Several bisphosphonates are now available for the treatment of osteoporosis. Porous hydroxyapatite/collagen (HA/Col) composite is an osteoconductive bone substitute which is resorbed by osteoclasts. The effects of the bisphosphonate alendronate on the formation of bone in porous HA/Col and its resorption by osteoclasts were evaluated using a rabbit model. Porous HA/Col cylinders measuring 6 mm in diameter and 8 mm in length, with a pore size of 100 μm to 500 μm and 95% porosity, were inserted into a defect produced in the lateral femoral condyles of 72 rabbits. The rabbits were divided into four groups based on the protocol of alendronate administration: the control group did not receive any alendronate, the pre group had alendronate treatment for three weeks prior to the implantation of the HA/Col, the post group had alendronate treatment following implantation until euthanasia, and the pre+post group had continuous alendronate treatment from three weeks prior to surgery until euthanasia. All rabbits were injected intravenously with either saline or alendronate (7.5 μg/kg) once a week. Each group had 18 rabbits, six in each group being killed at three, six and 12 weeks post-operatively. Alendronate administration suppressed the resorption of the implants. Additionally, the mineral densities of newly formed bone in the alendronate-treated groups were lower than those in the control group at 12 weeks post-operatively. Interestingly, the number of osteoclasts attached to the implant correlated with the extent of bone formation at three weeks. In conclusion, the systemic administration of alendronate in our rabbit model at a dose-for-weight equivalent to the clinical dose used in the treatment of osteoporosis in Japan affected the mineral density and remodelling of bone tissue in implanted porous HA/Col composites

Mononuclear osteoclast precursors are present in the wear-particle-associated macrophage infiltrate found in the membrane surrounding loose implants. These cells are capable of differentiating into osteoclastic bone-resorbing cells when co-cultured with the rat osteoblast-like cell line, UMR 106, in the presence of 1,25(OH). 2. vitamin D. 3. In order to develop an in vitro model of osteoclast differentiation which more closely parallels the cellular microenvironment at the bone-implant interface in situ, we determined whether osteoblast-like human bone-derived cells were capable of supporting the differentiation of osteoclasts from arthroplasty-derived cells and analysed the humoral conditions required for this to occur. Long-term co-culture of arthroplasty-derived cells and human trabecular-bone-derived cells (HBDCs) resulted in the formation of numerous tartrate-resistant-acid-phosphatase (TRAP) and vitronectin-receptor (VNR)-positive multinucleated cells capable of extensive resorption of lacunar bone. The addition of 1,25(OH). 2. vitamin D. 3. was not required for the formation of osteoclasts and bone resorption. During the formation there was release of substantial levels of M-CSF and PGE. 2. Exogenous PGE. 2. (10. −8. to 10. −6. M) was found to stimulate strongly the resorption of osteoclastic bone. Our study has shown that HBDCs are capable of supporting the formation of osteoclasts from mononuclear phagocyte precursors present in the periprosthetic tissues surrounding a loose implant. The release of M-CSF and PGE. 2. by activated cells at the bone-implant interface may be important for the formation of osteoclasts at sites of pathological bone resorption associated with aseptic loosening

Peri-prosthetic osteolysis and subsequent aseptic loosening is the most common reason for revising total hip replacements. Wear particles originating from the prosthetic components interact with multiple cell types in the peri-prosthetic region resulting in an inflammatory process that ultimately leads to peri-prosthetic bone loss. These cells include macrophages, osteoclasts, osteoblasts and fibroblasts. The majority of research in peri-prosthetic osteolysis has concentrated on the role played by osteoclasts and macrophages. The purpose of this review is to assess the role of the osteoblast in peri-prosthetic osteolysis. In peri-prosthetic osteolysis, wear particles may affect osteoblasts and contribute to the osteolytic process by two mechanisms. First, particles and metallic ions have been shown to inhibit the osteoblast in terms of its ability to secrete mineralised bone matrix, by reducing calcium deposition, alkaline phosphatase activity and its ability to proliferate. Secondly, particles and metallic ions have been shown to stimulate osteoblasts to produce pro inflammatory mediators in vitro. In vivo, these mediators have the potential to attract pro-inflammatory cells to the peri-prosthetic area and stimulate osteoclasts to absorb bone. Further research is needed to fully define the role of the osteoblast in peri-prosthetic osteolysis and to explore its potential role as a therapeutic target in this condition. Cite this article: Bone Joint J 2013;95-B:1021–5

Carbonate-substituted hydroxyapatite (CHA) is more osteoconductive and more resorbable than hydroxyapatite (HA), but the underlying mode of its action is unclear. We hypothesised that increased resorption of the ceramic by osteoclasts might subsequently upregulate osteoblasts by a coupling mechanism, and sought to test this in a large animal model. Defects were created in both the lateral femoral condyles of 12 adult sheep. Six were implanted with CHA granules bilaterally, and six with HA. Six of the animals in each group received the bisphosphonate zoledronate (0.05 mg/kg), which inhibits the function of osteoclasts, intra-operatively. After six weeks bony ingrowth was greater in the CHA implants than in HA, but not in the animals given zoledronate. Functional osteoclasts are necessary for the enhanced osteoconduction seen in CHA compared with HA

1. In five out of eleven cases of osteoclastoma it was found that osteoclasts were present inside clearly defined blood vessels either within the tumours or in the tissues immediately surrounding the tumours. In two further cases it was found that osteoclasts protruded into the vessels although they were not lying free within the vessels. 2. The possible modes of entry of these cells into the blood stream are discussed. Although accidental dissemination of osteoclasts into damaged blood vessels could not be excluded, it was felt that the process was equally likely to be related to some inherent property of the osteoclasts. From further observations it is suggested that osteoclasts are capable of local destruction of the connective tissues of the vessel walls, probably by enzyme action. Such an action might be analogous to the processes by which, in the opinion of many, osteoclasts bring about the resorption of bone. 3. There did not seem to be any relationship between the finding of intravascular osteoclasts and the malignancy of the tumour, assessing the latter either on histological or clinical grounds. The finding of intravascular osteoclasts does not therefore appear to be of any prognostic significance

Abundant implant-derived biomaterial wear particles are generated in aseptic loosening and are deposited in periprosthetic tissues in which they are phagocytosed by mononuclear and multinucleated macrophage-like cells. It has been stated that the multinucleated cells which contain wear particles are not bone-resorbing osteoclasts. To investigate the validity of this claim we isolated human osteoclasts from giant-cell tumours of bone and rat osteoclasts from long bones. These were cultured on glass coverslips and on cortical bone slices in the presence of particles of latex, PMMA and titanium. Osteoclast phagocytosis of these particle types was shown by light microscopy, energy-dispersive X-ray analysis and SEM. Giant cells containing phagocytosed particles were seen to be associated with the formation of resorption lacunae. Osteoclasts containing particles were also calcitonin-receptor-positive and showed an inhibitory response to calcitonin. Our findings demonstrate that osteoclasts are capable of phagocytosing particles of a wide range of size, including particles of polymeric and metallic bio-materials found in periprosthetic tissues, and that after particle phagocytosis, they remain fully functional, hormone-responsive, bone-resorbing cells

The continual cycle of bone formation and resorption is carried out by osteoblasts, osteocytes, and osteoclasts under the direction of the bone-signaling pathway. In certain situations the host cycle of bone repair is insufficient and requires the assistance of bone grafts and their substitutes. The fundamental properties of a bone graft are osteoconduction, osteoinduction, osteogenesis, and structural support. Options for bone grafting include autogenous and allograft bone and the various isolated or combined substitutes of calcium sulphate, calcium phosphate, tricalcium phosphate, and coralline hydroxyapatite. Not all bone grafts will have the same properties. As a result, understanding the requirements of the clinical situation and specific properties of the various types of bone grafts is necessary to identify the ideal graft. We present a review of the bone repair process and properties of bone grafts and their substitutes to help guide the clinician in the decision making process. Cite this article: Bone Joint J 2016;98-B(1 Suppl A):6–9

The cellular mechanisms which account for the formation of osteoclasts and bone resorption associated with enlarging benign and malignant mesenchymal tumours of bone are uncertain. Osteoclasts are marrow-derived, multinucleated, bone-resorbing cells which express a macrophage phenotype. We have determined whether tumour-associated macrophages (TAMs) isolated from benign and malignant mesenchymal tumours are capable of differentiating into osteoclasts. Macrophages were cultured on both coverslips and dentine slices for up to 21 days with UMR 106 osteoblastic cells in the presence of 1,25 dihydroxyvitamin D. 3. (1,25(OH). 2. D. 3. ) and human macrophage colony-stimulating factor (M-CSF) or, in the absence of UMR 106 cells, with M-CSF and RANK ligand. In all tumours, the formation of osteoclasts from CD14-positive macrophages was shown by the formation of tartrate-resistant-acid-phosphatase and vitronectin-receptor-positive multinucleated cells which were capable of carrying out lacunar resorption. These results indicate that the tumour osteolysis associated with the growth of mesenchymal tumours in bone is likely to be due in part to the differentiation of mononuclear phagocyte osteoclast precursors which are present in the TAM population of these lesions

The multifunctional adhesion molecule CD44 is a major cell-surface receptor for hyaluronic acid (HUA). Recent data suggest that it may also bind the ubiquitous bone-matrix protein, osteopontin (OPN). Because OPN has been shown to be a potentially important protein in bone remodelling, we investigated the hypothesis that OPN interactions with the CD44 receptor on bone cells participate in the regulation of the healing of fractures. We examined the spatial and temporal patterns of expression of OPN and CD44 in healing fractures of rat femora by in situ hybridisation and immunohistochemistry. We also localised HUA in the fracture callus using biotinylated HUA-binding protein. OPN was expressed in remodelling areas of the hard callus and was found in osteocytes, osteoclasts and osteoprogenitor cells, but not in cuboidal osteoblasts which were otherwise shown to express osteocalcin. The OPN signal in osteocytes was not uniformly distributed, but was restricted to specific regions near sites where OPN mRNA-positive osteoclasts were attached to bone surfaces. In the remodelling callus, intense immunostaining for CD44 was detected in osteocyte lacunae, along canaliculi, and on the basolateral plasma membrane of osteoclasts, but not in the cuboidal osteoblasts. HUA staining was detected in fibrous tissues but little was observed in areas of hard callus where bone remodelling was progressing. Our findings suggest that OPN, rather than HUA, is the major ligand for CD44 on bone cells in the remodelling phase of healing of fractures. They also raise the possibility that such interactions may be involved in the communication of osteocytes with each other and with osteoclasts on bone surfaces. The interactions between CD44 and OPN may have important clinical implications in the repair of skeletal tissues

Previous studies have shown that the activity of the cytostatic drug methotrexate (MTX) embedded in acrylic cement is not affected by thermal changes in the cement. MTX is slowly released from the cement for several months and remains biologically active throughout this period. Our aim was to determine whether MTX embedded in cement would control the local growth of a tumour. In 15 rabbits we injected 0.1 ml of VX. 2. tumour suspension into the proximal tibia. At 3, 5, 7, 10 and 14 days three animals were killed and the tibiae removed and examined histologically. With increasing growth of the VX. 2. carcinoma there was increased bone destruction and a rise in the numbers of osteoclasts, but after 14 days the numbers of osteoclasts had decreased. We then injected VX. 2. into the tibiae of another 45 rabbits. After 5 days most of the tumour was curetted out and the defect filled with cement containing either 0 g, 0.1 g, 0.5 g, 1.0 g or 2.0 g MTX/40 g cement. The rabbits were divided into three groups and killed at 3, 7 or 10 days after implantation of cement. The number of osteoclasts and the amount of bone destruction were measured in each tibia. In all three groups bone destruction and osteoclast proliferation were markedly decreased with higher doses of MTX, but bone destruction was not eliminated. Our findings show that in the higher doses used, which were not toxic to the animal, MTX-embedded cement may be of value in minimising the amount of tumour-induced osteolysis and may be a useful adjunct in the surgical management of pathological fractures

Extensive osteolysis adjacent to implants is often associated with wear particles of prosthetic material. We have investigated if RANKL, also known as osteoprotegerin ligand, osteoclast differentiation factor or TRANCE, and its natural inhibitor, osteoprotegerin (OPG), may be important in controlling this bone loss. Cells isolated from periprosthetic tissues containing wear particles expressed mRNA encoding for the pro-osteoclastogenic molecules, RANKL, its receptor RANK, monocyte colony-stimulating factor (M-CSF), interleukin (IL)-1β, tumour necrosis factor (TNF)α, IL-6, and soluble IL-6 receptor, as well as OPG. Osteoclasts formed from cells isolated from periprosthetic tissues in the presence and absence of human osteoblastic cells. When osteoclasts formed in the absence of osteoblastic cells, markedly higher levels of RANKL mRNA relative to OPG mRNA were expressed. Particles of prosthetic materials also stimulated human monocytes to express osteoclastogenic molecules in vitro. Our results suggest that ingestion of prosthetic wear particles by macrophages results in expression of osteoclast-differentiating molecules and the stimulation of macrophage differentiation into osteoclasts

We have used an experimental model employing the bent tail of rats to investigate the effects of mechanical forces on bones and joints. Mechanical strain could be applied to the bones and joints of the tail without direct surgical exposure or the application of pins and wires. The intervertebral disc showed stretched annular lamellae on the convex side, while the annulus fibrosus on the concave side was pinched between the inner corners of the vertebral epiphysis. In young rats with an active growth plate, a transverse fissure appeared at the level of the hypertrophic cell layer or the primary metaphyseal trabecular zone. Metaphyseal and epiphyseal trabeculae on the compressed side were thicker and more dense than those of the distracted part of the vertebra. In growing animals, morphometric analysis of hemiepiphyseal and hemimetaphyseal areas, and the corresponding trabecular bone density, showed significant differences between the compressed and distracted sides. No differences were observed in adult rats. We found no significant differences in osteoclast number between compressed and distracted sides in either age group. Our results provide quantitative evidence of the working of ‘Wolff’s law’. The differences in trabecular density are examples of remodelling by osteoclasts and osteoblasts; our finding of no significant difference in osteoclast numbers between the hemiepiphyses in the experimental and control groups suggests that the response of living bone to altered strain is mediated by osteoblasts

Biochemical markers of bone-turnover have long been used to complement the radiological assessment of patients with metabolic bone disease. Their implementation in daily clinical practice has been helpful in the understanding of the pathogenesis of osteoporosis, the selection of the optimal dose and the understanding of the progression of the onset and resolution of treatment. Since they are derived from both cortical and trabecular bone, they reflect the metabolic activity of the entire skeleton rather than that of individual cells or the process of mineralisation. Quantitative changes in skeletal-turnover can be assessed easily and non-invasively by the measurement of bone-turnover markers. They are commonly subdivided into three categories; 1) bone-resorption markers, 2) osteoclast regulatory proteins and 3) bone-formation markers. Because of the rapidly accumulating new knowledge of bone matrix biochemistry, attempts have been made to use them in the interpretation and characterisation of various stages of the healing of fractures. Early knowledge of the individual progress of a fracture could help to avoid delayed or nonunion by enabling modification of the host’s biological response. The levels of bone-turnover markers vary throughout the course of fracture repair with their rates of change being dependent on the size of the fracture and the time that it will take to heal. However, their short-term biological variability, the relatively low bone specificity exerted, given that the production and destruction of collagen is not limited to bone, as well as the influence of the host’s metabolism on their concentration, produce considerable intra- and inter-individual variability in their interpretation. Despite this, the possible role of bone-turnover markers in the assessment of progression to union, the risks of delayed or nonunion and the impact of innovations to accelerate fracture healing must not be ignored

Calcified matrix that is being absorbed has a characteristic appearance. At the junction of the epiphysis and metaphysis in the rat tibia this appearance can be seen near capillary endothelium as well as under osteoclasts. It is concluded that absorption can take place under the walls of capillaries without the presence of osteoclasts

We studied the morphology of the haversian canals in the osteopenic cortical bone of the medial femoral neck from patients with rheumatoid arthritis and compared the findings with those in patients with osteoarthritis and with uncomplicated coxa valga. In the rheumatoid bone, the diameters of the canals were larger and many more contained osteoclasts. Fewer haversian canals showed only lining cells than in the osteoarthritic or coxa valga patients. In bone from rheumatoid patients, especially in canals with osteoclasts, small blood vessels were frequently lined by tall endothelial cells with an infiltration of mononuclear cells. These morphological differences are discussed with reference to the possible mechanisms of loss of cortical bone in rheumatoid arthritis and other conditions

Out of 21 900 cases filed at the Latin-American Registry of Bone Pathology between April 1940 and July 1981, there were 987 with Paget's disease (4.51 per cent); 62 of these (6.28 per cent) were complicated by sarcoma and two were associated with giant-cell tumours of bone (osteoclastoma) without signs of malignancy. There was a slight predominance of men and the ages ranged from 45 to 87 years, with an average of 66 years. The most frequent sites were the femur (23 cases), the humerus (nine), the pelvis (10), and the tibia (nine). The low incidence of vertebral involvement (five cases) is noteworthy and is in sharp contrast to uncomplicated Paget's disease. The most common tumour type was osteosarcoma (39 cases), followed by fibrosarcoma (15 cases); other varieties (chondrosarcoma, malignant fibrous histiocytoma and reticulum-cell sarcoma) were much rarer. Most of the sarcomata occurred when the Paget's disease was polyostotic. Tumours often developed simultaneously, or at short time intervals, in the same or different bones; these bones had, in all cases, been affected by Paget's disease. The histological features of the osteosarcomata were characteristic, with large numbers of osteoclast giant cells, alternating with atypical osteoblasts, thus exaggerating the anarchic remodelling process of Paget's disease. The neighbouring areas of the pagetic bone showed an increased number of osteoclasts. These facts suggest a possible pathogenetic relationship between sarcoma and Paget's disease; the possibility of both processes having a viral aetiology is discussed

We have attempted to summarise in a short space investigations that have occupied several years, and we realise that whatever the merits of such an effort the results can only be modest. Many important aspects of the osteogenetic process still remain a mystery and thus are subjected to theory and controversy. Such is the case with this constant attendant at osteogenesis which is alkaline phosphatase. But of one thing we are certain, namely that bone is an organised "soft" tissue of which only part has been made rigid by the deposit of calcium salts. The organiser is the osteogenetic vessel from which springs the syncytial frame of cells and their connections on which the bone architecture is established. Endothelial cell, intermediate cell, osteoblast, osteocyte, osteoclast; these constitute the normal sequence of cellular phylogeny in the constant elaboration and removal of the bone substance. The initial cells on which the whole process rests are those of the capillary-sinusoid vessel which is responsible for providing the transudates on which the life and health of the whole syncytium depends. If our findings were confirmed, a better understanding of the nature and characteristics of primitive malignant bone tumours would be possible. Each type of tumour from endothelioma to malignant osteoclastoma, including reticulum-cell sarcoma and osteogenic sarcoma, would be initiated by a different cell of the syncytium, but in its monstrous deviation from the normal would still preserve most of the characteristics of its healthy ancestor. Thus the endothelioma causes bone expansion, bone reaction and even bone necrosis, but not proper bone formation, whereas the osteogenic sarcoma or osteoblastoma forms bone; and with the same fidelity to their origin osteoclasts are seen in the malignant osteolytic tumour. Over thirty years ago the late Sir Arthur Keith (1927) expressed his suspicion that the cells which assume a bone-forming role are derived from the endothelium of the capillary system. We hope we have contributed to show that his suspicion was right

Aims

Thresholds of acceptable early migration of the components in total knee arthroplasty (TKA) have traditionally ignored the effects of patient and implant factors that may influence migration. The aim of this study was to determine which of these factors are associated with overall longitudinal migration of well-fixed tibial components following TKA.

The Gorham-Stout Syndrome (Gorham’s massive osteolysis) is a rare condition in which spontaneous, progressive resorption of bone occurs. The aetiology is poorly understood. We report six cases of the condition and present evidence that osteolysis is due to an increased number of stimulated osteoclasts. This suggests that early potent antiresorptive therapy such as with calcitonin or bisphosphonates may prevent local progressive osteolysis

Aims

Local recurrence remains a challenging and common problem following curettage and joint-sparing surgery for giant cell tumour of bone (GCTB). We previously reported a 15% local recurrence rate at a median follow-up of 30 months in 20 patients with high-risk GCTB treated with neoadjuvant Denosumab. The aim of this study was to determine if this initial favourable outcome following the use of Denosumab was maintained with longer follow-up.