Serum bone sialoprotein: a marker of bone resorption in postmenopausal osteoporosis

Thirty healthy perimenopausal women who had normal lumber spine bone mineral density (LS-BMD) measured by dual energy X-ray absorptiometry (DEXA) participated in this study as controls. The pathological group comprised 50 postmenopausal osteoporotic women who had LS-BMD more that 2 SD below the normal mean of healthy perimenopausal women. Postmenopausal osteoporotic patients were allocated to three different therapeutic modalities (hormone replacement therapy HRT, alendronate or combined HRT and alendronate). Blood and urine samples were collected from all groups before and 12 months after treatment. Serum bone sialoprotein (BSP) was measured by a specific radioimmunoassay and urinary pyridinoline N-telopeptide of type l collagen (NTX ) were determined as biomarkers of bone resorption. In addition, serum IL-11 and TGF &#103 2 were measured by enzyme immunoassays. The results obtained showed that serum BSP was significantly elevated in postmenopausal osteoporosis compared to that of healthy perimenopausal controls. Significant positive correlations exist between serum BSP and biomarkers of bone resorption (Pyr,DPyr,NTX ) as well as bone resorptive cytokines (IL-11,TGF &#103 2 ). Serum BSP decreased after different antiresorptive treatments and this decrease paralleled the decrease of bone resorption markers and the increase of LS-BMD. Based on these data, circulating BSP appears to be a valuable marker of bone resorption and monitoring therapy with antiresorptive drugs in postmenopausal osteoporosis. (Pyr), deoxy-pyridinoline (DPyr) and     

Serum bone sialoprotein: a marker of bone resorption in postmenopausal osteoporosis.

Thirty healthy perimenopausal women who had normal lumber spine bone mineral density (LS-BMD) measured by dual energy X-ray absorptiometry (DEXA) participated in this study as controls. The pathological group comprised 50 postmenopausal osteoporotic women who had LS-BMD more that 2 SD below the normal mean of healthy perimenopausal women. Postmenopausal osteoporotic patients were allocated to three different therapeutic modalities (hormone replacement therapy HRT, alendronate or combined HRT and alendronate). Blood and urine samples were collected from all groups before and 12 months after treatment. Serum bone sialoprotein (BSP) was measured by a specific radioimmunoassay and urinary pyridinoline (Pyr), deoxy-pyridinoline (DPyr) and N-telopeptide of type 1 collagen (NTX) were determined as biomarkers of bone resorption. In addition, serum IL-11 and TGFbeta2 were measured by enzyme immunoassays. The results obtained showed that serum BSP was significantly elevated in postmenopausal osteoporosis compared to that of healthy perimenopausal controls. Significant positive correlations exist between serum BSP and biomarkers of bone resorption (Pyr,DPyr,NTX) as well as bone resorptive cytokines (IL-11,TGFbeta2). Serum BSP decreased after different antiresorptive treatments and this decrease paralleled the decrease of bone resorption markers and the increase of LS-BMD. Based on these data, circulating BSP appears to be a valuable marker of bone resorption and monitoring therapy with antiresorptive drugs in postmenopausal osteoporosis.     

Denosumab: mechanism of action and clinical outcomes

Aims: To describe the mechanisms of action of denosumab, a novel antiresorptive agent, contrasting it with other antiresorptive and anabolic osteoporosis treatments. Methods: Published papers related to the mechanism of action of approved osteoporosis treatments were sought through MEDLINE searches. Findings: Osteoporotic fractures carry a substantial burden of morbidity and mortality, but pharmacotherapy can prevent such fractures in high‐risk individuals. Antiresorptive drugs (e.g. bisphosphonates, oestrogen, denosumab) reduce bone turnover by distinct mechanisms. Denosumab, a recently approved therapy, is a fully human monoclonal antibody that binds the cytokine RANKL (receptor activator of NFκB ligand), an essential factor initiating bone turnover. RANKL inhibition blocks osteoclast maturation, function and survival, thus reducing bone resorption. In contrast, bisphosphonates bind bone mineral, where they are absorbed by mature osteoclasts, inducing osteoclast apoptosis and suppressing resorption. These differences in mechanism influence both the onset and reversibility of treatment. Discussion: Effective pharmacotherapy is necessary for patients at high risk of fracture. Among the treatment options for postmenopausal osteoporosis, there are significant differences in mechanism and dosing. Denosumab acts by a novel mechanism and is administered twice yearly by subcutaneous injection. Identified by Osteoporosis Canada Clinical Practice Guidelines as a first‐line agent for treatment of postmenopausal osteoporosis, denosumab represents an important addition to our treatment options.     

Higher efficacy of urinary bone resorption marker measurements in assessing response to treatment for osteoporosis in postmenopausal women

Osteoporosis has reached epidemic proportions. This situation has stimulated the development of biochemical markers to assist in assessing osteoporotic risk and monitoring treatment efficacy. Biochemical markers for assessing the level of bone resorption have been developed during the last few decades. One of the most widely used bone resorption markers is cross-linked N-terminal telopeptides (NTX). Measurements of urinary and serum NTX provide indications of the level of bone resorption during osteoporosis treatment. However, it remains unclear whether urinary or serum NTX measurements show better efficacy for assessing osteoporosis treatment effects during the early phase of treatment. Therefore, the primary aim of the present study was to compare the efficacies of urinary and serum NTX measurements for assessing the level of bone resorption during the early stage of osteoporosis treatment. We enrolled 43 postmenopausal Japanese women in an open-label randomized placebo-controlled trial. Overall, 21 women in the osteoporosis treatment group and 19 women in the placebo group completed the study. There was a significant reduction in urinary NTX in the treatment group, which was detectable as early as 4 weeks and maintained until 16 weeks, compared with the placebo group. On the other hand, serum NTX did not show a significant reduction in the treatment group compared with the placebo group until 16 weeks. These results indicate that urinary NTX measurements are more sensitive and show higher efficacy than serum NTX measurements for assessing treatment effect during the early phase of osteoporosis treatment in postmenopausal women.     

Bisphosphonate therapy for postmenopausal osteoporosis.

Bisphosphonates are agents that are potentially useful for treatment of osteoporosis. They are antiresorptive agents, increasing bone mass by decreasing the frequency of osteoclast activation or the depth of osteoclast resorption, or both. Intermittent cyclical therapy with etidronate has been shown to be effective for postmenopausal osteoporosis in two controlled studies. Several second- and third- generation bisphosphonates are undergoing active clinical trials.     

IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

T cell-produced cytokines play a pivotal role in the bone loss caused by inflammation, infection, and estrogen deficiency. IFN-gamma is a major product of activated T helper cells that can function as a pro- or antiresorptive cytokine, but the reason why IFN-gamma has variable effects in bone is unknown. Here we show that IFN-gamma blunts osteoclast formation through direct targeting of osteoclast precursors but indirectly stimulates osteoclast formation and promotes bone resorption by stimulating antigen-dependent T cell activation and T cell secretion of the osteoclastogenic factors RANKL and TNF-alpha. Analysis of the in vivo effects of IFN-gamma in 3 mouse models of bone loss - ovariectomy, LPS injection, and inflammation via silencing of TGF-beta signaling in T cells - reveals that the net effect of IFN-gamma in these conditions is that of stimulating bone resorption and bone loss. In summary, IFN-gamma has both direct anti-osteoclastogenic and indirect pro-osteoclastogenic properties in vivo. Under conditions of estrogen deficiency, infection, and inflammation, the net balance of these 2 opposing forces is biased toward bone resorption. Inhibition of IFN-gamma signaling may thus represent a novel strategy to simultaneously reduce inflammation and bone loss in common forms of osteoporosis.     

Use of bone alkaline phosphatase to monitor alendronate therapy in individual postmenopausal osteoporotic women.

BACKGROUND: Biochemical bone markers are sensitive to the changes in bone turnover that result from treatment of postmenopausal osteoporotic women with antiresorptive therapies. Although information is available on the use of bone markers in monitoring therapy in groups of subjects, less is known regarding how these markers perform in individual patients. METHODS: Serum bone alkaline phosphatase (bone ALP) concentrations, measured with the Tandem(R) Ostase(R) assay, were used to monitor the biochemical response of bone in postmenopausal women with osteoporosis receiving either 10 mg/day alendronate therapy (n = 74) or calcium supplementation (n = 148) for 24 months. RESULTS: Bone ALP decreased significantly from baseline at 3 months (P 相似文献   

Assessment of bone turnover in postmenopausal osteoporosis by measurement of serum bone Gla-protein

Controversy persists regarding the abnormality of bone turnover responsible for bone loss in women with postmenopausal osteoporosis. To evaluate this, we measured serum bone Gla-protein (BGP), a specific marker for bone turnover, in 62 untreated patients with postmenopausal osteoporosis. Results were compared with those in 142 normal women and were expressed as standard deviations from the age-adjusted predicted mean (Z score). Serum BGP was increased (+0.48 S.D., p = 0.002) in the osteoporotic patients; 9.7% of patients were greater than 2 S.D. above but none were greater than 2 S.D. below the normal mean. Moreover, when data from normal postmenopausal women (ages 51 to 75 years) and the osteoporotic patients were merged, significant negative correlation existed (r = -0.36, p less than 0.001) between serum BGP and bone density of the lumbar spine assessed by dual photon absorptiometry. Serum alkaline phosphatase, a less specific marker for bone formation, was also increased (+0.96 S.D., p less than 0.001) in the osteoporotic patients. The data suggest that overall bone turnover is increased in patients with postmenopausal osteoporosis and do not support the concept that an absolute decrease in bone formation is the major cause of the bone loss.     

绝经后妇女血清基质金属蛋白酶与骨转换生化指标及骨密度的关系

目的探讨绝经后妇女血清基质金属蛋白酶(MMP)-1和MMP-2与骨密度及骨转换生化指标之间的关系。方法采用酶联免疫吸附法测定297名48~80岁女性志愿者的血清MMP-1、MMP-2和血清骨碱性磷酸酶(BAP)、血清骨钙素(OC)及血清Ⅰ型胶原氨基末端肽(NTX),用双能X线吸收法测定腰椎正位1~4总体、股骨颈、华氏区、髋部总体的骨密度。结果MMP-1与骨密度及骨转换生化指标无明显相关性;MMP-2与骨密度呈较弱的负相关,校正年龄与体重指数后,MMP-2与股骨颈、髋部骨密度的相关性消失;MMP-2与BAP、OC、NTX正相关(P<0.01);绝经后骨质疏松症患者血清MMP-2水平高于年龄匹配的正常对照组和骨量减少组(P<0.01)。结论绝经后妇女血清MMP-2与骨转换生化指标相关联,血清MMP-2水平升高可能为高骨代谢转换过程(如绝经后骨质疏松症)中的一种伴随表现。     

Biological effects of bisphosphonates in patients with rheumatoid arthritis

Loss of bone mineral density(BMD) has frequently been observed in patients with rheumatoid arthritis (RA) and main causes of osteoporosis were reported to be steroid osteoporosis, postmenoposal osteoporosis, and disuse bone atrophy associated with polyarticular impairment. It is becoming clear that the increase in bone resorption such as these osteoporosis and RA is underling the molecular mechanism; the facilitation of osteoclast differentiation and activation by the inflammatory cytokines TNFalpha and IL-1. Bisphosphonates, which are taken up by osteoclasts and macrophages to inhibit the activity of these cytokines, are expected to function as an inhibitor of inflammation induced by these cells. Bisphosphonates reduce also osteoclast numbers and activity by induction of osteoclast apoptosis, and could be a therapeutic goal for new anti-osteoclast drugs. As for the periarticular osteoporosis, bisphosphonate has also anti inflammatory effects and inhibition of bone destruction in RA.     

Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy

While platelet-activating factor (PAF) is produced in various diseases associated with bone resorption, its functions in bone metabolism remain unknown. Using PAF receptor-deficient mice, we evaluated the role of PAF in the development of bone resorption following ovariectomy, a model of postmenopausal osteoporosis. Through observations of bone mineral density and histomorphometric parameters, it was found that bone resorption was markedly attenuated in PAF receptor-deficient mice, indicating that PAF links estrogen depletion and osteoporosis in vivo. Osteoclasts expressed higher amounts of the enzymes required for PAF biosynthesis than osteoblasts. TNF-alpha and IL-1beta increased the acetyl-coenzyme A:lyso-PAF acetyltransferase activity in osteoclasts. Osteoclasts, but not osteoblasts, expressed the functional PAF receptor. PAF receptor stimulation prolonged the survival of osteoclasts in vitro. Furthermore, osteoclasts treated with a PAF receptor antagonist, and also those from PAF receptor-deficient mice, showed reductions in survival rate and Ca resorption activity. Consistently, in organ cultures, bone resorption was significantly suppressed by a PAF receptor antagonist treatment or genetic PAF receptor deficiency. Thus, these results suggest that, through the inflammatory cytokines, estrogen depletion enhances PAF production as a unique autocrine factor for osteoclast functions. Inhibition of PAF function might pave the way for a new strategy to prevent postmenopausal bone loss without disturbing osteoblast functions.     

Teriparatide (rhPTH 1-34) for the treatment of osteoporosis

Osteoporosis is a skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture. Osteoporosis develops through an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts resulting in increased bone loss. Numerous agents used for the prevention and treatment of osteoporosis slow bone loss by decreasing both bone resorption and formation. These include bisphosphonates, hormone replacement therapy, selective oestrogen receptor modulators and calcitonins. All reduce vertebral fracture risk and some reduce non-vertebral fracture risk, but none routinely increases bone mass and strength or restores lost bone architecture. In many respects, antiresorptive therapies halt the progression of osteoporosis. However, for patients who have osteoporosis, particularly those who have sustained their first fracture and are at high risk for subsequent fractures, there is a need to develop agents that stimulate bone formation and, thus, reverse osteoporosis. Teriparatide is the recombinant human 1-34 amino acid sequence of parathyroid hormone recently approved in the US for the treatment of men and postmenopausal women at high risk for osteoporotic fracture and in Europe for the treatment of postmenopausal women with osteoporosis. When given by once-daily injection, teriparatide increases bone mass by stimulating formation of new bone, resulting in the restoration of bone architecture.     

Relationship of bone turnover parameters,endogenous hormones and vit D deficiency to hip fracture in elderly postmenopausal women

Hip fracture is one of the severest consequences of osteoporosis affecting elderly women, but abnormalities of bone turnover responsible for bone loss have not been clearly defined. This study evaluated the relationship of bone turnover parameters to hip fracture in postmenopausal elderly women. We also investigated the effects of endogenous hormones and vitamin D deficiency on osteoporotic hip fracture. The subjects were 21 osteoporotic patients with hip fracture (study group) and 20 healthy postmenopausal women (control group). We measured osteocalcin levels, total and bone alkaline phosphatase (T-ALP and B-ALP), calcitonin, intact parathyroid hormone (iPTH), serum 25 hydroxyvitamin D (25OHD), urinary free deoxypyridinoline (D-pyr) and cross-linked N-telopeptides of type 1 collagen (NTx) levels. Serum T-ALP and B-ALP levels in the study group were lower than those of the control group. The mean serum 25OHD levels in the study group were not significantly different from the control group, but in five cases the mean serum iPTH level was increased. The mean urinary NTx levels were significantly increased in the study group compared with the control group (p<0.05). There was no significant increase in urinary free D-pyr between the two groups. There was significant correlation between serum T-ALP levels and B-ALP levels and between serum iPTH levels and B-ALP levels. The mean serum SHBG level in the study group was higher than in the control group (p<0.05). These data suggest that postmenopausal hip fracture patients have biochemical evidence of decreased bone formation and increased bone resorption compared with postmenopausal healthy subjects. We suggest these abnormalities play a role in the decrease of bone mass and the consequent increase in bone fragility that characterises osteoporotic hip fracture.     

RISEDRONATE: CLINICAL USAGE

Risedronate is a new bisphosphonate – a family of drugs that inhibit bone resorption – and thus can be used in various bone conditions involving increased levels of bone resorption, such as postmenopausal osteoporosis, glucocorticoid-induced bone loss, and Paget's disease of bone. In placebo-controlled clinical trials, risedronate has been shown to prevent bone loss in postmenopausal women, to decrease the incidence of vertebral and non vertebral (including hip) fractures in postmenopausal women with osteoporosis, and to prevent bone loss in men and women treated with moderate to high doses of glucocorticoids. Risedronate has also been shown substantially to decrease the severity of bone pain and the level of bone turnover in Paget's disease of bone, and to improve the radiographic lesions of this disease. Risedronate is safe and well tolerated. Thus, risedronate is a new option for the management of postmenopausal osteoporosis, Paget's disease of bone and corticosteroid-induced bone loss.     

Comparison of serum and urinary C-terminal telopeptide of type I collagen in aging, menopause and osteoporosis.

BACKGROUND: Urinary C-terminal telopeptide of type I collagen (u-CTx) has been reported to be a sensitive biochemical marker of bone turnover. There have been two assays for urinary CTx, which are alpha-CTx and beta-CTx. A newly developed immunoassay for serum CTx (s-CTx) is now available for assessment of bone resorption. We evaluated the effects of aging, menopause, and osteoporosis on the measurements of serum CTx and compared them to urinary CTx assays. Methods: In 79 premenopausal healthy women, 80 postmenopausal healthy women, 61 osteoporotic patients with vertebral fractures and 34 osteoporotic patients with hip fractures, s-CTx and urinary beta-CTx (u-betaCTx) were measured by ELISAs, and urinary alpha-CTx (u-alphaCTx) was measured by an RIA. RESULTS: In all subjects, s-CTx significantly correlated with both u-alphaCTx (r=0.54) and u-betaCTx (r=0.51). There was no significant difference among s-CTx, u-alphaCTx and u-betaCTx in the T-scores of the postmenopausal group over the premenopausal group. These findings indicate that the value of s-CTx, as well as urinary CTxs, reflected the increase of bone resorption associated with menopause with a high degree of sensitivity. Patients with vertebral fractures had moderately increased concentrations of bone resorption markers compared to age-matched healthy postmenopausal women (T-score; s-CTx: 0.8, u-alphaCTx: 0.9, u-betaCTx: 0.7), whereas bone resorption markers in hip fracture patients were greatly increased compared to healthy postmenopausal women (T-score; s-CTx: 1.1, u-alphaCTx: 1.3 u-betaCTx: 1.3). The T-scores of u-CTxs against the postmenopausal group in vertebral fracture group and in hip fracture group were not significantly different from those of s-CTx. CONCLUSIONS: s-CTx, as well as urinary CTxs, reflects the increase of bone resorption in patients with vertebral fractures and hip fractures.     

Inflammatory cytokines for osteoclastogenesis

Bone homeostasis is maintained by a balance between bone resorption by osteoclasts and bone formation by osteoblasts. Osteoclast maturation requires stimulation by RANKL on osteoblasts and various stimuli. Pro-inflammatory cytokines such as IL-1 and TNF-alpha cause an imbalance in bone metabolism by favouring bone resorption via the induction of RANKL on osteoblasts and induction of osteoclast maturation. These inflammatory signals originate from the immune system, the largest source of cell-derived regulatory signals and such immunological signals to the bone induce osteoclast maturation, resulting in secondary osteoporosis. Actually, such phenomena mainly occur at the interface between proliferating synovium and bone tissue in rheumatoid arthritis (RA). Thus, therapeutic strategies for these conditions, an anti-TNF-alpha antibody, effective for treating RA disease activity, also reduce secondary osteoporosis and joint destruction.     

Osteoprotegerin serum levels in women: correlation with age,bone mass,bone turnover and fracture status

Pre-clinical data have shown that osteoprotegerin (OPG) inhibits osteoclast function and therefore plays an important role in bone remodelling. This study aimed to evaluate the clinical value of serum OPG. Do higher OPG serum levels reflect decreased bone resorption and perhaps higher bone mass in women? Serum OPG levels were measured in 177 healthy women (aged 17-85 years) and in 48 untreated patients (mean age 71 +/- 5) with established osteoporosis, and related to age, bone mass, markers of bone turnover and, in the case of patients with osteoporosis, to pre-existing vertebral fractures. In healthy women OPG levels showed a positive correlation with age (r = 0.25, p < 0.001) but not to bone mass or markers of bone turnover. In women with osteoporosis, however, there was a strong relationship between serum OPG and markers of bone turnover (serum c-terminal crosslinked telopeptides of thpe I collagen (sCTX): r = +0.82, p < 0.0001; osteocalcin (OC): r = +0.69, p < 0.0001), with patients who had higher levels of bone-turnover markers showing higher serum levels of OPG. After adjustment for bone mass and bone markers, patients with pre-existing vertebral fractures had significantly lower serum OPG levels than patients without fractures (57 +/- 8 vs. 97 +/- 10 pg/ml, [mean +/- SE], p < 0.01). The age-dependent increase of OPG as an antiresorptive factor may reflect an insufficient paracrine mechanism of bone cells to compensate for bone loss in older age. In patients with osteoporosis, however, OPG correlated strongly with markers of bone turnover; this may point toward a higher level of RANKL/OPG expression in these patients. Finally, low OPG serum levels seem to be associated with vertebral fractures. We hypothesise that low OPG levels in preset conditions of bone turnover may indicate a higher risk of fracture in patients with osteoporosis.     

The treatment of osteoporosis. Antiresorptive therapy

Antiresorptive pharmacologic interventions for the prevention and treatment of osteoporosis are discussed. These interventions include estrogen; calcitonin; biphosphonates; and selective estrogen receptor modulators and their use in postmenopausal osteoporosis, steroid-induced osteoporosis, and osteoporosis in men. The effects of antiresorptive therapy on bone mineral density, biomarkers of bone turnover, and fracture risk are discussed.     

Relationships between serum adiponectin,leptin concentrations and bone mineral density,and bone biochemical markers in Chinese women

BackgroundAdiponectin and leptin, as the main circulating peptides secreted by adipose tissue, are potential contributors to bone metabolism. However, their association with bone mineral density (BMD) is unknown. We investigated whether these serum adipocytokines concentrations are associated with BMD and bone turnover markers.MethodsSerum adiponectin, leptin concentrations, bone turnover biochemical markers, and BMD were determined in 265 premenopausal and 336 postmenopausal Chinese women.ResultsIn postmenopausal Chinese women, the multiple linear stepwise regression analysis showed that year since menopause, lean mass, estradiol, and adiponectin, but not fat mass, leptin, were independent predictors of BMD in postmenopausal Chinese women. However, in premenopausal Chinese women, adiponectin was not the predictor of BMD. The significant positive correlations between adiponectin and bone-specific alkaline phosphatase (BAP), bone cross-linked N-telopeptides of type I collagen (NTX) were found only in postmenopausal women. Serum BAP, and NTX, but not adiponectin, decreased in response to alendronate therapy.ConclusionsAdiponectin was an independent predictor of BMD, and positively correlated with bone turnover biochemical markers in postmenopausal Chinese women, but not premenopausal women. It suggested that adiponectin may exert a negative effect on bone mass by promoting excessive bone resorption associated with bone loss. However, these effects may be mediated by menopausal status.     

Effect of sex hormones on bone in primary osteoporosis

The effect of sex hormones on bone tissue was studied in 12 osteoporotic patients. Surfaces of bone undergoing formation and resorption were determined by quantitative microradiography of iliac crest biopsy samples before and after treatment with estrogens in 11 postmenopausal women and with testosterone in one gonadally competent man. Before treatment, bone resorption was greater than normal in all but one patient and bone formation was normal. After treatment, bone resorption decreased to within the normal range in all patients, and bone formation did not change significantly. Biochemical studies showed significant decreases in serum calcium, phosphorus, and alkaline phosphatase levels and in urinary excretion of calcium and hydroxyproline. These changes are believed to be the consequence of the effect of the hormones on bone. The data indicate that the major effect of sex hormones in osteoporosis is an inhibition of bone resorption.