Showing papers by "Nuffield Orthopaedic Centre published in 2003"

Zoledronic Acid Treatment of 5T2MM‐Bearing Mice Inhibits the Development of Myeloma Bone Disease: Evidence for Decreased Osteolysis, Tumor Burden and Angiogenesis, and Increased Survival

Abstract: Multiple myeloma is characterized by the growth of plasma cells in the bone marrow and the development of osteolytic bone disease. Myeloma cells are found closely associated with bone, and targeting this environment may therefore affect both the bone disease and the growth of myeloma cells. We have investigated the effect of the potent bisphosphonate, zoledronic acid, on the development of bone disease, tumor burden, and disease-free survival in the 5T2MM model of myeloma. 5T2MM murine myeloma cells were injected intravenously into C57BL/KaLwRij mice. After 8 weeks, all animals had a paraprotein. Animals were treated with zoledronic acid (120 μg/kg, subcutaneously, twice weekly) or vehicle, from the time of tumor cell injection or from paraprotein detection for 12 or 4 weeks, respectively. All animals injected with tumor cells developed osteolytic lesions, a decrease in cancellous bone volume, an increase in osteoclast perimeter, and a decrease in bone mineral density. Zoledronic acid prevented the formation of lesions, prevented cancellous bone loss and loss of bone mineral density, and reduced osteoclast perimeter. Zoledronic acid also decreased paraprotein concentration, decreased tumor burden, and reduced angiogenesis. In separate experiments, Kaplan-Meier analysis demonstrated a significant increase in survival after treatment with zoledronic acid when compared with control (47 vs. 35 days). A single dose of zoledronic acid was also shown to be effective in preventing the development of osteolytic bone disease. These data show that zoledronic acid is able to prevent the development of osteolytic bone disease, decrease tumor burden in bone, and increase survival in a model of established myeloma.

Intraosseous lipoma: report of 35 new cases and a review of the literature

Abstract: To identify the common imaging features of intraosseous lipomas on radiographs, magnetic resonance imaging (MRI) and computed tomography (CT), and review their histological features. Thirty-five previously unreported cases of intraosseous lipoma were reviewed and a meta-analysis was performed of another 110 cases identified from the English language literature. The mean age at presentation is 43 years. Sex distribution is nearly equal. Lipomas occur most frequently in the lower limb (71% overall), particularly in the os calcis (32%). Other common sites include the metaphyses of long bones, where lesions are typically eccentric. Lipomas are usually well defined, but marginal sclerosis is commoner in lesions of the os calcis (61%) than at other sites (38%). Calcification is also more frequent in the os calcis (62%), and almost invariably centrally located. Calcification at other sites is less common (30%), and is more variable in appearance. Bone expansion is less common (30%), and usually minimal. Fat necrosis and cyst formation identified on MRI is common (67%), and more frequent in the os calcis. Although there is correlation between the histological and radiological features of intraosseous lipomas in general, some discrepancies occur in the radiological appearances of lipomas in different sites. The evidence that these lesions are true benign tumours of fat is controversial. Several aetiological factors have been implicated in their development. The constant location of os calcis lesions at the critical angle suggests an aetiology that may be related to biomechanical lines of stress. In other instances it is possible that involution of pre-existing lesions may lead to the development of lipomas.

Genetics of neuroendocrine and carcinoid tumours.

Abstract: Neuroendocrine tumours (NETs) originate in tissues that contain cells derived from the embryonic neural crest, neuroectoderm and endoderm. Thus, NETs occur at many sites in the body, although the majority occur within the gastro-entero-pancreatic axis and can be subdivided into those of foregut, midgut and hindgut origin. Amongst these, only those of midgut origin are generally argentaffin positive and secrete serotonin, and hence only these should be referred to as carcinoid tumours. NETs may occur as part of complex familial endocrine cancer syndromes, such as multiple endocrine neoplasia type 1 (MEN1), although the majority occur as non-familial (i.e. sporadic) isolated tumours. Molecular genetic studies have revealed that the development of NETs may involve different genes, each of which may be associated with several different abnormalities that include point mutations, gene deletions, DNA methylation, chromosomal losses and chromosomal gains. Indeed, the foregut, midgut and hindgut NETs develop via different molecular pathways. For example, foregut NETs have frequent deletions and mutations of the MEN1 gene, whereas midgut NETs have losses of chromosome 18, 11q and 16q and hindgut NETs express transforming growth factor-alpha and the epidermal growth factor receptor. Furthermore, in lung NETs, a loss of chromosome 3p is the most frequent change and p53 mutations and chromosomal loss of 5q21 are associated with more aggressive tumours and poor survival. In addition, methylation frequencies of retinoic acid receptor-beta, E-cadherin and RAS-associated domain family genes increase with the severity of lung NETs. Thus the development and progression of NETs is associated with specific genetic abnormalities that indicate the likely involvement of different molecular pathways.

A mobile-bearing total knee prosthesis compared with a fixed-bearing prosthesis: A MULTICENTRE SINGLE-BLIND RANDOMISED CONTROLLED TRIAL

Abstract: Before proceeding to longer-term studies, we have studied the early clinical results of a new mobile-bearing total knee prosthesis in comparison with an established fixed-bearing device. Patients requiring bilateral knee replacement consented to have their operations under one anaesthetic using one of each prosthesis. They also agreed to accept the random choice of knee (right or left) and to remain ignorant as to which side had which implant. Outcomes were measured using the American Knee Society Score (AKSS), the Oxford Knee Score (OKS), and determination of the range of movement and pain scores before and at one year after operation. Preoperatively, there was no systematic difference between the right and left knees. One patient died in the perioperative period and one mobile-bearing prosthesis required early revision for dislocation of the meniscal component. At one year the mean AKSS, OKS and pain scores for the new device were slightly better (p < 0.025) than those for the fixed-bearing device. There was no difference in the range of movement. We believe that this is the first controlled, blinded trial to compare early function of a new knee prosthesis with that of a standard implant. It demonstrates a small but significant clinical advantage for the mobile-bearing design.

Multiple myeloma biology: lessons from the 5TMM models.

Abstract: Multiple myeloma (MM) is a B cell neoplasm characterized by the monoclonal proliferation of plasma cells in the bone marrow, the development of osteolytic lesions and the induction of angiogenesis. These different processes require three-dimensional interactions, with both humoral and cellular contacts. The 5TMM models are suitable models to study these interactions. These murine models originate from spontaneously developed myeloma in elderly mice, which are propagated by in vivo transfer of the myeloma cells into young syngeneic mice. In this review we report on studies performed in the 5TMM models with special emphasis on the homing of the myeloma cells, the characterization of the migrating and proliferating clone and the identification of the isotype switch variants. The bone marrow microenvironment was further targeted with osteoprotegerin (OPG) to block the RANK/RANKL/OPG system and with potent bisphosphonates. Both treatments resulted in a significant protection against myeloma-associated bone disease, and they decreased myeloma disease, as evidenced by a lower tumor load and an increased survival of the mice. These different studies demonstrate the strength of these models, not only in unraveling basic biological processes but also in the testing of potentially new therapeutic targets.

Strain distribution within the human femur due to physiological and simplified loading: Finite element analysis using the muscle standardized femur model

Abstract: The aim of the current work was to study the effect of simplified loading on strain distribution within the intact femur using the Muscle Standardized Femur finite element model and to investigate whether the interaction between the intact human femur and the muscles which are attached to the bone surface could accurately be represented by concentrated forces, applied through the centroids of their attachment areas. An instant at 10 per cent of the gait cycle during level walking was selected as the reference physiological load case; nine load cases were analysed. Comparison of the calculated results for the physiological load case with muscle forces uniformly distributed over their attachment areas showed good agreement with in vivo measurements of strain values and femoral head displacement in humans. Simplified load cases generated unrealistic displacement results and high strain magnitudes, exceeding the physiological range. It was found that when muscles with large attachment areas are included in the model and the muscle forces are simplified, stress and strain distributions will be affected not only on the external bone surface in the vicinity of the load application node, but also on the internal surface of the cortical bone. However, applying muscle forces as concentrated loads at the centroids of the attachment areas can serve as first indicators of the physiological stress and strain levels, if results from nodes and elements in the vicinity of the load application nodes are discarded. Omitting muscle forces or fixing the femur in mid-shaft leads to large unphysiological strain values.

Site and Gender Specificity of Inheritance of Bone Mineral Density

Abstract: Differences in genetic control of BMD by skeletal sites and genders were examined by complex segregation analysis in 816 members of 147 families with probands with extreme low BMD. Spine BMD correlated more strongly in male-male comparisons and hip BMD in female-female comparisons, consistent with gender- and site-specificity of BMD heritability. Introduction: Evidence from studies in animals and humans suggests that the genetic control of bone mineral density (BMD) may differ at different skeletal sites and between genders. This question has important implications for the design and interpretation of genetic studies of osteoporosis. Methods: We examined the genetic profile of 147 families with 816 individuals recruited through probands with extreme low BMD (T-score < −2.5, Z-score < −2.0). Complex segregation analysis was performed using the Pedigree Analysis Package. BMD was measured by DXA at both lumbar spine (L1-L4) and femoral neck. Results: Complex segregation analysis excluded purely monogenic and environmental models of segregation of lumbar spine and femoral neck BMD in these families. Pure polygenic models were excluded at the lumbar spine when menopausal status was considered as a covariate, but not at the femoral neck. Mendelian models with a residual polygenic component were not excluded. These models were consistent with the presence of a rare Mendelian genotype of prevalence 3–19 %, causing high BMD at the hip and spine in these families, with additional polygenic effects. Total heritability range at the lumbar spine was 61–67 % and at the femoral neck was 44–67 %. Significant differences in correlation of femoral neck and lumbar spine BMD were observed between male and female relative pairs, with male-male comparisons exhibiting stronger lumbar spine BMD correlation than femoral neck, and female-female comparisons having greater femoral neck BMD correlation than lumbar spine. These findings remained true for parent-offspring correlations when menopausal status was taken into account. The recurrence risk ratio for siblings of probands of a Z-score < −2.0 was 5.4 at the lumbar spine and 5.9 at the femoral neck. Conclusions: These findings support gender- and site-specificity of the inheritance of BMD. These results should be considered in the design and interpretation of genetic studies of osteoporosis.

UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy.

Abstract: Gout, which is commonly associated with hyperuricemia, affects 0.2% of the population. Hyperuricemia has a heterogeneous etiology that may be due to either over production and/or reduced renal clearance, of urate. In order to identify the mechanisms underlying reduced excretion of urate, we undertook positional cloning studies of familial juvenile hyperuricaemic nephropathy (FJHN), which is an autosomal dominant disorder characterized by hyperuricaemia, a low fractional renal excretion of urate, and chronic renal failure that is associated with interstitial fibrosis. The FJHN locus has been previously localized to a 22 centiMorgan interval flanked centromerically by D16S401 and telomerically by D16S3069, on chromosome 16p11-p13. This interval contains over 120 genes and we selected 13 renal expressed sequences to search for mutations in 5 unrelated FJHN families that contained 21 affected and 24 unaffected members. This revealed 5 heterozygous missense mutations (Cys77Tyr, Cys126Arg, Asn128Ser, Cys255Tyr and Cys300Gly) that altered evolutionary conserved residues in the gene encoding UROMODULIN. UROMODULIN, which is an 85 Kda glycoprotein, has roles in renal stone formation, the modulation of immune responses, and urothelial cytoprotection. The results of our studies, which have identified the gene causing FJHN, now indicate a further, novel role for UROMODULIN in urate metabolism.

Vascularity in a new model of atrophic nonunion

Abstract: Our aim was to develop a clinically relevant model of atrophic nonunion in the rat to test the hypothesis that the vessel density of atrophic nonunion reaches that of normal healing bone, but at a later time-point. Atrophic nonunion is usually attributed to impaired blood supply and is poorly understood. We determined the number of blood vessels at the site of an osteotomy using immunolocalisation techniques in both normally healing bones and in atrophic nonunion. At one week after operation there were significantly fewer blood vessels in the nonunion group than in the healing group. By eight weeks, the number in the atrophic nonunion group had reached the same level as that in the healing group. Our findings suggest that the number of blood vessels in atrophic nonunion reaches the same level as that in healing bone, but at a later time-point. Diminished vascularity within the first three weeks, but not at a later time-point, may prevent fractures from uniting.

Dynamic foot movement in children treated for congenital talipes equinovarus

Abstract: The aim of this study was to define objectively gait function in children with treated congenital talipes equinovarus (CTEV) and a good clinical result The study also attempted an analysis of movement within the foot during gait We compared 20 children with treated CTEV with 15 control subjects Clinical assessment demonstrated good results from treatment Three-dimensional gait analysis provided kinematic and kinetic data describing movement and moments at the joints of the lower limb during gait A new method was used to study movement within the foot during gait The data on gait showed significantly increased internal rotation of the foot during walking which was partially compensated for by external rotation at the hip A mild foot drop and reduced plantar flexor power were also observed Dorsiflexion at the midfoot was significantly increased, which probably compensated for reduced mobility at the hindfoot Patients treated for CTEV with a good clinical result should be expected to have nearly normal gait and dynamic foot movement, but there may be residual intoeing, mild foot drop, loss of plantar flexor power with compensatory increased midfoot dorsiflexion and external hip rotation

Power Doppler ultrasound of rheumatoid synovitis: quantification of therapeutic response

Abstract: The aim of this study is to quantify power Doppler assessment of therapeutic response in rheumatoid synovitis. 13 patients (6 male, 7 female) with rheumatoid arthritis, who had an acute exacerbation of small joint synovitis in the hands, were examined with quantitative power Doppler, before and after intravenous corticosteroid treatment. All patients were examined by a single radiologist, using an ATL HDI 5000 ultrasound machine (ATL, Boswell). The images were analysed using a specially developed software package (HDI Lab), which quantifies power Doppler signal. All patients improved clinically following treatment, which was reflected in functional disability scores, and in the C-reactive protein levels and erythrocyte sedimentation rate. In all cases, there was a significant decrease in synovial vascularity as measured by the mean amplitude of signal on quantitative power Doppler. Quantitative power Doppler may allow objective assessment of treatment in small joint synovitis.

Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism.

Abstract: Summary background Familial isolated hyperparathyroidism (FIHP) is an autosomal dominant disorder characterized by uniglandular or multiglandular parathyroid tumours that occur in the absence of other endocrine tumours. The disorder may represent either an early stage of multiple endocrine neoplasia type 1 (MEN1), or an allelic variant of MEN1, or a distinct entity involving another locus. We have explored these possibilities in seven families in whom primary hyperparathyroidism occurred as the sole endocrinopathy. methods Seven FIHP families were ascertained and venous blood samples obtained from 35 members (17 affected and 18 unaffected) for DNA sequence analysis of the MEN1 gene. The mean (± SD) follow-up period in the 17 affected members was 15·06 (± 8·83) years. results Four heterozygous germline mutations of the MEN1 gene were identified. These consisted of two 4-bp intragenic deletions that would result in prematurely truncated proteins, and two missense (Asp153Val and Ala411Pro) mutations. Furthermore, analysis of parathyroid tumour DNA from one individual revealed a loss of the wild-type allele and retention of the mutant allele, consistent with Knudson's ‘two-hit’ model of hereditary cancer and a tumour suppressor role for MEN1 in FIHP. conclusions Our results provide further support for FIHP being a distinct allelic variant of MEN1, and an analysis of the 16 mutations reported to date indicate that FIHP is associated with a higher frequency of missense MEN1 mutations.

Investigation of the role of ANKH in ankylosing spondylitis

Abstract: Objective. The ank/ank mouse develops a phenotype similar to ankylosing spondylitis (AS) in humans. ANKH, the human homolog of the mutated gene in the ank/ank mouse, has been implicated in familial autosomal-dominant chondrocalcinosis and autosomal-dominant craniometaphyseal dysplasia. This study was undertaken to investigate the role of ANKH in susceptibility to and clinical manifestations of AS. Methods. Sequence variants were identified by genomic sequencing of the 12 ANKH exons and their flanking splice sites in 48 AS patients; variants were then screened in 233 patients and 478 controls. Linkage to the ANKH locus was assessed in 185 affected-sibling-pair families. Results. Five single-nucleotide polymorphisms were identified within the coding region and flanking splice sites. No association between either susceptibility to AS or its clinical manifestations and these novel polymorphisms, or between disease susceptibility and 3 known promoter variants, was seen. No linkage between the ANKH locus and AS was observed. Multipoint exclusion mapping rejected the hypothesis of a locus of a magnitude lambdagreater than or equal to1.4 (logarithm of odds score 10% to the AS sibling recurrence risk ratio) within this area contributing to AS. Conclusion. These findings indicate that ANKH is not significantly involved in susceptibility to or clinical manifestations of AS.

MRI of mycetoma of the foot: two cases demonstrating the dot-in-circle sign.

Abstract: Radiological and histological findings of two patients with fungal mycetoma of the foot are presented MRI revealed multiple 2-5 mm lesions of high signal intensity interspersed within a low-intensity matrix Within many of the lesions a minute low-intensity focus was identified Ultrasound showed distinct hyperechoic foci within a hypoechoic mass We speculate that the low-signal matrix represents fibrous tissue, the high-intensity lesions correspond to granulomata and the central low-signal focus to the characteristic organised fungal elements (grains) present in this condition This "dot-in-circle sign" on MRI reflects the unique pathological features of mycetoma and is likely to be a highly specific sign for this lesion

The role of surgery in frozen shoulder.

Abstract: Frozen shoulder is a common disorder which is characterised by pain and loss of movement. Its cause is poorly understood and its management is disputed because of lack of supporting evidence. Duplay, 1 in 1872, used the term “peri-arthritis scapulohumerale” to describe the condition. In 1934, Codman 2 introduced the term frozen shoulder and set certain criteria for diagnosis and management. Neviaser 3 used the term adhesive capsulitis to reflect his findings at surgery and at post-mortem. Zuckerman and Cuomo 4 defined the condition as one of uncertain aetiology characterised by substantial restriction of both active and passive movement in the shoulder occurring in the absence of a known intrinsic disorder of the shoulder. The aetiology remains unknown, although some aspects of the pathophysiology have recently been documented. 5 The symptoms are generally self-limiting over one to three years. The role of treatment which includes physiotherapy, analgesics, injection of cortisone, manipulation and surgical release, must be assessed in the context of a tendency to self-resolution. This review examines the evidence to support interventional procedures in treating this painful and often debilitating condition.

The effect of particle size and electrical charge on macrophage-osteoclast differentiation and bone resorption

Abstract: In aseptic loosening, there is commonly periprosthetic bone loss and a heavy macrophage infiltrate in response to biomaterial wear particles generated from the implant materials. Macrophages which have phagocytosed wear particles are known to be capable of differentiation into bone resorbing osteoclasts. In this investigation we determine the role of particle size and particle charge on this process. Mouse monocytes and macrophages were co-cultured with osteoblast-like UMR106 cells and 1,25 dihydroxyvitamin D3 in the presence or the absence of (i) various sizes of latex beads (0.1, 1, 10 and 100 microm) and (ii) uncharged, positively- or negatively-charged sephadex beads of uniform shape and composition. The extent of osteoclast differentiation by monocytes or foreign body macrophages was determined by the expression of the osteoclast-associated enzyme tartrate-resistant acid phosphatase and lacunar bone resorption. No significant difference in the extent of osteoclast formation and bone resorption was noted in response to particle size. Osteoclast formation was also not significantly different in the presence of positively/negatively charged and uncharged particles. These findings indicate that osteoclast formation is not significantly influenced by particle characteristics, such as particle size. They also add support to the hypothesis that macrophage involvement in periprosthetic osteolysis is not dependent on particle phagocytosis and that it may be induced by particle contact.

Internal fixation for osteomyelitis of cervical spine: the issue of persistence of culture positive infection around the implants.

Abstract: ¶Background. We describe the management of osteomyelitis of the cervical spine, utilizing internal fixation with subsequent removal and culture of the implants. Four out of five patients had evidence of bacterial colonisation in close proximity to the internal fixation device.

Molecular cloning of the cell surface antigen identified by the osteoprogenitor-specific monoclonal antibody, HOP-26

Abstract: Bone is a highly organized structure comprising a calcified connective tissue matrix formed by mature osteoblasts, which develop from the proliferation and differentiation of osteoprogenitor cells. The osteogenic cell lineage is thought to arise from a population of uncommitted multipotential stromal precursor cells (SPC) which reside close to all bone surfaces, in the bone marrow spaces and the surrounding connective tissue. These SPC also give rise to related cell lineages which form cartilage, smooth muscle, fat, and fibrous tissue. Due to the lack of well defined cell surface markers, little is known of the precise developmentally regulated changes in phenotype which occur during the differentiation and maturation of human osteoprogenitor cells into functional osteoblasts and ultimately, terminally differentiated osteocytes. In order to identify antibody reagents with greater specificity for osteoprogenitors we generated a series of antibodies following immunization with freshly isolated human bone marrow stromal fibroblasts. One such antibody, HOP-26, reacts with a cell surface antigen expressed by SPC and developing bone cells. We now demonstrate that this mAb identifies a member of the tetraspan family of cell surface glycoproteins, namely CD63. Western blot analysis of human bone marrow stromal cells (HBMSC) has revealed that like a well defined CD63 mAb 12F12, HOP-26 interacts with a heavily glycosylated cell surface protein with an apparent molecular weight of 50-60 kD.

Bisphosphonates and osteoprotegerin as inhibitors of myeloma bone disease.

Abstract: BACKGROUND A major clinical feature in multiple myeloma is the development of osteolytic bone disease. The increase in bone destruction is due to uncontrolled osteoclastic bone resorption. Until recently the factors responsible for mediating the increase in osteoclast formation in myeloma have been unclear. However, recent studies have implicated a number of factors, including the ligand for receptor activator of NFκB (RANKL) and macrophage inflammatory protein-1α. The demonstration that increased osteoclastic activity plays a central role in this process and the identification of molecules that may play a critical role in the development of myeloma bone disease have resulted in studies aimed at identifying new approaches to treating this aspect of myeloma. METHODS Studies have been performed to determine the ability of recombinant osteoprotegerin (Fc.OPG), a soluble decoy receptor for RANKL, and potent new bisphosphonates to inhibit the development of myeloma bone disease in the 5T2MM murine model of multiple myeloma. RESULTS Fc.OPG was shown to prevent the development of osteolytic bone lesions in 5T2MM bearing animals. These changes were associated with a preservation of the cancellous bone loss induced by myeloma cells and an inhibition of osteoclast formation. Bisphosphonates, including ibandronate and zoledronic acid, were also shown to inhibit the development of osteolytic bone lesions in the 5T2MM model and alternative models of myeloma bone disease. CONCLUSIONS Bisphosphonates and Fc.OPG are effective inhibitors of the development of osteolytic bone lesions in pre-clinical murine models of myeloma bone disease. Cancer 2003;97(3 Suppl):818–24. © 2003 American Cancer Society. DOI 10.1002/cncr.11125

Ulnar nerve compression at guyon's canal by an anomalous abductor digiti minimi muscle: the role of ultrasound in clinical diagnosis

Abstract: Anomalous variations of abductor digiti minimi are commonly found at Guyon's canal but rarely cause ulnar nerve compression. We report such a case with particular emphasis on the effectiveness of ultrasound to detect and delineate anatomical structures in this region.

Arthroplasty of the elbow in haemophilia

Abstract: Total elbow replacement can be a valuable option for the treatment of the elbow in haemophilia where there are associated arthropathic changes. We describe the outcome of seven elbow replacements in five consecutive patients with severe haemophilia A (native factor levels < 1%) at a mean of 42 months (25 to 65) after operation. All the patients had excellent relief of pain and improvement in function. One failure was due to infection in an immunocompromised patient with both HIV and Hepatitis C antibodies who was on anti-retroviral chemotherapy. The implant was revised at 30 months in a one-stage procedure and showed no evidence of loosening or infection 35 months later.

Osteoclast formation from circulating precursors in osteoporosis.

Abstract: Objective: An imbalance between bone formation and bone resorption is thought to underlie the pathogenesis of reduced bone mass in osteoporosis. Bone resorption is carried out by osteoclasts, which are formed from marrow‐derived cells that circulate in the monocyte fraction. The aim of this study was to determine the role of osteoclast formation in the pathogenesis of bone loss in osteoporosis.Methods: The proportion of circulating osteoclast precursors and their relative sensitivity to the osteoclastogenic effects of M‐CSF, 1,25(OH)2D3 and RANKL were assessed in primary osteoporosis patients and normal controls.Results: Although there was no difference in the number of circulating osteoclast precursors in osteoporosis patients and normal controls. osteoclasts formed from osteoporosis patients exhibited substantially increased resorptive activity relative to normal controls. Although no increased sensitivity to the osteoclastogenic effects of 1,25(OH)2D3 or M‐CSF was noted, increased bone resorption was f...