Iliac crest trabecular bone mass and structure in patients with non-steroid treated rheumatoid arthritis.

Iliac crest trabecular bone volume and structure have been studied in bone biopsy specimens from 48 patients with classical or definite rheumatoid arthritis, none of whom had received steroids. Results were compared with those obtained from healthy controls matched for age and sex. The mean trabecular bone volume in female patients aged 34-50 years was significantly lower than in controls (p less than 0.01); in male patients aged 34-50 years values were also lower than those in controls (mean (SD) 17.8 (3.2) v 22.4 (5.6)% total medullary volume), though this difference was not statistically significant. Values in older patients were similar to those of controls. The mean trabecular plate thickness was significantly lower in female patients in all three age groups when compared with the controls (p less than 0.005, 0.05, and 0.005). Similar but non-significant changes were seen in male patients. The mean trabecular plate density, an index of trabecular number, and the mean trabecular plate separation showed no age related change in either male or female patients, in contrast with the female control group, in whom the mean trabecular plate density decreased and separation increased with age. These results suggest that non-steroid treated rheumatoid arthritis is associated with premature bone loss, the structural basis of which is trabecular thinning.     

Reduced bone formation in non-steroid treated patients with rheumatoid arthritis.

The cellular basis of trabecular bone loss in rheumatoid arthritis was investigated in 45 non-steroid treated patients. Mean wall thickness, an indicator of the amount of bone formed per remodelling unit, mean interstitial bone thickness, which is related to resorption depth, and the extent of trabecular surface covered by osteoid, which reflects the number of remodelling units, were assessed in iliac crest biopsy specimens. The mean wall thickness was significantly reduced in the patient group when compared with controls matched for age and sex (mean (SD) 39.8 (5.4) v 51.6 (9.7) microns). There was no significant difference between patients and controls in the mean interstitial bone thickness (51.0 (26.4) v 61.4 (31.9) microns) or osteoid surface (16.7 (11.4) v 21.0 (10.5)%). These results show that reduced bone formation at the remodelling unit level is the predominant mechanism of bone loss in rheumatoid arthritis.     

Bone metabolism and histomorphometric changes in rheumatoid arthritis

OBJECTIVE: We studied bone metabolism and histomorphometry in 66 patients with rheumatoid arthritis. METHODS: Cross-sectional study. RESULTS: BMD at the forearm but not at the lumbar spine was decreased. Age. body mass index and fibrinogen correlated significantly with decreased BMD, whereas age and disease duration were predictors of vertebral fractures. Biochemical parameters were normal but 25 vitamin D levels were markedly reduced. There were significant decreases in bone volume, mean wall thickness, mineral apposition rate (with highly prolonged mineralisation lag time), number of osteoclasts, and osteoclast surface, and increases in resorption surfaces. Mean plate trabecular separation and density were also deeply affected. CONCLUSIONS: Patients with rheumatoid arthritis showed a reduced bone volume and decreased bone turnover, which is further aggravated by microarchitectural deterioration stressing the severe osteoporosis associated with the disease. These findings are consistent with the effect of hypovitaminosis D and low values of vitamin D in serum.     

Osteocyte viability with glucocorticoid treatment: relation to histomorphometry

BACKGROUND: Glucocorticoid induced osteoporosis is a common clinical problem. OBJECTIVE: To determine the pathophysiology of glucocorticoid induced osteoarthritis at the organ level. METHODS: Iliac crest biopsy specimens were obtained from nine patients receiving prednisone treatment for rheumatoid arthritis. Osteocyte viability and histomorphometric indices were assessed. RESULTS: Compared with controls, glucocorticoid treated subjects had reduced trabecular thickness and increased erosion. The number of viable osteocytes was significantly decreased in glucocorticoid treated patients compared with controls. CONCLUSION: The impaired bone formation, increased erosion and, importantly, loss of viable osteocytes are all likely to contribute to the increased risk of fracture in these patients.     

Quantitative histologic studies on the pathogenesis of periarticular osteoporosis in rheumatoid arthritis

The pathogenesis of periarticular osteopenia in rheumatoid arthritis (RA) was investigated by histomorphometry on juxtaarticular bone removed during joint surgery. Twenty areas from 12 RA patients were compared with 14 areas from 6 osteoarthritis (OA) patients. There was no difference between the 2 groups in the percent of total bone volume. However, increased bone formation was suggested by an increase in the percent of active osteoid surface in RA compared with that in OA. Bone resorption was also increased in RA, as evidenced by increases versus OA in percent total resorptive surface, percent active resorptive surface, and number of osteoclasts. These results demonstrate increased turnover of bone in RA, especially in the resorptive phase of the periarticular trabecular bone. It is proposed that soluble factor(s) synthesized in the contiguous rheumatoid synovium may be transferred to the periarticular bone space, stimulating osteoclasts to resorb bone.     

Parathyroid hormone and bone biomechanics

Parathyroid hormone (PTH) treatment, either in the form of teriparatide or recombinant human PTH(1–34), reduces the fracture risk of osteoporotic women by enhancing both structural and material biomechanical properties. Cortical bone thickness and cross-sectional moment of inertia increase because of new bone formation on periosteal and endocortical surfaces. Intracortical porosity is increased yet preferential localization near the endocortical surface limits any negative biomechanical effects. Greater trabecular bone volume results from a positive basic multicellular unit bone balance and renewed modeling. Initial increases in trabecular thickness are eventually reduced as a result of trabecular tunneling, increasing trabecular number, and connectivity. These geometrical and architectural alterations are the predominant mechanism by which PTH increases structural strength, stiffness, and energy absorption. PTH also positively alters material-level strength, modulus, and toughness. These changes are counterintuitive based on known effects of decreasing average tissue mineralization and increasing tissue heterogeneity. This combination of enhanced structural and material biomechanical properties makes PTH an effective treatment for reducing fracture risk despite smaller gains in bone mineral density compared to other osteoporosis agents.     

缺碘大鼠的骨发育障碍

目的　研究碘缺乏对大鼠骨发育和骨转换的影响。方法　复制生长发育期碘缺乏大鼠动物模型 ,测定血清中TT3 、TT4、FT4含量 ,对股骨远端 2 /3进行骨计量学测定。结果　碘缺乏大鼠血清TT4、FT4含量显著下降 ,TT3 含量代偿性增加。碘缺乏大鼠骨小梁骨量较正常大鼠明显减少 ,骨小梁体积(TBV) /全部骨组织体积减少约 47% ,TBV/海绵骨体积减少约 3 5 % ,平均骨小梁板厚度减少约 3 6% ,骨小梁表面 /TBV较正常大鼠增加约 3 4% (P <0 .0 1) ,骨皮质平均厚度较正常组减少了 16% (P <0 .0 5 )。碘缺乏大鼠四环素单标记线占全部骨小梁表面的百分比、四环素双标记线占全部骨小梁表面的百分比、平均类骨质宽度、骨小梁类骨质表面占骨小梁表面的百分比、矿化沉积率和组织水平骨形成率均低于正常对照组 (P <0 .0 5或P <0 .0 1) ,矿化延迟时间 (P <0 .0 5 )和类骨质成熟时间 (P <0 .0 1)大于正常大鼠。结论发育期的骨骼对T4的缺乏非常敏感。T4降低时骨骼发育不良 ,骨小梁骨量减少 ,皮质骨的生长也受到影响。碘缺乏组大鼠成骨细胞活性降低和类骨质矿化障碍     

The relationship between postoperative results and bone dynamics in RA patients who underwent cementless Ortholoc II TKA: histomorphometric study

We previously reported a histomorphometric study of iliac bone obtained at the time of cementless total knee arthroplasty (TKA) in patients with rheumatoid arthritis (RA). In this paper, we further extended our analysis to investigate the postoperative results and radiographs after TKA in association with bone metabolism. All the patients were female, ranging in age from 38 to 68 years (mean, 56.8 years). Histomorphometric results demonstrated that bone volume and trabecular thickness were decreased, whereas bone absorption and bone formation rate (BFR) were increased. The bone in patients with mutilating disease (MUD) showed remarkably increased bone turnover and osteoporosis compared with those of the more erosive subset (MES) patients. Sixteen out of the 20 patients were alive at the time of follow-up (follow-up period between 5 years 10 months and 8 years 11 months). Among them, 10 patients could be further examined. Radiolucent lines (RLL) were assessed by the modified Knee Society evaluation (scoring) system. The number of RLL (N-RLL) were correlated with BFR in morphometric examination. In addition, the weight-bearing zones in the N-RLL were more significantly correlated with BFR. The Japanese Orthopedic Association (JOA) score and pain score negatively correlated with eroded bone surface. The present study indicated that bone dynamics, rather than the bone volume at the time of TKA, were involved in the presence of RLL and in pain after surgery for TKA. Received: May 8, 1999 / Accepted: January 24, 2000     

Osteoprotegerin protects against generalized bone loss in tumor necrosis factor-transgenic mice

OBJECTIVE: To investigate the role of tumor necrosis factor (TNF) in systemic bone loss of chronic inflammatory conditions, such as rheumatoid arthritis (RA), and to address the therapeutic potential of osteoclast blockade. METHODS: We investigated systemic bone changes in human TNF transgenic (hTNFtg) mice, which spontaneously developed severe inflammatory arthritis. RESULTS: Osteodensitometry revealed a significant decrease in trabecular bone mineral density (BMD) (-37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (-85%) compared with wild-type controls. Osteoclast-covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly elevated, suggesting increased osteoclast-mediated bone resorption in hTNFtg mice. Osteoprotegerin (OPG) completely blocked TNF-mediated bone loss by increasing BMD (+89%) and bone volume (+647%). Most strikingly, formation of primary spongiosa was dramatically increased (+563%) in hTNFtg mice after OPG treatment. Osteoclast-covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast-mediated bone resorption. OPG did not influence levels of hTNF, TNF receptor I (TNFRI), interleukin-1beta (IL-1beta), and IL-6. However, OPG decreased bone formation parameters (osteoblast-covered bone surface and serum osteocalcin levels), which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti-TNF treatment did not affect generalized bone loss in hTNFtg mice. Anti-TNF, however, did not affect levels of TNF and TNFRI at the concentrations tested. These data indicate that generalized bone loss due to increased TNF can be blocked by OPG. CONCLUSION: OPG may represent a potent tool for preventing generalized loss of bone mass in chronic inflammatory disorders, especially RA.     

Bone histomorphometry and structure in corticosteroid treated chronic active hepatitis.

Transiliac biopsies from 34 female patients with corticosteroid treated chronic active hepatitis have been examined to determine the contributions made by decreased bone formation and increased bone resorption to bone loss associated with this condition and to determine the structural basis of the bone loss. Mean wall thickness was significantly reduced when compared with control values (p less than 0.001) as was the bone formation rate at tissue (p less than 0.005) and basic multicellular unit (p less than 0.005) level. The osteoid maturation period and the bone formation period were significantly prolonged (p less than 0.02 and 0.05). The total resorption surfaces were significantly increased (p less than 0.02) but the mean interstitial bone thickness was normal. The mean trabecular plate thickness was significantly reduced (p less than 0.005). These findings indicate that decreased bone formation plays a major role in bone loss associated with corticosteroid treated chronic active hepatitis and that the structural basis of bone loss is trabecular thinning.     

The relationship between postoperative results and bone dynamics in RA patients who underwent cementless Ortholoc II TKA: histomorphometric study

Abstract

We previously reported a histomorphometric study of iliac bone obtained at the time of cementless total knee arthroplasty (TKA) in patients with rheumatoid arthritis (RA). In this paper, we further extended our analysis to investigate the postoperative results and radiographs after TKA in association with bone metabolism. All the patients were female, ranging in age from 38 to 68 years (mean, 56.8 years). Histomorphometric results demonstrated that bone volume and trabecular thickness were decreased, whereas bone absorption and bone formation rate (BFR) were increased. The bone in patients with mutilating disease (MUD) showed remarkably increased bone turnover and osteoporosis compared with those of the more erosive subset (MES) patients. Sixteen out of the 20 patients were alive at the time of follow-up (follow-up period between 5 years 10 months and 8 years 11 months). Among them, 10 patients could be further examined. Radiolucent lines (RLL) were assessed by the modified Knee Society evaluation (scoring) system. The number of RLL (N-RLL) were correlated with BFR in morphometric examination. In addition, the weight-bearing zones in the N-RLL were more significantly correlated with BFR. The Japanese Orthopedic Association (JOA) score and pain score negatively correlated with eroded bone surface. The present study indicated that bone dynamics, rather than the bone volume at the time of TKA, were involved in the presence of RLL and in pain after surgery for TKA.     

Quantitative histology of myeloma-induced bone changes

S ummary . In order to quantify bone changes which occur in multiple myeloma, undecalcified transiliac bone biopsies from 118 myelomatous patients were analysed by histomorphometric methods. Osteoclastic resorption surfaces were increased compared with controls, and the number of osteoclasts/mm² of bone section was significantly greater in the areas massively invaded by plasma cells than in less invaded areas. The osteoid surfaces were also increased and the percentage of trabeculae that exhibited tetracycline labelling was also greater, indicating increased formation surfaces. However, reduced thickness of the osteoid seams and a low calcification rate, measured after tetracycline double labelling, suggests a reduced activity for each osteoblast. The mean trabecular bone volume was not reduced as compared with controls, but the biopsies showed a heterogeneous distribution of osteolytic and osteosclerotic areas. In the invaded areas, no major histomorphometric difference was found between patients receiving chemotherapy and untreated patients, demonstrating that if usual chemotherapies reduce the tumour mass, they do not improve histological bone lesions in areas still invaded by plasma cells.     

Studies of histamine in the rheumatoid joint

Summary Fragments of synovial membranes from three patients with rheumatoid arthritis were incubated in Dulbecco's modified Eagle's medium (DMEM). Histamine was released into the medium at rates up to 649.3 ng/g synovium/day. To investigate whether histamine in synovial fluid may have more than a vasoactive role, cells cultured from human trabecular bone adjacent to a rheumatoid joint and human adherent rheumatoid synovial cells were incubated with different concentrations of histamine for 5 min. Histamine increased the intracellular content of cyclic AMP up to three fold in a dose-related manner but had no effect on synovial cells. This offers preliminary evidence that cells grown from human trabecular bone have histamine receptors.     

Bone changes in myelofibrosis with myeloid metaplasia: a histomorphometric and microcomputed tomographic study

Myelofibrosis with myeloid metaplasia (MMM) is a clonal disorder of the haematopoietic stem cell which can be associated with marrow fibrosis and/or osteosclerosis. Because bone progenitors and mature bone cells are influenced by the marrow microenvironment, cellular and tissular changes were assessed by histomorphometry in MMM. Thirteen patients, with a clinical proven MMM, had a bone biopsy of the iliac crest with double tetracycline labelling and osteoclast count. Histomorphometry was done at the 2D level (bone volume, osteoid parameters, bone histodynamic parameters and osteoclast count) and 3D level by microcomputed tomography. All patients had clusters of abnormal megakaryocytes in bone marrow. Newly apposed bone packets were observed in 12 patients and corresponded to an increased thickness of some bone units with new lamellae or focal areas of woven bone anchored on the pre-existing trabeculae. Osteoid parameters were unchanged, only bone formation rate appeared considerably increased in seven patients. There was a net tendency for decrease in osteoclast number and conversion of trabecular pillars into plates. An uncoupling of bone remodelling was evidenced with an increased life-span of osteoblasts associated with a normal/reduced osteoclast activity. A very complex network of factors is candidate to explain bone changes observed in MMM.     

A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength

Diseases such as osteoporosis are associated with reduced bone mass. Therapies to prevent bone loss exist, but there are few that stimulate bone formation and restore bone mass. Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily, which act as pleiotropic regulators of skeletal organogenesis and bone homeostasis. Ablation of the BMPR1A receptor in osteoblasts increases bone mass, suggesting that inhibition of BMPR1A signaling may have therapeutic benefit. The aim of this study was to determine the skeletal effects of systemic administration of a soluble BMPR1A fusion protein (mBMPR1A-mFc) in vivo. mBMPR1A-mFc was shown to bind BMP2/4 specifically and with high affinity and prevent downstream signaling. mBMPR1A-mFc treatment of immature and mature mice increased bone mineral density, cortical thickness, trabecular bone volume, thickness and number, and decreased trabecular separation. The increase in bone mass was due to an early increase in osteoblast number and bone formation rate, mediated by a suppression of Dickkopf-1 expression. This was followed by a decrease in osteoclast number and eroded surface, which was associated with a decrease in receptor activator of NF-κB ligand (RANKL) production, an increase in osteoprotegerin expression, and a decrease in serum tartrate-resistant acid phosphatase (TRAP5b) concentration. mBMPR1A treatment also increased bone mass and strength in mice with bone loss due to estrogen deficiency. In conclusion, mBMPR1A-mFc stimulates osteoblastic bone formation and decreases bone resorption, which leads to an increase in bone mass, and offers a promising unique alternative for the treatment of bone-related disorders.     

The effects of bone turnover rate on subchondral trabecular bone structure and cartilage damage in the osteoarthritis rat model

The effects of bone turnover rate on subchondral trabecular changes and cartilage destruction were evaluated in an iodoacetate-induced osteoarthritis rat model. Thirty female rats were randomly divided into three groups as the ovariectomized group, the no-treatment group and the bisphosphonate medication group. Arthritis was induced by a single intra-articular iodoacetate injection into the right tibiofemoral joint. Eight weeks after this injection, tibiofemoral joints on both sides were scanned with a micro-CT. Subchondral trabecular indices were measured on both sides of the tibial lateral condyle epiphysis. In the ovariectomized group, the percentage of bone volume, trabecular thickness and trabecular bone pattern factor of the arthritic sides were lower than those of the control sides, while trabecular separation and structure model index of the arthritic sides were higher than those of the control sides (p < 0.05). In the no-treatment group, only trabecular thickness of the arthritic sides was lower than in the control sides (p < 0.05). In the bisphosphonate medication group, trabecular indices were no different between the arthritic and control sides. Articular cartilage destruction and severity of arthritis increased significantly in the order: ovariectomized group < no-treatment group < bisphosphonate medication group (p < 0.05). After osteoarthritis development, severities of subchondral trabecular changes appeared to be strongly affected by bone turnover rate. Furthermore, a correlation was found between cartilage destruction severity and subchondral trabecular change in the intra-articular iodoacetate-injected osteoarthritis rat model.     

Bone mineral loss,bone histomorphometry and vitamin D metabolism in patients with rheumatoid arthritis on long-term glucocorticoid treatment

Summary Long-term glucocorticoid treatment might interfere with the vitamin D metabolism. The serum concentrations of 25-OHD were significantly reduced whereas the circulating levels of 1,25-(OH)₂D were normal in 50 patients with rheumatoid arthritis on long-term treatment with small doses of prednisone. The bone mineral content of the forearm was significantly reduced, but the degree of bone loss did not correlate with duration of treatment or dose of prednisone given. Quantitative bone histomorphometry was performed in 18 patients. Apart from a significant correlation between serum 25-OHD and the fractional trabecular bone volume, no relationships were observed between bone histomorphometry and vitamin D metabolites or serum iPTH. The results indicate that the bone loss was due to a decreased osteoblastic activity rather than to an impaired vitamin D metabolism.     

Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor-mediated arthritis

OBJECTIVE: Increased osteoclast activity is a key factor in bone loss in rheumatoid arthritis (RA). This suggests that osteoclast-targeted therapies could effectively prevent skeletal damage in patients with RA. Zoledronic acid (ZA) is one of the most potent agents for blocking osteoclast function. We therefore investigated whether ZA can inhibit the bone loss associated with chronic inflammatory conditions. METHODS: Human tumor necrosis factor (TNF)-transgenic (hTNFtg) mice, which develop severe destructive arthritis as well as osteoporosis, were treated with phosphate buffered saline, single or repeated doses of ZA, calcitonin, or anti-TNF, at the onset of arthritis. RESULTS: Synovial inflammation was not affected by ZA. In contrast, bone erosion was retarded by a single dose of ZA (-60%) and was almost completely blocked by repeated administration of ZA (-95%). Cartilage damage was partly inhibited, and synovial osteoclast counts were significantly reduced with ZA treatment. Systemic bone mass dramatically increased in hTNFtg mice after administration of ZA, which was attributable to an increase in trabecular number and connectivity. In addition, bone resorption parameters were significantly lowered after administration of ZA. Calcitonin had no effect on synovial inflammation, bone erosion, cartilage damage, or systemic bone mass. Anti-TNF entirely blocked synovial inflammation, bone erosion, synovial osteoclast formation, and cartilage damage but had only minor effects on systemic bone mass. CONCLUSION: ZA appears to be an effective tool for protecting bone from arthritic damage. In addition to their role in antiinflammatory drug therapy, modern bisphosphonates are promising candidates for maintaining joint integrity and reversing systemic bone loss in patients with arthritis.     

Articular mastocytosis in rheumatoid arthritis

The number and distribution of mast cells were assessed in 116 synovial membranes from patients with rheumatoid arthritis and in 30 control specimens. Rheumatoid synovial membranes contained a mean of 48.5 mast cells per 20 high-power fields (HPF) (range 0-252), and control synovial membranes had a mean of 3.9 mast cells per 20 HPF (range 0-13) (P less than 0.001). In a comparison of high and low mast cell subgroups in rheumatoid arthritis, counts were directly related to the intensity of clinical synovitis in the affected joint, but not to hemoglobin concentration or erythrocyte sedimentation rate. Joints excised from 5 patients with rheumatoid arthritis were characterized by active bone remodeling with increased osteoid, active resorption by osteoclasts, and trabecular osteoporosis. Mast cells were prominent in both extraosseous pannus and intraosseous invasive tissue. The possible roles of mast cells in the pathogenesis of rheumatoid arthritis are discussed.     

Bone loss in patients with rheumatoid arthritis — effect of steroids measured by low dose quantitative computed tomography

Summary For 2 years bone density changes in patients with rheumatoid arthritis were monitored to determine the effect of low dose corticosteroid treatment. Sixteen berimenopausal females were studied. Of these nine were treated with 5 to 20 mg prednisone per day and seven had no steroids. The differential effects on trabecular bone density and on cortical bone in the radius and the tibia were examined with high precision peripheral quantitative computed tomography (QCT). Steroid therapy did hot influence cortical bone loss and had only a minor influence on trabecular bone density. Of greater importance was the influence of estrogen depletion. Corticosteroids and estrogen depletion, however, cannot explain fully the yearly loss of 5.7% in the trabecular and 4% in the cortical bone of the radius.