Loading-related reorientation of bone proteoglycan in vivo. Strain memory in bone tissue?

The load-carrying capacity of the skeleton is achieved and maintained as the result of a continued functional stimulus to the cell populations responsible for bone remodeling. Although some bone cells have been assumed to be influenced by the load-induced changes in strain throughout the matrix, no evidence is available to indicate which cells are susceptible to such strain change or how such transient events provide a sustained influence on cell behaviour. In the present study, we showed that a short period of dynamic loading in vivo affects the orientation of proteoglycan within bone tissue. This reorientation declines only slowly, thus providing a persistent record of the tissue's recent strain history. Such a record has the ability not only to "capture" strain transients but also to "update" and "average" them. In this way, the bone cells could be presented with a sustained and coherent stimulus directly related to dynamic strain transients. These transients are the tissue's principal function variable.     

Microcracks in cortical bone: How do they affect bone biology?

Microcrack accumulation in cortical bone has been implicated in skeletal fragility and stress fractures. These cracks have also been shown to affect the mechanical and material properties of cortical bone. Their growth has been linked to osteocyte apoptosis and the initiation of the remodeling process, which also has a role in their repair. Clinically, osteoporosis is diagnosed using dual energy x-ray absorptiometry. However, evidence now indicates that bone mass alone is insufficient to satisfactorily explain the skeletal fragility of osteoporosis and consideration needs to be given to bone quality in the diagnosis and treatment of the disease. Bone quality includes parameters such as trabecular and cortical microarchitecture, morphology, bone turnover, degree of mineralization of the bone matrix, and significantly, the amount of microdamage present in the bone. Current clinical treatments concentrate on the inhibition of osteoclast activity to maintain bone mass in osteoporotic patients. However, these cells have a major role in removing existing microcracks from the bone matrix, and hence the use of bone resorption-inhibiting drugs may lead to insufficient bone repair and therefore an increase in microdamage accumulation and loss of bone quality.     

Megakaryocyte population in human bone marrow increases with estrogen treatment: a role in bone remodeling?

Skeletal effects of conventional hormone replacement therapy (HRT) are predominately antiresorptive, while high doses of estrogen have anabolic effects. The mechanisms mediating these effects are unclear but may involve cells in the bone marrow. We have investigated the in vivo effects of estrogen on the megakaryocyte (MK) population in bone marrow in 10 postmenopausal women before and after 2 years of conventional HRT, in 11 women after long-term, high-dose estradiol therapy, and in 2 premenopausal and 4 postmenopausal women who had received no previous estrogen treatment. Transiliac crest biopsies were halved and either decalcified and paraffin wax embedded for immunolocalization studies or dehydrated and embedded in LR White resin for histology. MKs were identified morphologically, and the bone marrow cell population and MK number quantified by cell counting in a defined area of view (1 mm(2)) from 5 randomly selected fields of bone marrow. Compared with pretreatment values, significantly higher MK numbers were found after conventional HRT treatment (before treatment, mean +/- SEM; 7.3 +/- 1.1 vs. after treatment, 18.0 +/- 1.6/5 mm(2); p < 0.0001), while the greatest MK number was associated with long-term, high-dose estradiol treatment (32.8 +/- 2.1/5 mm(2); p < 0.0001). Total bone marrow cell number did not differ significantly between groups. Immunolocalization studies revealed more intense estrogen receptor (ER)beta expression in MKs in the high-dose estradiol-treated group but similar levels of weak ERalpha staining in MKs in the control and high-dose estrogen-treated groups. Positive immunoreactivity for transforming growth factor (TGF)beta1, 2, and 3 and TGFbeta receptor I, II, and III was detected in MKs, with more intense staining being demonstrated in the high-dose estradiol-treated group, particularly for TGFbeta2 and TGFbetaRI and II. Our results demonstrate an increase in the MK population in bone marrow from women treated with estrogen. The ability of MKs to express ERs and synthesise TGFbeta, a potent mitogen in osteoblast differentiation, suggests that these cells may play a role in mediating estrogen-induced effects on bone.     

β2-microglobulin in Paget's bone disease

On the basis of earlier findings of increased serum ₂-microglobulin concentration in women with postmenopausal osteoporosis, we decided to study serum ₂-microglobulin concentration in other bone diseases. In 28 patients with untreated Paget's bone disease, serum ₂-microglobulin concentration was normal (1.49±0.41 mg/liter versus 1.36±0.21 mg/liter in 42 control subjects, P= ns), a finding that contradicts reports in the literature. We found that serum ₂-microglobulin concentration was related negatively and significantly (r²=–0.154, P=0.0354) with serum total alkaline phosphatase concentration, but not with serum tartrate-resistant acid phosphatase concentration (p =ns). Urinary elimination of ₂-microglobulin was lower in the patients with Paget's disease than in the controls (34±28 versus 120±21 mg/liter, P<0.001). These findings suggest that ₂-microglobulin behaves similarly to osteocalcin (BGP) in Paget's bone disease and that its concentration remains within normal levels perhaps because of the rate of reuptake of ₂-microglobulin in bone neoformation.     

Anti-infective reconstituted bone xenograft used for primary bone grafting to repair contaminated defect in the radius in dogs

Objective: To investigate the effect of anti-infective reconstituted bone xenograft as a primary graft to repair a segmental with severe contamination. Methods: A canine model of contaminated defect of 1.5 cm in size in the radius was used, in which antiinfective reconstituted bone xenograft or reconstituted bone xenograft was implanted as a primary graft followed by internal fixation. The effectiveness of the two grafting materials in repairing a contaminated segmental defect was compared. Resuits: The animals which had received implant of anti-infective reconstituted bone xenograft should largely healed defects 6 months after operation while the defects implanted wit]h reconstituted bone xenograft remained unrepaired witla bone infection. Conclusions: Besides its strong osteoinductive and osteoconductive activity, anti-infective reconstituted bone xenograft is highly antibacterial and can be used as a primary graft to repair the severely contaminated segmental defect.     

Denosumab in giant cell tumour of bone in the pelvis and sacrum: Long-term therapy or bone resection?

IntroductionSurgery of GCTB in sacrum and pelvis is challenging, with high rates of complications and local recurrence. Denosumab can consolidate the peripheral rim of the tumour, thus reducing the rate of morbidities of surgery. The aim of this paper is to evaluate the use of denosumab in pelvic/sacrum giant cell tumours of bone (GCTB).Patients and methodsWe retrospectively reviewed a cohort of 26 patients with aggressive GCTB in sacrum or pelvis treated with denosumab at two referral centres. Clinical response and local recurrence were recorded and the radiologic responses were evaluated with the MDA criteria.Results69% of the pelvic GCTB treated with denosumab presented partial or good radiologic responses (type 2A or 2B) after 49 weeks of treatment. Denosumab was administered as adjuvant therapy prior and after surgery in 11 patients (group A), and as the only treatment in 15 patients (group B). In group A, 62% of local recurrence was observed in patients treated with intralesional curettage. No recurrences were identified after en bloc resection. In group B, 9 patients were on continuous bimonthly long term denosumab administration with type 2A and 2B responses. Six patients stopped denosumab and 66% remained stable after 10 months of follow-up.ConclusionsLong-term denosumab therapy can be considered with curative intent for pelvic and sacrum GCTB. If surgical intervention is required wide resection may be advisable to reduce the risk of recurrence.     

Ectopic bone formation of human bone morphogenetic protein-2 gene transfected goat bone marrow-derived mesenchymal stem cells in nude mice

onemorphogenetic proteins (BMPs)haveapowerfulcapacitytoelicitnewboneformation .ThereareseveraldeliverymethodsofBMPsintreatingbonedefects ,oneofwhichisgenetherapy .Retrovirus,adenovirusandadeno associatedvirushavebeenutilizedtodeliverBMPgene .1,2 Sincethedirectuseofthesevectorshasseveraldisadvantages ,wehavedevelopedexvivo genetherapytechniquewhichinvolvestheisolationandcultivationofautologousbonemarrow derivedmesenchymalstemcells (MSCs) ,transfectionofthecellsinvitroandimplantationofthesec…     

Are bone autografts still necessary in 2006? A three-year retrospective study of bone grafting

Autograft is considered as the gold standard in bone grafting. However, the development of tissue banks has allowed for a wider use of bone allografts, with good results. Demineralised Bone Matrix (DBM) and recombinant human Bone Morphogenetic Proteins (rh-BMP's) were also introduced to replace the time-honoured autograft. Is there currently still a place for bone autograft? The authors reviewed the orthopaedic surgical activity in their institution during the period 2003-2005, and traced all the surgical procedures in which bone grafting was performed. Tracking forms from the tissue bank were reviewed to assess the surgical indications. Between 2003 and 2005, the use of autografts decreased from 1.3% to 0.9% of all surgical interventions, particularly owing to their decreased use in primary fusions, while the use of allografts increased from 10.7% to 12.7%. Indications for allografts covered all fields of orthopaedic surgery, including nonunions. Processed allografts represented 90% of all grafts used. DBM and rh-BMP were used on an exceptional basis. There is currently a trend for surgeons to use allografts as substitutes for autografts, as processing of the allografts increases their safety while preserving most of their biological and mechanical properties. Autografting is now limited to revision operations after failed fusions, and to combined use at the junction with massive allografts. DBM and rh-BMP are still controversial but they might replace autografts, even in their currently remaining indications, if their cost effectiveness and efficiency are established.     

Seasonal changes in biochemical markers of bone metabolism and hip bone mineral status in older northern Chinese men and women

目的为了解北方老年人骨矿状态和骨代谢是否存在季节变化。方法沈阳市60-75岁老年人59人,其中男性30人,女性29人。于3月份（春季）和9月份（季秋）分别采集清晨空腹静脉血和尿,分析血浆中钙、磷、甲状旁腺激素、25（OH）D、1,25（OH）2D、骨钙素;尿中钙、磷、脱氧吡啶啉（DPD）。用DPX-L双能X线吸收仪（Lunar,USA）测定研究对象髋部骨密度和骨矿含量。结果男女血浆25（OH）D、钙（经血浆蛋白调整）和磷含量秋季均高于春季,而甲状旁腺激素含量秋季低于春季。男性血浆1,25（OH）2D含量秋季高于春季（P〈0.05）。女性尿中DPD/肌酐比值秋季低于春季（P〈0.05）。女性股骨径骨矿含量和全髋部骨密度秋季比春季分别高2.5%和1%（P〈0.05）。在男性全髋部骨密度秋季比春季高0.9%,但差异没有统计学意义。其它指标没有观察到季节变化。结论中国北方老年人维生素D营养状态、骨代谢和髋部骨矿状态存在季节变化。     

Immune system and bone metabolism: Does thymectomy influence postmenopausal bone loss in humans?

Recent studies of animal models have suggested that an increase in the number of T cells due to both peripheral expansion and increased thymic T cell output plays a key role in the regulation of bone loss after ovariectomy. Osteoclastogenic cytokines which are either produced by T cells or activate T cells have also been implicated in ovx induced bone loss. Among them are TNF alpha and IL-7. The present study investigates the role of thymectomy (THX) and IL-7 in bone metabolism in humans. We studied T cells subsets, cytokine production and bone metabolism in 13 women thymectomized for Myasthenia gravis as compared to healthy controls. Our data demonstrate that the number of CD4+ and TNF-producing T cells is lower in THX women as compared to euthymic controls. However in THX women the residual T cells produce higher levels of IL-7 and RANKL. Furthermore, flow cytometry shows that IL-7 is produced by T and B cells. Serum levels of TNF alpha were unaffected by THX and both serum TNF alpha and the RANKL/OPG correlated inversely with BMD. There were no differences in bone turnover and bone mineral density between THX women and the controls. These data suggest that THX decreases the number of TNF-producing CD4+ T cells but does not alters serum TNF levels. The RANKL/OPG ratio and indices of bone metabolisms are also not affected by THX, although THX increases the levels of IL-7 and RANKL. Further studies are needed to clarify the role of thymus in bone metabolism and osteoclastogenesis in postmenopausal women.     

Does homocysteine contribute to bone disease in hyperparathyroidism?

BACKGROUND: Osteoporosis is a complication of hyperparathyroidism (HPT). Hyperhomocysteinemia (HHCy) is an independent risk factor for osteoporotic fractures. We hypothesize that HHCy correlates with bone disease in HPT. METHODS: A prospectively collected database of 250 patients treated for HPT was reviewed. Patients were categorized into 3 groups: group I, normal renal function; group 2, mild renal insufficiency; and group 3, secondary HPT with end-stage renal disease on dialysis. Serum homocysteine levels, markers of bone metabolism, and bone density studies were examined. RESULTS: The prevalence of HHCy in group 1 (208 patients) was 5%, in group 2 (23 patients), 82%, and in group 3 (19 patients), 78%. Mean (+/-SD) preoperative homocysteinemia (HCy) levels in groups 1, 2, and 3 were 9.3 +/- 4.0, 20 +/- 10.2, and 20.6 +/- 12.3 micromol/L, respectively. Elevated serum markers of bone metabolism increased significantly with decreasing renal function. CONCLUSIONS: Prevalence of HHCy is low in HPT patients with normal renal function. It is significantly greater in those with dialysis-independent and -dependent renal insufficiency. HHCy correlates with other serum markers of bone metabolism in HPT and may be useful for monitoring progression or improvement.     

Can bone loss in rheumatoid arthritis be prevented?

Rheumatoid arthritis (RA) is a systemic inflammatory disease that can lead to local joint deformations (bone erosions and joint space narrowing) and to extra-articular phenomena, including generalized osteoporosis. In addition, in patients with RA, the risk of vertebral and nonvertebral fractures is doubled. High disease activity (inflammation), immobility, and glucocorticoid use are common factors that substantially increase fracture risk in these patients, on top of the background fracture risk based on classical risk factors such as high age, low body mass, and female gender. New insights on the links between the immune system and the bone system, the field of osteoimmunology, have shown that local and generalized bone loss share common pathways. The receptor activator of nuclear factor κB ligand/osteoprotegerin pathway (RANKl/OPG) is one of the most important pathways, as it is (strongly) upregulated by inflammation. In modern treatment of RA with biologics, for example, TNFα-blocking agents and combination therapy of conventional disease-modifying antirheumatic drugs (DMARDs), clinical remission is a realistic treatment goal. As a consequence, in recent studies, it has been documented that both local and generalized bone loss is absent or minimal in those patients who are in clinical remission.     

Joint depression in tibial plateau fractures: To bone graft or not to bone graft?

Tibial plateau fractures with significant joint depression and metaphyseal comminution pose a challenge. In order to prevent the collapse of the articular surface, some authors propose filling the subchondral void created during reduction with bone graft/substitute, which can add further complications. We present two cases of tibial plateau fractures with severe joint depression of the lateral condyle; both treated with a periarticular rafting construct, in one caseadditional bone substitute was used and in the other case no bone graft/substitute was used; their final outcomes were reported. The treatment of joint depression in tibial plateau fractures using periarticular rafting constructs without bone graft, may be also a valid option, to achieve good final results without the morbidity associated with the use of bone graft/substitutes.     

Speed of sound in bone at the tibia: is it related to lower limb bone mineral density in spinal-cord-injured individuals?

STUDY DESIGN: A cross-sectional study evaluating BMD at the hip and tibia, and SOS at the radius and mid-tibia in individuals with spinal cord injury (SCI) and a subgroup of non-SCI individuals. OBJECTIVES: To investigate the speed of sound (SOS) in bone in relation to bone mineral density (BMD). SETTING: Kinesiology Department, McMaster University, Ontario, Canada. METHODS: In 14 individuals with SCI and 10 non-SCI individuals, proximal femur and tibia BMD were measured using dual energy X-ray absorptiometry, and radius and tibia SOS were measured with an ultrasonometer. T-scores were calculated using healthy reference databases. Inter-relationships between measurement techniques were determined using Pearson's correlation coefficients. P-values less than 0.05 were considered statistically significant. RESULTS:: The average ages of the SCI and non-SCI groups were 33+/-9 and 27+/-6 years, respectively. Lesion level ranged from C4 to T12 and average time postinjury was 12 years, with a range of 1.6-25 years. Using the WHO criteria for osteoporosis, nine of 14 SCI subjects were osteoporotic at the hip, with the remainder in the osteopenic range. Tibia SOS T-scores were in the osteoporotic range for one subject with SCI, and two were in the osteopenic range. Among non-SCI individuals, one male had a tibia SOS T-score of -1.4, all others were within the normal range. Hip BMD and tibia SOS were significantly correlated (r=0.46, P<0.01). Hip BMD and tibia BMD were more strongly correlated (r=0.80, P<0.0005). Tibia BMD was not significantly correlated with SOS at the tibia (r=0.35, P=0.09). Radius SOS T-scores were positive and not significantly correlated with any lower limb variable. CONCLUSION: Lower-limb bone mass is reduced in spinal cord-injured individuals, but SOS at the mid-tibia is not. It remains to be determined whether ultrasound measurements can predict fracture in the SCI population.     

Can computerised tomography replace bone scintigraphy in detecting bone metastases from breast cancer? A prospective study

BACKGROUND: The aim of this study was to determine whether bone scans (BS) can be avoided if pelvis was included in CT thorax and abdomen to detect bony metastases from breast cancer. MATERIALS AND METHODS: Results of 77 pairs of CT (thorax, abdomen, and pelvis) and BS in newly diagnosed patients with metastatic breast cancer (MBC) were compared prospectively for 12 months. Both scans were blindly assessed by experienced radiologists and discussed at multidisciplinary team meetings regarding the diagnosis of bone metastases. RESULTS: CT detected metastatic bone lesions in 43 (98%) of 44 patients with bone metastases. The remaining patient had a solitary, asymptomatic bony metastasis in shaft of femur. BS was positive in all patients with bone metastases. There were 11 cases of false positive findings on BS. CONCLUSION: Our findings suggest routine BS of patients presenting with MBC is not required if CT (thorax, abdomen, and pelvis) is performed.     

How can bone turnover modify bone strength independent of bone mass?

The amount of bone turnover in the skeleton has been identified as a predictor of fracture risk independent of areal bone mineral density (aBMD) and is increasingly cited as an explanation for discrepancies between areal bone mineral density and fracture risk. A number of mechanisms have been proposed to explain how bone turnover influences bone biomechanics, including regulation of tissue degree of mineralization, the disconnection or fenestration of individual trabeculae by remodeling cavities, and the ability of cavities formed during the remodeling process to act as stress risers. While these mechanisms can influence bone biomechanics, they also modify bone mass. If bone turnover is to explain any of the observed discrepancies between fracture risk and areal bone mineral density, however, it must not only modify bone strength, but must also modify bone strength in excess of what would be expected from the associated change in bone mass. This article summarizes biomechanical studies of how tissue mineralization, trabecular disconnection, and the presence of remodeling cavities might have an effect on cancellous bone strength independent of bone mass. Existing data support the idea that all of these factors may have a disproportionate effect on bone stiffness and/or strength, with the exception of average tissue degree of mineralization, which may not affect bone strength independent of aBMD. Disproportionate effects of mineral content on bone biomechanics may instead come from variation in tissue degree of mineralization at the micro-structural level. The biomechanical explanation for the relationship between bone turnover and fracture incidence remains to be determined, but must be examined not in terms of bone biomechanics, but in terms of bone biomechanics relative to bone mass.     

Megaprosthesis in large bone defects: Opportunity or chimaera?

Introduction

The development of new megaprosthesis for the treatment of large bone defects provides important options to orthopaedic oncologic surgeons for the replacement of skeletal segments, such as the long bones of the upper and lower limbs and the relative joints. We implanted megaprosthesis using either a one-step or two-step technique depending on the patient's condition. The aim of this study was to evaluate retrospectively both clinical and radiological outcomes in patients who underwent lower limb megaprosthesis implant.

Materials and methods

A total of 32 patients were treated with mono- and bi-articular megaprosthesis subdivided as follows: proximal femur, distal femur, proximal tibia and total femur. The mean follow-up of patients was about 18 months (range 3 months to 5 years). Clinical and serial radiographic evaluations were conducted using standard methods (X-ray at 45 days, 3, 6, 12, 18 and 24 months) and blood parameters of inflammation were monitored for at least 2 months.

Results

Although the mean length of follow-up was only 18 months, the first patients to enter the study were monitored for 5 years and showed encouraging clinical results, with good articulation of the segments, no somato-sensory or motor deficit and acceptable functional recovery. During surgery and, more importantly, in pre-operative planning, much attention should be given to the evaluation of the extensor apparatus, preserving it and, when necessary, reinforcing it with tendon substitutes.

Discussion

Megaprosthesis in extreme cases of severe bone loss and prosthetic failure is a potential solution for the orthopaedic surgeon. In oncological surgery, the opportunity to restore functionality to the patient (although not ad integrum) is important for both the patient and the surgeon. The high mortality associated with cancer precludes long-term patient follow-up; therefore, there is a lack of certainty about the survival of this type of prosthesis and any medium- to long-term complications that may occur. Nevertheless, patients should be considered as an oncologic patient, not because of the disease, but because of the limited therapeutic options available.

Conclusions

Megaprosthesis provides a valuable opportunity to restore functionality to patients with highly disabling diseases.