mouse mesenchymal stem cells. Materials and Methods: D1 cells, known as multipotent mouse mesenchymal stem cells, were cultured in the presence of osteogenic differentiation medium (ODM) for 7 days, then treated with alendronates, and 2 days later the cells were used for testing. The cell proliferation was analyzed using an MTT assay. Alizarin red staining was done for mineralization. Alkaline phosphatase activity was measured using a commercial ELISA kit. Calcification was analyzed using energy dispersive X-ray spectrophometric analysis (EDX). Osteogenic gene expression was analyzed using RT-PCR. The change of CD 44 expression was observed using confocal microscopy and FACS analysis. Results: The D1 cells, in the presence of ODM, differentiated into osteoblasts. The evidence of osteogenic differentiation was confirmed by the positive stain by Alizarin red S, the increased activity of ALP, the increased mRNA expression of osteocalcin, a calcium peak in the EDX analysis, and by the positive immunofluorescence staining against CD 44 (an antigen detected on osteoblasts). With the addition of alendronate in the ODM medium, the osteogenic differentiation was enhanced. The enhancing effect was confirmed by the increased intensity of the Alizarin red S staining, higher activity of ALP, the higher mRNA expression of osteocalcin, a higher calcium peak in the EDX analysis, and by the increased immunofluorescence staining against CD 44 in the FACS analysis. Conclusion: We have demonstrated that alendronate enhances osteogenic differentiation when given to mouse mesenchymal stem cells in association with the ODM. Alendronate may increase the bone density not only by inhibiting the osteoclastic activity but also by increasing the osteogenic differentiation of the mesenchymal stem cells

Introduction: Progression of collapse in osteonecrosis of the femoral head (ONFH) is greatly influenced by repair reactions, especially bone resorptive activity. This study was performed to test if systemic alendronate treatment, a potent inhibitor of osteoclast activity, can prevent the development of collapse in ONFH. Materials and Methods: Daily administration of oral alendronate (5mg/day) was started in 14 hips in 11 patients with ONFH (Alendronate group). At the beginning of the study (3, 6, 12 months), plain radiographs, T1-weighted MR imaging, and biochemical makers of osteoclast activity (N-telopeptide of type-I collagen) and osteoblast activity (Bone-specific alkaline phosphatase), were examined. At 12 months, MR imaging was repeated. Eleven hips in 6 patients with ONFH who did not receive alendronate administration were considered as the control group. Results: There was no significant difference with respect to gender distribution, etiology factors, initial ARCO stages, and extent of necrosis in the two groups. In the alendronate group, there was an early decrease of osteoclast activity at 3 months, with a decrease to 62% at 12 months, while the decrease of osteoblast activity was smaller with 80% at 12 months. Development of collapse was observed in 4 of the 11 hips (36%) in the control group, and in none of the 14 hips in the alendronate group. There was a significant difference of collapse development between the two groups (p=0.026, Mann-Whitney U-test). Signal change on serial MR images was observed in 5 of 9 hips (56%) in the control group, with only one of 9 hips (11%) in the alendronate group. Discussion: The low incidence of signal change on serial MR images may reflect the decrease of repair activity in the alendronate group. The present study was the first clinical trial to show that alendronate has a significant preventive effect of collapse development in patients with osteonecrosis of the femoral head

Introduction. Osteonecrosis (ON) is one of the most debilitating skeletal disorders. Most patients with ON of the femoral head eventually require surgery, usually total hip arthroplasty, within a few years of disease onset. Previous reports have shown that alendronate reduces osteoclastic activity and reduces the incidence of femoral head collapse in osteonecrotic hips. A randomized study to examine the ability of alendronate to delay or prevent femoral head collapse was performed. Methods. From June 2005 to December 2006, sixty four patients were enrolled and randomly assigned to alendronate or placebo. Five patients were excluded from the analysis because of their failure to adhere to the study protocol. Disease progression was evaluated using radiographs and magnetic resonance imaging (MRI). Results. While the proportion of patients in the alendronate group who underwent total hip arthroplasty was 13% (4 of 31 patients), the proportion of patients undergoing the procedure in the placebo group was 29% (8 of 28 patients; p=0.22, cumulative incidence between the two groups by log-rank test). As such, there was a numerical reduction in the rate of total hip arthroplasty in the alendronate group compared to placebo that did not achieve statistical significance likely because the study was originally powered to detect a between-group difference based on event rates of 35.7% and 3.4% in the placebo and alendronate groups, respectively. Conclusion. Alendronate treatment shows promise for the treatment of atraumatic osteonecrosis. However, additional studies are needed to confirm our results. Osteotomy or bone grafting still remains the procedure of choice for osteonecrosis of the femoral head prior to collapse. Disclosure. The study was supported in part by Merck Sharp & Dohme (I.A) Corp. Taiwan Branch. All these schools received some financial reimbursement for the study

Recent epidemiological studies have demonstrated that more than half of postmenopausal women with osteoporosis (PWOP) treated with an antiresorptive drug plus calcium (Ca) and vitamin D, have serum levels of 25(OH)D3< 30ng/ml. Chronic low levels of vitamin D can contribute to the inefficiency of main antiresorptive treatment. A possible explanation for this phenomenon is the non-compliance with the daily supplementation of Ca and vitamin D. A fixed combination of Alendronate Once Weekly (OW) 70mg plus 2800 UI of cholecalciferol (AL+D) made its appearance in the market two years ago as a solution to this problem. The current study was designed to assess the efficacy of AL+D versus the old scheme of Alendronate 70 OW plus daily Ca 500mg + 400 UI of vitamin D (AL+S) on serum levels of 25(OH)D3. 100 randomly assigned PWOP treated already for 1 to 5 years with AL+S have changed their treatment to AL+D for one year. Serum levels of 25(OH)D3 (Biomedica.co.at/vitamind) has been measured before and after 12 months and also their BMD (Hologic Delphi), PTH, TSH, serum chemistry and hematology has been recorded for safety reasons. At the end of the study only 83 PWOP (MA=59,9±6,6 yrs) appeared for comparison. Our results are as follow:. The mean plasma level of 25(OH)D3 under AL+S treatment and before taking AL+D is 24,3±8,4 ng/mL and. The plasma levels of 25(OH)D3 after 12 months of treatment with AL+D are 33,3±9 ng/mL. The paired t-test has been used to compare the levels of 25(OH)D3 between treatment groups. There is a highly important statistical difference (t=−8.989, df=82, p< 0,0001) between treatment groups. From the above data it can be concluded that fixed combination of AL+D can improve the 25(OH)D3 status over 12 months versus AL+S probably because it assures a better compliance of vitamin D

Introduction. Fixation patterns of cementless stem were known as proximal or distal part. Distal fixation was seen in fully porous coated stem and stress shielding of the proximal femur was indicative. These phenomena did not lower the clinical results, but technical difficulties were more and more in revision surgery because of infection or dislocation. There was lot of reports that alendronate was effective for treatment of osteoporosis by induction of apoptosis in osteoclasts. We can expect alendronate to modify the bone quality around the stem after cementless THA. Objectives. We studied prospectively that quantitative computed tomography (QCT) measured bone mineral density around the stem between alendronate group and control. We tried to clarify that stress shielding after cementless THA can be prevented by use of alendronate or not. Materials and methods. From September 2011, 60 patients underwent total hip arthroplasty with cementless stems. Thirty patients took alendronate (35mg/week) after surgery (Group A) and remaining 30 patients were control (Group C). Between two groups, gender, age at surgery, diagnosis and body mass index were similar. Two types of stem were used as Zweimuller type or taperlock type. Just after THA, femoral shaft divided by Gruen zone measured bone mineral density (BMD) with QCT and forearm also measured BMD by DEXA. Following examination was performed at 6 months, 12 months and 24 months after surgery. Results. Gender of two groups was as follow: four males and twenty-six females in Group A and two males and twenty-eight females in Group C. The age at surgery was 67.6+7.9y in group A and 62.5+13.3y in group C. Zweimuller type was used for 18 patients and taperlock type was used for 12 patients in group A. Zweimuller type was used for 14 patients and taperlock type was used for 16 patients in group C. BMD of forearm were not different between two groups and it meant that bone quality and osteoporosis of groups was similar. On the other hands, femoral BMD of group A was higher than that of group C. Especially BMD of group C was relatively low in zone 1 and 7. Conclusion. Weekly use of alendronate (35mg) might be useful for preventing stress shielding after cementless THA

Titanium (Ti) is well known in orthopedic implant materials such as total hip replacement arthroplasty. Osseointegration of orthopedic implants is defined as the formation of a direct interface between the implant and the bone without intervening soft tissue. Unmodified Ti is not sufficient to complete adhesion between Ti surface and host bone with subsequent implant loosening over time and ultimately implant failure. An effective approach to enhance the biological activity of orthopedic implants and improve post-implantation healing is to modify the implant surface. The aim of this study was to investigate the effect of functionalized titanium (Ti) with alendronate (Aln) and bone morphogenic protein-2 (BMP-2) for enhancement of osteoblast activity in vitro. Aln and/or BMP-2 were sequentially immobilized to the heparinized-Ti (Hep-Ti) surface. The compositions of pristine Ti and Hep-Ti with or without Aln and/or BMP-2 were characterized by scanning electron microscope (SEM) and X-ray photoelectron spectroscopy (XPS). Osteoblast activities on all Ti substrates were investigated by cell proliferation assays, alkaline phosphate (ALP) activity, calcium deposition, gene expressions of osteocalcin and osteopontin. The modified Ti surface with heparin, Aln, BMP-2 and Aln/BMP-2 showed similar morphologies compared to that of pristine Ti on scanning electron microscope (SEM) and X-ray photoelectron spectroscopy (XPS). Aln or BMP-2 from Aln/Hep-Ti, BMP-2/Hep-Ti or Aln/BMP-2/ Hep-Ti substrates exhibited sustained release profiles up to 4 weeks. No significant cytotoxic effects were observed for incubation periods for up to 48 h. the ALP activity of MG-63 cells cultured on Hep-Ti was not significantly different compared to those cultured on pristine Ti for 7, 14, and 21 days. Alkaline phosphatase(ALP) activities of osteoblasts cultured on Ti groups immobilized with Aln, BMP-2, or Aln/BMP-2 were significantly increased when compared to pristine Ti(p < 0.05). Calcium deposition was markedly increased in Aln/BMP-2/Hep-Ti compared to Aln/Hep-Ti or BMP-2/Hep-Ti, respectively (p < 0.05). mRNA expressions of osteocalcin(OCN) and osteopontin(OPN) of osteoblasts grown on Aln/Hep-Ti, BMP-2/Hep-Ti, and Aln/BMP-2/Hep-Ti were significantly higher than of those grown on pristine Ti (p < 0.05). Based on the results of the in vitro studies, we showed that co-delivery of alendronate and BMP-2 had an additive effect on osteoblast activity and mineralization when compared with pristine Ti as well as alendronate or BMP-2 alone. Functionalized Ti systems with alendronate and BMP-2 can give a good solution to solve the most common problems associated with orthopedic and dental implants. Furthermore, in vivo studies required to determine the optimal doses of alendronate and BMP-2 for clinical application

Introduction. Achieving durable implant–host bone fixation is the major challenge in uncemented revision hip arthroplasty when significant bone stock deficiencies are encountered. The purpose of this study was to develop an experimental model which would simulate the clinical revision hip scenario and to determine the effects of alendronate coating on porous tantalum on gap filling and bone ingrowth in the experimental model. Methods. Thirty-six porous tantalum plugs were implanted into the distal femur, bilaterally of 18 rabbits for four weeks. There were 3 groups of plugs inserted; control groups of porous tantalum plugs (Ta) with no coating, a 2nd control group of porous tantalum plugs with micro-porous calcium phosphate coating, (Ta-CaP) and porous tantalum plugs coated with alendronate (Ta-CaP-ALN). Subcutaneous fluorochrome labelling was used to track new bone formation. Bone formation was analysed by backscattered electron microscopy and fluorescence microscopy on undecalcified histological sections. Results. The relative increase in mean volume of gap filling, bone ingrowth and total bone formation was 124%, 232% and 170% respectively in Ta-CaP-ALN compared with the uncoated porous tantalum (Ta) controls, which was statistically significant. The contact length of new bone formation on porous tantalum implants in Ta-CaP-ALN was increased by 700% (8-fold) on average compared with the uncoated porous tantalum (Ta) controls. Discussion. Alendronate coated porous tantalum significantly modulated implant bioactivity compared with controls. This study has demonstrated the significant enhancement of bone-implant gap filling and bone ingrowth, which can be achieved by coating porous tantalum with alendronate. It is proposed that, when faced with the clinical problem of revision joint replacement in the face of bone loss, the addition of alendronate as a surface coating would enhance biological fixation of the implant and promote the healing of bone defects

Introduction: Achieving durable implant–host bone fixation is the major challenge in uncemented revision hip arthroplasty when significant bone stock deficiencies are encountered. The purpose of this study was. to develop an experimental model which would simulate the clinical revision hip scenario and. determine the effects of alendronate coating on porous tantalum on gap filling and bone ingrowth in the experimental model. Methods: Thirty-six porous tantalum plugs were implanted into the distal femur, bilaterally of 18 rabbits for four weeks. There were 3 groups of plugs inserted; control groups of porous tantalum plugs (Ta) with no coating, a 2nd control group of porous tantalum plugs with micro-porous calcium phosphate coating, (Ta-CaP) and porous tantalum plugs coated with alendronate (Ta-CaP-ALN). Subcutaneous fluorochrome labelling was used to track new bone formation. Bone formation was analysed by backscattered electron microscopy and fluorescence microscopy on undecalcified histological sections. Results: The relative increase in mean volume of gap filling, bone ingrowth and total bone formation was 124 %, 232 % and 170 % respectively in Ta-CaP-ALN compared with the uncoated porous tantalum (Ta) controls, which was statistically significant. The contact length of new bone formation on porous tantalum implants in Ta-CaP-ALN was increased by 700% (8-fold) on average compared with the uncoated porous tantalum (Ta) controls. Discussion: Alendronate coated porous tantalum significantly modulated implant bioactivity compared with controls. This study has demonstrated the significant enhancement of bone-implant gap filling and bone ingrowth, which can be achieved by coating porous tantalum with alendronate. It is proposed that, when faced with the clinical problem of revision joint replacement in the face of bone loss, the addition of alendronate as a surface coating would enhance biological fixation of the implant and promote the healing of bone defects

Introduction: Achieving durable implant–host bone fixation is the major challenge in uncemented revision hip arthroplasty when significant bone stock deficiencies are encountered. The purpose of this study was 1) to develop an experimental model which would simulate the clinical revision hip scenario and 2) determine the effects of alendronate coating on porous tantalum on gap filling and bone ingrowth in the experimental model. Methods: Thirty-six porous tantalum plugs were implanted into the distal femur, bilaterally of 18 rabbits for four weeks. There were 3 groups of plugs inserted; control groups of porous tantalum plugs (Ta) with no coating, a 2. nd. control group of porous tantalum plugs with micro-porous calcium phosphate coating, (Ta-CaP) and porous tantalum plugs coated with alendronate (Ta-CaP-ALN). Subcutaneous fluorochrome labelling was used to track new bone formation. Bone formation was analysed by backscattered electron microscopy and fluorescence microscopy on undecalcified histological sections. Results: The relative increase in mean volume of gap filling, bone ingrowth and total bone formation was 124 %, 232 % and 170 % respectively in Ta-CaP-ALN compared with the uncoated porous tantalum (Ta) controls, which was statistically significant. The contact length of new bone formation on porous tantalum implants in Ta-CaP-ALN was increased by 700% (8-fold) on average compared with the uncoated porous tantalum (Ta) controls. Discussion: Alendronate coated porous tantalum significantly modulated implant bioactivity compared with controls. This study has demonstrated the significant enhancement of bone-implant gap filling and bone ingrowth, which can be achieved by coating porous tantalum with alendronate. It is proposed that, when faced with the clinical problem of revision joint replacement in the face of bone loss, the addition of alendronate as a surface coating would enhance biological fixation of the implant and promote the healing of bone defects

Introduction: In avascular necrosis [AVN] of the femoral head the dead bone undergoes osteoclastic osteolysis and is replaced by newly synthesized, immature, weak bone, which cannot withstand the daily loads. The articular surface might caves in because of these changes, and osteoarthritic joint changes can develop. Alendronate interferes with the osteoclastic activities, it can slow-down the bone turnover of the necrotic bone and can differ these changes. The aim of this study is to delay the speedy renewal of living epiphyses by alendronate medication in order to describe the effects of it on the fate of the necrotic femoral heads in rats. Methods: Sixty female sprague-dawley rats, 6-month old weighing about 400–500 grams, underwent surgical AVN of the right femoral heads. Forty-four rats, the treated group, were treated with alendronate 200 μgm/kg/day. Sixteen rats, the control group, were treated with saline. Both groups were daily injected subcutaneously for six weeks and sacrificed. Both femoral heads were harvested and were evaluated microscopically and stained by H& E. Results: The necrotic femoral heads of the control group, which were not treated by alendronate, were severely distorted with osteoarthrosis features as; collapse of the epiphysis, pannus formation, filling of spaces by chronically and mildly inflamed densely textured fibrous tissue which was polluted by numerous tiny particles of necrotic bone. Additionally, large chunks of necrotic articular cartilage were haphazardly scattered in the fibrous tissue. All hematopoietic and fat cells of the intertrabecular spaces of the epiphysis were replaced by fibrous tissue. More often than not, the cartilage of the physis was focally or entirely absent such that osseous trabeculae of the epiphysis and metaphysis linked with each other, forming so-called epiphyseal-metaphyseal bridges. The above described alterations were encountered in all animals, yet their severity varied. The decisive difference between the necrotic femoral heads of otherwise untreated in opposition to the alendronate-medicated rats was the preservation of a hemispherical configuration of the femoral heads. There was no distortion of the femoral heads in the alendronate-treated animals and the femoral heads preserved their roundness. All femoral heads of the non-operated left hips were microscopically normal. Discussion: It has become clear that the degree of architectural distortion of the femoral epiphyses depends on the extent of bone turnover leading to resorption of all debris and its replacement by living osseous and soft tissues. The more rapidly and more extensively the reconstruction of living epiphyses progresses, the smaller is the prospect of reshaping a hemispherical or near-hemispherical femoral head. The recently rebuilt epiphyses cannot carry daily transarticular loads without caving in. The revascularization-related reconstitution of weak bony trabeculae is blamed for the collapse of the femoral heads. If this indeed is the case, the remodeling of the necrotic femoral heads should be delayed, rather than sped-up. Alendronate interferes with the osteoclastic activities and hence, slowing-down the bone turnover. The osteoclastic activity is detrimental for the conservation of a hemispherical femoral head because of the rapidly occurring replacement of the necrotic bone by living tissues. Halting the activities of the osteoclasts by a biphosphonate would stop the hasty osteoneogenesis, which is responsible for the early femoral capital disfigurement and might delay the regeneration of osteo-arthiritic changes of the joint later on

Purpose: Porous tantalum has been shown to be very effective in achieving bone ingrowth. However, in some circumstances, bone quality or quantity is insufficient to allow adequate bone ingrowth. We hypothesized that the addition of alendronate to porous tantalum would enhance the ability of porous tantalum to achieve bone ingrowth in these challenging situations, such as when a gap exists between the implant and bone. We evaluated the effect of alendronate coated porous tantalum on new bone formation in an animal model incorporating a gap between implant and bone. Method: Thirty-six cylindrical porous tantalum implants were bilaterally implanted into the distal femur of 18 rabbits for 4 weeks. There were 3 groups of implants inserted; a control group of porous tantalum with no coatings, porous tantalum with micro-porous calcium phosphate coating, and porous tantalum coated with micro-porous calcium phosphate and alendronate. Subcutaneous fluorescent labeling was used to track new bone formation. Bone formation was analyzed by backscattered electron microscopy and fluorescent microscopy on undecalcified samples. Results: The relative increase in mean volume of gap filling, bone ingrowth and total bone formation was 143% (p< 0.001), 259% (p< 0.001) and 193% (p< 0.001) respectively in the alendronate coated porous tantalum compared with the uncoated porous tantalum controls. The relative increase in the percentage of new bone-implant contact length was increased by 804% on average in the alendronate coated porous tantalum compared with the uncoated tantalum controls. Conclusion: This study demonstrated the significant enhancement of bone-implant gap filling and bone ingrowth which can be achieved by coating porous tantalum with alendronate. It is proposed that, when faced with the clinical problem of revision joint replacement in the face of bone loss (at the hip, knee or elsewhere), the addition of an alendronate-delivery surface coating would enhance biological fixation of the implant and promote the healing of bone defects

Bisphosphonates are systemically used for the treatment of metabolic bone diseases such as osteoporosis or aseptic loosening after joint replacement surgeries, and there are limited studies on their effects when applied locally. Furthermore, effects of biphosphonates in osteomyelitis treatment are not well-known. A prospective longitudinal randomised controlled study was designed for the rat tibia to test the efficacy of local or systemically administered bisphosphonates for controlling the localised osteolytic reactions and possible effects on local infection control. Osteomyelitis was induced in the tibia of 72 Wistar albino rats with S. aureus ATCC 25923 strain. All rats in all treatment groups were given curettage and debridement surgery. Rats in Group I were left without any bone grafting. In Group II, dead space was grafted with plain bone graft, while in Group III rats were treated with vancomycin-loaded bone grafts. In group IV, defects were filled with vancomycin-loaded bone grafts, and this was combined with weekly subcutaneous alendronate application at a dose of 240 μg/kg/wk. At Group V defects were grafted with alendronate impregnated bone graft. Finally, rats in Group VI received vancomycin + alendronate impregnated grafts. Dependent variables were groups (n=6) and time (n=2) whereas independent variables were swab cultures, radiology, quantitative computerised tomography, dual energy X-ray absorptiometry and histopathology. Within three weeks, S.aureus was isolated in all groups. Within six weeks, S.aureus was eradicated in Groups II and IV according to the results of swab cultures. Radiological diaphyseal widening was significantly lower (p=0.037) in Group VI at three weeks. Bone deformation, diaphyseal widening and osteolysis scores were lower in this group at six weeks. Bone mineral content and density measured by quantitative computerised tomography were significantly higher (p=0.001) in Groups IV and VI at six weeks. Bone mineral density measured by dual energy X-ray absorptiometry was significantly higher in Group IV at six weeks. Histology revealed marked osteoblastic activity in Groups IV and VI at six weeks

Background: The pathogenesis of CN is still unknown. An increase of the bone blood supply seems to be one of the mechanisms involved. A feature of CN is a bone reabsorption. IGF-1 can influence the bone tissue by various mechanisms but its vasodilatory effects in others tissues are well-known. Alendronate have an inhibitory effect on bone reabsorption. Aim of this study is to evaluate the effect of alendronate on foot bone density in CN and above all if this effect can be mediated by a modification in IGF-1 levels. Methods: Twenty patients with a diagnosis of acute CN of the foot were enrolled. According to the randomization, 11 patients were treated with 70 mg of alendronate per os once a week (TG) and 9 patients were followed as control group (CG). Markers of bone turnover [urinary hydroxyprolin, serum collagen carboxyl-terminal telopeptide of type 1 collagen (ICTP), serum bone alkaline phosphatase (B-ALP)], IGF-1 and BMD by dual energy X-ray absorptiometry (DEXA). Results: ICTP didn’t show significant difference between the two groups (0,54±0,05 ng/ml vs 0,56±0,06 ng/ml p< 0,6) at the outset, after six months the treated group had a significant decrease of this parameter (0,54±0,05 ng/ml vs 0,30±0,03 ng/ml p< 0,05). In TG hydroxyprolin followed the same trend showing a significant decrease after the six month treatment (18±3,2 mg/l vs 13±3,6 mg/l p< 0,05). At the same time B-ALP reduction was almost significant (36±4,8% vs 23±3,9% p=0,06). DEXA demonstrated an improvement in total foot mineralization in the TG(0,18±0,06 g/cm2 vs 0,24±0,08 g/cm2 p< 0,05) and in the distal phalanxes (0,194 g/cm2 vs 0,242 g/cm2 p< 0,01) (fig. 3). Only the TG showed a significant decrease of IGF-1 throughout the trial (142,8±24 vs 123,5±41 ng/ml p< 0,05). Conclusions: The increase in bone blood flow could be linked to the vascular effects of IGF-1. Alendronate in acute phase helps to stop bone reabsorption and this effect could be mediated by the decrease of IGF-1 levels

The purpose of this study was to investigate the efficacy of oral alendronate for the older children with osteogenesis imperfecta. Eight boys and 6 girls with average age of 9.7 years were given oral alendronate, 10mg everyday for those > 35kg, 10mg every other day for those 20 – 35 kg, and 10mg every three days for those < 20 kg. Treatment period averaged 3.3 years (range, 2.1 to 3.6). The number of fractures decreased by 39% in the lower extremity, although not statistically significant. Ten patients or their parents reported improved well-being during the treatment period. Z score for bone mineral density improved from −3.75 to −1.18 in the lumbar spine, and from −3.84 to −2.74 in the femur neck. Restoration of the collapsed vertebral bodies was observed, and the metaphyseal bands appeared on the simple radiographs. Urinary excretion of calcium and N-telopeptide of type I collagen were decreased by 64% and 47%, respectively. Abdominal discomfort was reported in five patients, one of which needed temporary switch to intravenous protocol. Iliac crest biopsy including the physis showed expanded primary spongiosa area with numeric multi-nucleated cells, which had heterogenous immunoreactivity for osteoclast markers. This study revealed beneficial effects of oral alendronate in osteogenesis imperfecta patients, supported by radiological, biochemical and histological findings. We believe that oral alendronate is a more convenient method of bisphosphonate treatment for osteogenesis imperfecta, especially in older children

Purpose: Bone remodelling and osteolysis around total hip prostheses remains an ineluctable corollary of prosthetic loosening. Alendronate (biphosphonate) has proven its efficacy for the treatment of osteoporosis of the lumbar spine and the femoral neck. There has been some in vitro work pointing out its contribution to the inhibition of osteolysis induced by particles. One in vivo study has demonstrated its interest in prevention of osteolysis around non-cemented total hip arthroplasties. The purpose of our work was to study the efficacy of this drug in the prevention of periprosthetic osteolysis around cemented total hip arthroplasties using biphotonic absortiometry (DPX). Material and methods: The series included 38 patients who underwent unilateral total hip arthroplasty for degenerative hip disease. After double blinded randomisation, 20 patients were given 10 mg Alendronate per day with 600 mg calcium and 18 patients were given a placebo with 600 mg calcium for two years. All patients were followed with standard x-rays and DPX of the operated hip. Examinations were performed on the fourth postoperative day and on the third, sixth, twelveth and twenty-fourth postoperative month. The analysis concerned the periprosthetic zones defined by Gruen. Results: DPX demonstrated significant reduction in bone mineral density (BMD) in all patients included in the study. This reduction was the same for the two groups early in the study and reached a maximum at three months; a divergence was observed thereafter. For the placebo group, the loss reached a plateau up to the sixth month after which the BMD started to rise progressively remaining at 12.7% reduction at two years (p< 0.002). In the ALN group, there was no plateau, BMD increased directly to reach 6.9% bone loss at two years (p< 0.003). Discussion:The use of Alendronate enabled a significant reduction of periprosthetic bone loss at two years post-op. Our results are the first to our knowledge demonstrating a beneficial effect in vivo of the use of Alen-dronate on bone behaviour around cemented total hip arthroplasties. Conclusion: Taking into account the short follow-up in this series, and its small size, other studies are indispensable to confirm this beneficial effect in vivo. The action of Alendronate could facilitate revision surgery by preserving bone stock

Introduction: Screw loosening is a common complication of osteoporotic fracture fixation leading to implant loosening, fracture malunion and non-union. Because recent animal studies have shown that bisphosphonates improve implant fixation we wanted to assess whether alendronate (ALN) improves screw fixation in a clinical setting of osteoporotic fractures. Methods: Sixteen consecutive patients with AO/OTA A1 pertrochanteric fractures were selected. Inclusion criteria were: female over the age of 65, BMD T-score less than −2.5 SD. Fractures were fixed with a pertrochanteric fixator and 4 hydroxyapatite (HA)-coated screws. Two screws were implanted in the femoral head (screw positions 1 and 2) and two in the femoral diaphysis (screw positions 3 and 4). Patients were randomized to either postoperative systemic administration of ALN, 70 mg per week for 3 months (Group A) or no ALN. Fixators were removed at 3 months post-op in all patients. Results: All the fractures healed. No differences in screw insertion torque between the two groups were found. No pin loosening or infection occurred. The combined mean extraction torque of the screws implanted at positions 1 and 2 (cancellous bone) was 3181 ± 1385 N/mm in Group A and 1890 ± 813 N/mm in Group B (p < 0.001). The combined mean extraction torque of the screws implanted at positions 3 and 4 (cortical bone) was 4327 ± 1720 N/mm in Group A and 3785 ± 1181 N/mm in Group B (ns). Discussion and Conclusion: This is the first study to demonstrate in a clinical setting improved screw fixation following post-operative ALN treatment. We observed a two-fold fixation increase in the screws implanted in cancellous bone. With cortical bone, the difference in screw fixation was less marked. Besides its bone preserving ALN should be recommended as an effective solution to improve fixation in osteoporotic bone

Bone healing especially in elderly patients is a complex process with limited therapeutic options. In recent years the use of BMP2 for fracture healing is investigated extensively. However, for many applications superficial amounts of BMP2 were required for efficacy due to the absence of sustained release carriers and severe side effects have reported thereby limiting the use of BMP2. Here we present an alternative method based on the use of a combination of low molecular weight compounds, testosterone and alendronate, with established safety profiles in men. Moreover, in contrast to BMP2 which activates both osteoblasts and osteoclasts, this combination of drugs enhances osteoblast activity but simultaneously inhibits osteoclast activity resulting in a net effect of bone growth. Human primary osteoblasts were obtained from bone of patients requiring knee prostheses and cultured in the presence of various concentrations testosterone with and without alendronate. Optimal concentrations were selected and used to stimulate 5×8 mm porcine bone biopsies for 4 weeks. Medium was exchanged regularly and ALP activity was determined. At endpoint biopsies were analyzed in a MicroCT (Bruker Skyscan 1076) to analyze bone volume (BV), trabecular thickness (Tb.Th) and tissue volume (TV). Bone strength was measured using Hounsfield (H10KT) test equipment. The data obtained showed a significant and dose dependent increase in ALP activity of primary osteoblasts (day 7–10) indicating robust activation of osteoblast activity. Optimal and synergistic ALP activation was observed when treating cells with 15–375 nM testosterone in combination with 2 μM alendronate. Significant inhibition (75%) of osteoclast activity was observed by alendronate (2–10 μM) which was further enhanced by high testosterone levels. This concept was further tested in bovine bone biopsies cultured for 4 weeks in the presence of 75 nM testosterone and 2 μM alendronate. MicroCT analysis of the biopsies revealed a ± 40% increase in both bone volume (trabecular and cortical bone) and bone strength. Moreover bone mineral density was increased by 20% indicating increased mineralization of bone tissue. Treatment of human primary osteoblasts or human or bovine bone explants with a combination of an androgen (testosterone) and a bisphosphonate (alendronate) significantly enhance bone growth and bone mineral density. Moreover, bone strength was increased indicating the formation of high quality bone tissue. These findings are the basis for the development of sustained release materials to be applied locally at the bone fracture site, which would allow for low amounts of the drugs and no systemic exposure. By encapsulating testosterone and alendronate in a biodegradable polymer coating, a sustained release up to 5 weeks can be achieved, and the loaded coating can be applied in combination with collagen membranes to improve bone healing or as a coating onto implants to improve osseo-integration