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Bone & Joint Research
Vol. 7, Issue 10 | Pages 548 - 560
1 Oct 2018
Qayoom I Raina DB Širka A Tarasevičius Š Tägil M Kumar A Lidgren L

During the last decades, several research groups have used bisphosphonates for local application to counteract secondary bone resorption after bone grafting, to improve implant fixation or to control bone resorption caused by bone morphogenetic proteins (BMPs). We focused on zoledronate (a bisphosphonate) due to its greater antiresorptive potential over other bisphosphonates. Recently, it has become obvious that the carrier is of importance to modulate the concentration and elution profile of the zoledronic acid locally. Incorporating one fifth of the recommended systemic dose of zoledronate with different apatite matrices and types of bone defects has been shown to enhance bone regeneration significantly in vivo. We expect the local delivery of zoledronate to overcome the limitations and side effects associated with systemic usage; however, we need to know more about the bioavailability and the biological effects. The local use of BMP-2 and zoledronate as a combination has a proven additional effect on bone regeneration. This review focuses primarily on the local use of zoledronate alone, or in combination with bone anabolic factors, in various preclinical models mimicking different orthopaedic conditions.

Cite this article: I. Qayoom, D. B. Raina, A. Širka, Š. Tarasevičius, M. Tägil, A. Kumar, L. Lidgren. Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair: A review. Bone Joint Res 2018;7:548–560. DOI: 10.1302/2046-3758.710.BJR-2018-0015.R2.


The Journal of Bone & Joint Surgery British Volume
Vol. 34-B, Issue 4 | Pages 646 - 698
1 Nov 1952
Duraiswami PK

1 . The magnitude of the problem of congenital anomalies becomes evident when one takes into consideration the fact that they cause the death of approximately one quarter of the human race either before or shortly after birth, and handicap an appreciable proportion of the survivors throughout their lives. Further, a significant percentage of infants judged to be normal at birth are found in later life to suffer from "disguised" anomalies of the skeleton and soft tissues. Though the study of genetic factors leading to congenital defects has attracted a great deal of attention during the last few decades, the importance of environmental causes of human malformations has received relatively less emphasis. The association of congenital anomalies such as cataract and cardiac septal defects with maternal intercurrent infection of rubella during the early months of pregnancy demonstrates clearly that changes in the germplasm cannot always be invoked as the cause of developmental abnormalities. Congenital malformations that are sometimes genetically determined, such as microphthalmos, cleft palate, and certain skeletal abnormalities, can be caused in the offspring not only by maternal nutritional deficiencies and x-radiation but also, at least in some animals, such as chickens, rats and rabbits, by the introduction of certain substances like insulin into the environment of the embryo during its development. 2. Since very little is known of the detailed histology of the early human embryo, the histological examination of cases of perverted growth is mainly limited to aborted foetuses which, unfortunately, tend to present varying degrees of post-mortem degeneration before accurate histological methods can be applied. It is exactly in this field that animal experiments can offer valuable help. According to Mall and other embryologists the pathological changes that take place in human foetuses and those obtained experimentally in animals are not merely "analogous or similar but identical.". 3. An attempt has been made to review, in some detail, the more important work which has been carried out on experimental teratogenesis, on the epidemiological implications of developmental arrests in humans, and on foetal abnormalities associated with maternal metabolic and hormonal disorders during pregnancy. 4. The technique employed for injection of insulin into the egg yolk has been described. Methods used for the estimation of blood sugar in chick embryos at various stages after injection of insulin and special histochemical techniques for localising polysaccharides in cartilage have been outlined. 5. A few salient experimental results have been tabulated, and some of the insulin-induced abnormalities have been illustrated. 6. The possible mechanism of action of insulin in the causation of the various developmental anomalies has been discussed. Broadly speaking, insulin seems to affect primarily the part or tissue which is in the most active stage of growth or differentiation at the time of the injection. Within the range of 0·05 to 6 units of insulin employed, the incidence, severity and distribution of the deformities appear to increase with the dose of the hormone. It has been observed that the hypoglycaemia caused by insulin injection is not counteracted till about the twelfth day of incubation, presumably because of excessive accumulation of glycogen in the yolk-sac membrane immediately after the injection, and because of lack of glycogen storage in the embryonic liver and the absence of active secretion in the endocrine glands concerned with the carbohydrate metabolism of the embryo. It has been suggested that this unchecked hypoglycaemia may deprive the mesenchyme, pre-cartilage and cartilage of glycogen and mucopolysaccharides (chondroiten-sulphuric acid complexes), depending on the time of injection and the dose of insulin, and thus not only give rise to a variety of single and multiple deformities in the cartilaginous skeleton but also interfere with the normal endochondral ossification, resulting in a generalised developmental disturbance of bone resembling osteogenesis imperfecta in the human. 7. Insulin-induced abnormalities can be prevented to a remarkable extent by injecting nicotinamide and riboflavin into eggs along with insulin. 8. The question of the practical application of the knowledge gained from experimental observations on insulin-induced developmental abnormalities in explaining the possible causation of congenital anomalies in humans by genetic and environmental teratogenic factors, has been discussed. It is suggested that the orderly progression from the mesenchymatous condensation to cartilage, and then through calcified cartilage to bone, may be disturbed by these teratogenic factors at critical phases during the development of the embryo, and a variety of single and multiple skeletal deformities may thus be induced. 9. A plea is made for routine pathological and radiological examination of aborted foetuses and stillborn infants more or less on the lines followed for experimentally induced deformities with a view to applying the knowledge gained from animal experiments to a better understanding of the etiology and pathology of human congenital anomalies. 10. As regards the possible prevention of these deformities, it is not always easy to offer sound eugenic advice in the cases of congenital malformations determined partly or completely by genetic factors, for two important reasons. First, it is often difficult to distinguish between genetically determined congenital anomalies and their phenocopies. Secondly, genetically determined developmental defects sometimes show surprisingly variable expressivity and penetrance. For the conditions in which both genetic and environmental factors are involved, the most profitable immediate line of attack would be on the environmental factors. A relatively simpler problem is presented by the malformations which are, for all practical purposes, entirely caused by environmental factors. Measures to prevent congenital anomalies caused by prenatal rubella, such as exposure of girls to the disease during childhood and protection of pregnant women during the early stages of pregnancy by immune serum, are under active consideration. 11 . Further energetic investigation of the causes of permaturity, stillbirths, monstrosities and congenital malformations is urgently needed, before embarking on a successful programme for prevention. "The day of successful prophylaxis is not yet, but it is much nearer than seemed possible a few years ago."


Bone & Joint Research
Vol. 6, Issue 4 | Pages 231 - 244
1 Apr 2017
Zhang J Yuan T Zheng N Zhou Y Hogan MV Wang JH

Objectives

After an injury, the biological reattachment of tendon to bone is a challenge because healing takes place between a soft (tendon) and a hard (bone) tissue. Even after healing, the transition zone in the enthesis is not completely regenerated, making it susceptible to re-injury. In this study, we aimed to regenerate Achilles tendon entheses (ATEs) in wounded rats using a combination of kartogenin (KGN) and platelet-rich plasma (PRP).

Methods

Wounds created in rat ATEs were given three different treatments: kartogenin platelet-rich plasma (KGN-PRP); PRP; or saline (control), followed by histological and immunochemical analyses, and mechanical testing of the rat ATEs after three months of healing.


Bone & Joint Research
Vol. 7, Issue 4 | Pages 318 - 324
1 Apr 2018
González-Quevedo D Martínez-Medina I Campos A Campos F Carriel V

Objectives

Recently, the field of tissue engineering has made numerous advances towards achieving artificial tendon substitutes with excellent mechanical and histological properties, and has had some promising experimental results. The purpose of this systematic review is to assess the efficacy of tissue engineering in the treatment of tendon injuries.

Methods

We searched MEDLINE, Embase, and the Cochrane Library for the time period 1999 to 2016 for trials investigating tissue engineering used to improve tendon healing in animal models. The studies were screened for inclusion based on randomization, controls, and reported measurable outcomes. The RevMan software package was used for the meta-analysis.


Bone & Joint Research
Vol. 7, Issue 5 | Pages 336 - 342
1 May 2018
Hotham WE Malviya A

This systematic review examines the current literature regarding surgical techniques for restoring articular cartilage in the hip, from the older microfracture techniques involving perforation to the subchondral bone, to adaptations of this technique using nanofractures and scaffolds. This review discusses the autologous and allograft transfer systems and the autologous matrix-induced chondrogenesis (AMIC) technique, as well as a summary of the previously discussed techniques, which could become common practice for restoring articular cartilage, thus reducing the need for total hip arthroplasty. Using the British Medical Journal Grading of Recommendations, Assessment, Development and Evaluation (BMJ GRADE) system and Grade system. Comparison of the studies discussed shows that microfracture has the greatest quantity and quality of research, whereas the newer AMIC technique requires more research, but shows promise.

Cite this article: W. E. Hotham, A. Malviya. A systematic review of surgical methods to restore articular cartilage in the hip. Bone Joint Res 2018;7:336–342. DOI: 10.1302/2046-3758.75.BJR-2017-0331.


The Bone & Joint Journal
Vol. 100-B, Issue 6 | Pages 811 - 821
1 Jun 2018
Fu K Duan G Liu C Niu J Wang F

Aims

The aim of this study was to investigate the changes in femoral trochlear morphology following surgical correction of recurrent patellar dislocation associated with trochlear dysplasia in children.

Patients and Methods

A total of 23 patients with a mean age of 9.6 years (7 to 11) were included All had bilateral recurrent patellar dislocation associated with femoral trochlear dysplasia. The knee with traumatic dislocation at the time of presentation or that had dislocated most frequently was treated with medial patellar retinacular plasty (Group S). The contralateral knee served as a control and was treated conservatively (Group C). All patients were treated between October 2008 and August 2013. The mean follow-up was 48.7 months (43 to 56). Axial CT scans were undertaken in all patients to assess the trochlear morphological characteristics on a particular axial image which was established at the point with the greatest epicondylar width based on measurements preoperatively and at the final follow-up.


Bone & Joint Research
Vol. 7, Issue 4 | Pages 274 - 281
1 Apr 2018
Collins KH Hart DA Seerattan RA Reimer RA Herzog W

Objectives

Metabolic syndrome and low-grade systemic inflammation are associated with knee osteoarthritis (OA), but the relationships between these factors and OA in other synovial joints are unclear. The aim of this study was to determine if a high-fat/high-sucrose (HFS) diet results in OA-like joint damage in the shoulders, knees, and hips of rats after induction of obesity, and to identify potential joint-specific risks for OA-like changes.

Methods

A total of 16 male Sprague-Dawley rats were allocated to either the diet-induced obesity group (DIO, 40% fat, 45% sucrose, n = 9) or a chow control diet (n = 7) for 12 weeks. At sacrifice, histological assessments of the shoulder, hip, and knee joints were performed. Serum inflammatory mediators and body composition were also evaluated. The total Mankin score for each animal was assessed by adding together the individual Modified Mankin scores across all three joints. Linear regression modelling was conducted to evaluate predictive relationships between serum mediators and total joint damage.


Bone & Joint Research
Vol. 5, Issue 9 | Pages 403 - 411
1 Sep 2016
Mrosek EH Chung H Fitzsimmons JS O’Driscoll SW Reinholz GG Schagemann JC

Objectives

We sought to determine if a durable bilayer implant composed of trabecular metal with autologous periosteum on top would be suitable to reconstitute large osteochondral defects. This design would allow for secure implant fixation, subsequent integration and remodeling.

Materials and Methods

Adult sheep were randomly assigned to one of three groups (n = 8/group): 1. trabecular metal/periosteal graft (TMPG), 2. trabecular metal (TM), 3. empty defect (ED). Cartilage and bone healing were assessed macroscopically, biochemically (type II collagen, sulfated glycosaminoglycan (sGAG) and double-stranded DNA (dsDNA) content) and histologically.


Bone & Joint Research
Vol. 5, Issue 4 | Pages 137 - 144
1 Apr 2016
Paterson SI Eltawil NM Simpson AHRW Amin AK Hall AC

Objectives

During open orthopaedic surgery, joints may be exposed to air, potentially leading to cartilage drying and chondrocyte death, however, the long-term effects of joint drying in vivo are poorly understood. We used an animal model to investigate the subsequent effects of joint drying on cartilage and chondrocytes.

Methods

The patellar groove of anaesthetised rats was exposed (sham-operated), or exposed and then subjected to laminar airflow (0.25m/s; 60 minutes) before wounds were sutured and animals recovered. Animals were monitored for up to eight weeks and then sacrificed. Cartilage and chondrocyte properties were studied by histology and confocal microscopy, respectively.


Bone & Joint Research
Vol. 7, Issue 3 | Pages 244 - 251
1 Mar 2018
Tawonsawatruk T Sriwatananukulkit O Himakhun W Hemstapat W

Objectives

In this study, we compared the pain behaviour and osteoarthritis (OA) progression between anterior cruciate ligament transection (ACLT) and osteochondral injury in surgically-induced OA rat models.

Methods

OA was induced in the knee joints of male Wistar rats using transection of the ACL or induction of osteochondral injury. Changes in the percentage of high limb weight distribution (%HLWD) on the operated hind limb were used to determine the pain behaviour in these models. The development of OA was assessed and compared using a histological evaluation based on the Osteoarthritis Research Society International (OARSI) cartilage OA histopathology score.


Objectives

The lack of effective treatment for cartilage defects has prompted investigations using tissue engineering techniques for their regeneration and repair. The success of tissue-engineered repair of cartilage may depend on the rapid and efficient adhesion of transplanted cells to a scaffold. Our aim in this study was to repair full-thickness defects in articular cartilage in the weight-bearing area of a porcine model, and to investigate whether the CD44 monoclonal antibody biotin-avidin (CBA) binding technique could provide satisfactory tissue-engineered cartilage.

Methods

Cartilage defects were created in the load-bearing region of the lateral femoral condyle of mini-type pigs. The defects were repaired with traditional tissue-engineered cartilage, tissue-engineered cartilage constructed with the biotin-avidin (BA) technique, tissue-engineered cartilage constructed with the CBA technique and with autologous cartilage. The biomechanical properties, Western blot assay, histological findings and immunohistochemical staining were explored.


Bone & Joint Research
Vol. 6, Issue 2 | Pages 98 - 107
1 Feb 2017
Kazemi D Shams Asenjan K Dehdilani N Parsa H

Objectives

Mesenchymal stem cells have the ability to differentiate into various cell types, and thus have emerged as promising alternatives to chondrocytes in cell-based cartilage repair methods. The aim of this experimental study was to investigate the effect of bone marrow derived mesenchymal stem cells combined with platelet rich fibrin on osteochondral defect repair and articular cartilage regeneration in a canine model.

Methods

Osteochondral defects were created on the medial femoral condyles of 12 adult male mixed breed dogs. They were either treated with stem cells seeded on platelet rich fibrin or left empty. Macroscopic and histological evaluation of the repair tissue was conducted after four, 16 and 24 weeks using the International Cartilage Repair Society macroscopic and the O’Driscoll histological grading systems. Results were reported as mean and standard deviation (sd) and compared at different time points between the two groups using the Mann-Whitney U test, with a value < 0.05 considered statistically significant.


Bone & Joint Research
Vol. 7, Issue 1 | Pages 58 - 68
1 Jan 2018
Portal-Núñez S Ardura JA Lozano D Martínez de Toda I De la Fuente M Herrero-Beaumont G Largo R Esbrit P

Objectives

Oxidative stress plays a major role in the onset and progression of involutional osteoporosis. However, classical antioxidants fail to restore osteoblast function. Interestingly, the bone anabolism of parathyroid hormone (PTH) has been shown to be associated with its ability to counteract oxidative stress in osteoblasts. The PTH counterpart in bone, which is the PTH-related protein (PTHrP), displays osteogenic actions through both its N-terminal PTH-like region and the C-terminal domain.

Methods

We examined and compared the antioxidant capacity of PTHrP (1-37) with the C-terminal PTHrP domain comprising the 107-111 epitope (osteostatin) in both murine osteoblastic MC3T3-E1 cells and primary human osteoblastic cells.


The Bone & Joint Journal
Vol. 99-B, Issue 11 | Pages 1537 - 1544
1 Nov 2017
Wahl P Guidi M Benninger E Rönn K Gautier E Buclin T Magnin J Livio F

Aims

Calcium sulphate (CaSO4) is a resorbable material that can be used simultaneously as filler of a dead space and as a carrier for the local application of antibiotics. Our aim was to describe the systemic exposure and the wound fluid concentrations of vancomycin in patients treated with vancomycin-loaded CaSO4 as an adjunct to the routine therapy of bone and joint infections.

Patients and Methods

A total of 680 post-operative blood and 233 wound fluid samples were available for analysis from 94 implantations performed in 87 patients for various infective indications. Up to 6 g of vancomycin were used. Non-compartmental pharmacokinetic analysis was performed on the data from 37 patients treated for an infection of the hip.


The Bone & Joint Journal
Vol. 98-B, Issue 9 | Pages 1270 - 1275
1 Sep 2016
Park S Kang S Kim JY

Aims

Our aim was to investigate the predictive factors for the development of a rebound phenomenon after temporary hemiepiphysiodesis in children with genu valgum.

Patients and Methods

We studied 37 limbs with idiopathic genu valgum who were treated with hemiepiphyseal stapling, and with more than six months remaining growth at removal of the staples. All children were followed until skeletal maturity or for more than two years after removal of the staples.


Bone & Joint Research
Vol. 3, Issue 6 | Pages 193 - 202
1 Jun 2014
Hast MW Zuskov A Soslowsky LJ

Tendinopathy is a debilitating musculoskeletal condition which can cause significant pain and lead to complete rupture of the tendon, which often requires surgical repair. Due in part to the large spectrum of tendon pathologies, these disorders continue to be a clinical challenge. Animal models are often used in this field of research as they offer an attractive framework to examine the cascade of processes that occur throughout both tendon pathology and repair. This review discusses the structural, mechanical, and biological changes that occur throughout tendon pathology in animal models, as well as strategies for the improvement of tendon healing.

Cite this article: Bone Joint Res 2014;3:193–202.


The Journal of Bone & Joint Surgery British Volume
Vol. 94-B, Issue 7 | Pages 865 - 874
1 Jul 2012
Mills LA Simpson AHRW

This review is aimed at clinicians appraising preclinical trauma studies and researchers investigating compromised bone healing or novel treatments for fractures. It categorises the clinical scenarios of poor healing of fractures and attempts to match them with the appropriate animal models in the literature.

We performed an extensive literature search of animal models of long bone fracture repair/nonunion and grouped the resulting studies according to the clinical scenario they were attempting to reflect; we then scrutinised them for their reliability and accuracy in reproducing that clinical scenario.

Models for normal fracture repair (primary and secondary), delayed union, nonunion (atrophic and hypertrophic), segmental defects and fractures at risk of impaired healing were identified. Their accuracy in reflecting the clinical scenario ranged greatly and the reliability of reproducing the scenario ranged from 100% to 40%.

It is vital to know the limitations and success of each model when considering its application.


Bone & Joint Research
Vol. 6, Issue 4 | Pages 253 - 258
1 Apr 2017
Hsu C Lin C Jou I Wang P Lee J

Objectives

Osteoarthritis (OA) is the most common form of arthritis, affecting approximately 15% of the human population. Recently, increased concentration of nitric oxide in serum and synovial fluid in patients with OA has been observed. However, the exact role of nitric oxide in the initiation of OA has not been elucidated. The aim of the present study was to investigate the role of nitric oxide in innate immune regulation during OA initiation in rats.

Methods

Rat OA was induced by performing meniscectomy surgery while cartilage samples were collected 0, 7, and 14 days after surgery. Cartilage cytokine levels were determined by using enzyme-linked immunosorbent assay, while other proteins were assessed by using Western blot


Bone & Joint Research
Vol. 3, Issue 4 | Pages 89 - 94
1 Apr 2014
Cook JL Hung CT Kuroki K Stoker AM Cook CR Pfeiffer FM Sherman SL Stannard JP

Cartilage repair in terms of replacement, or regeneration of damaged or diseased articular cartilage with functional tissue, is the ‘holy grail’ of joint surgery. A wide spectrum of strategies for cartilage repair currently exists and several of these techniques have been reported to be associated with successful clinical outcomes for appropriately selected indications. However, based on respective advantages, disadvantages, and limitations, no single strategy, or even combination of strategies, provides surgeons with viable options for attaining successful long-term outcomes in the majority of patients. As such, development of novel techniques and optimisation of current techniques need to be, and are, the focus of a great deal of research from the basic science level to clinical trials. Translational research that bridges scientific discoveries to clinical application involves the use of animal models in order to assess safety and efficacy for regulatory approval for human use. This review article provides an overview of animal models for cartilage repair.

Cite this article: Bone Joint Res 2014;4:89–94.


Bone & Joint 360
Vol. 6, Issue 1 | Pages 3 - 6
1 Feb 2017
Horn A Eastwood D