Characteristics of biochemical markers for bone formation in the elderly

Currently, several promising biochemical markers for bone metabolism have been postulated and expected to be applied to their clinical use. Among these markers, circulating levels of bone Gla-protein (BGP) and carboxyterminal peptide of type I procollagen (P1CP) have been established as non-invasive indices to assess bone turnover, especially bone formation. We investigated age-related effects on serum levels of both peptides and relationships between loss of bone mass and biochemical indices in the elderly. Fasting blood sample were obtained from 330 healthy volunteers to simultaneously measure serum BGP, serum P1CP and serum tartrate-resistant acid phosphatase (TRACP) as a marker for bone resorption. Serum BGP levels were found almost stable throughout life in men with a tendency to decrease in the elderly. Serum P1CP levels linearly decreased towards 50 to 60 years of age in men, followed by its constant increase with aging afterwards. Although a constant increase in serum P1CP levels were noted in women with aging, serum BGP levels were found remarkably elevated during menopausal periods of 50 to 70 years of age, followed by its wide distribution in the elderly. Both serum BGP and P1CP levels were elevated accompanied with age-related decrease in glomerular filtration rates in the elderly. In addition, a bone specific index, TRACP/BGP ratio consolidated the negative correlation between serum TRACP and % changes of bone mineral density (BMD). However, TRACP/P1CP ratio had nothing to do with % change of BMD. In conclusion, loss of bone mass could be predicted by bone specific indices, particularly in elderly women with widely distributed bone turnover. The data in this paper were reported in part in International Coference on Osteoporosis, Kobe, November 1991.     

A novel immunoassay for the determination of tartrate-resistant acid phosphatase 5b from rat serum.

Osteoclasts secrete tartrate-resistant acid phosphatase 5b (TRACP 5b) into the circulation. We have developed an immunoassay for the determination of rat TRACP 5b activity. Intra-assay variation of the immunoassay was 4.5%, interassay variation was 3.8%, dilution linearity was 104.6 +/- 7.6%, and recovery of recombinant rat TRACP was 99.1 +/- 5.8%. We studied serum TRACP 5b as a marker of bone resorption using orchidectomized (ORC) rats as a model for osteoporosis and age-matched sham-operated rats as controls in a 6-month study. After the operation, trabecular bone mineral density decreased significantly more in the ORC group than in the sham group, whereas cortical bone mineral density increased similarly in both groups. Serum TRACP 5b activity was significantly elevated within the first week after ORC, returned to the control level in the third week, and was not increased above the sham level at any of the later time points. At 6 months, trabecular bone volume was 80% lower in ORC rats than in controls. Osteoclast number per trabecular bone perimeter was slightly increased, but the absolute number of osteoclasts in trabecular bone was significantly decreased. These results suggest that absolute bone resorption is increased within the first week after ORC. Later, it is decreased because there is less bone to be resorbed. However, relative bone resorption (compared with the amount of remaining bone) is still increased, leading to further bone loss. We conclude that serum TRACP 5b is a useful marker for monitoring changes in the bone resorption rate in rat ORC model.     

第二代骨吸收生化标志物——血清抗酒石酸酸性磷酸酶5b的临床研究

目的　对血清TRACP5b作为骨吸收生化标志物进行临床研究。方法　利用BoneTRAP试剂盒 ,对 473例正常及骨质疏松患者血清做TRACP5b检测及分析。结果　男性和女性 ,随年龄的增加 ,特别是男性更年期及女性绝经期后 ,血清TRACP5b水平均不断升高 ,表明骨吸收增强 ;当患有骨质疏松后 ,血清中TRACP5b的水平高于同龄人 ,且男性及女性骨质疏松患者血清TRACP5b水平均高于正常人 ,统计学提示有显著性差异。结论　血清TRACP5b是一个较好的骨吸收监测指标     

Biochemical markers of bone turnover in patients with localized and metastasized prostate cancer

OBJECTIVE: To evaluate and compare the value of several markers of bone turnover in different stages of prostate cancer, as bone metastases are a common feature in this disease, and for assessing bone metastases both bone formation and bone resorption markers are diagnostic. PATIENTS AND METHODS: The prospective study included 219 men, i.e. 129 undergoing radical retropubic prostatectomy (RRP) and 25 with bone metastases due to prostate cancer, and 65 with benign urological disorders who served as controls. Before any treatment the concentrations of alkaline phosphatase (ALP), osteocalcin, serum C-terminal telopeptide of type I collagen (S-CTX) and tartrate-resistant acid phosphatase type 5b (TRACP5b) were determined. RESULTS: Men undergoing RRP were divided into those with lymph node-negative, localized (pT3, 101) and lymph node-positive (28) disease, after histological examination. The controls had the lowest marker levels while patients with bone metastases due to prostate cancer had the highest levels, with significance for ALP, osteocalcin and TRACP5b. Patients with lymph node-positive cancer had significantly high serum levels of TRACP5b and ALP but not for osteocalcin and S-CTX. CONCLUSIONS: Bone turnover markers represent a new diagnostic tool in prostate cancer; the present data show that both bone resorption and bone formation are crucial for detecting bone metastases in prostate cancer. The value of bone turnover markers in high-risk patients should be evaluated in a longitudinal study.     

Increased bone resorption and decreased bone formation in Chinese patients with hip fracture

Biochemical markers of bone formation (bone-specific alkaline phosphatase and osteocalcin) and bone resorption (hydroxyproline excretion and bone isoenzyme of acid phosphatase) were measured in 30 patients (15 M and 15 F) with hip fracture and 30 healthy subjects matched for age and sex. Bone isoenzyme of tartrate-resistant acid phosphatase (TRACP) was measured by a recently developed specific immunoassay. Serum osteocalcin concentration and bone-specific alkaline phosphatase activity were significantly lower and serum TRACP concentration and urinary hydroxyproline excretion were elevated in patients compared with healthy subjects. We suggest that there is reduced bone formation and increased bone resorption in patients with hip fracture.     

The association of bone metabolism with bone mineral density, serum sex hormone concentrations, and regular exercise in middle-aged men

Physical activity is an important factor in attaining bone mass. Our aim was to investigate if low to moderate intensity exercise affects bone resorption [serum tartrate-resistant acid phosphatase (TRAP) 5b activity] and formation (serum osteocalcin concentration) in a randomized controlled exercise intervention trial in Finnish middle-aged men. In addition, the relations of these bone turnover markers with bone mineral density (BMD) and serum sex hormone concentrations [circulating testosterone (T), estradiol (E2), and sex hormone-binding globulin (SHBG) concentrations] were evaluated. Serum TRAP 5b activity and osteocalcin concentration were measured at randomization and after 1 and 4 years of the exercise intervention. BMDs of the lumbar spine (L2-L4), femoral neck, and total proximal femur were measured with a dual-energy X-ray absorptiometry (DXA). At randomization, TRAP 5b activity was strongly correlated with the osteocalcin concentration (Spearman r = 0.541, P < 0.0001). In addition, TRAP 5b activity was significantly correlated with proximal femur BMD values (r = -0.201, P = 0.018) and osteocalcin concentration with femoral neck and proximal femur BMD values (r = -0.187, P = 0.028; r = -0.240, P = 0.005, respectively). Serum E2, free E2, and free T concentrations were inversely correlated with both bone turnover markers. After 1 year of exercise intervention, TRAP 5b activity was significantly lower in the exercise than reference group (P = 0.006). However, after 4 years of exercise intervention, the difference was no longer statistically significant. There were no differences in the osteocalcin concentrations between the study groups during the intervention. Our results show a connection between serum TRAP 5b activity and osteocalcin concentration. Furthermore, our results suggest that low to moderate exercise intervention and serum sex hormone concentrations may induce changes in bone metabolism in middle-aged men. However, exercise-induced effects on bone metabolism should be confirmed in other randomized controlled exercise trials taking into account exercise intensity and dose-response issues.     

Significance of Serum TRACP in Rheumatoid Arthritis

Human serum contains two related isoforms of TRACP: TRACP 5a and TRACP 5b. Serum TRACP 5a protein is increased in about one third of rheumatoid arthritis (RA) sera. This study was undertaken to examine the significance of serum TRACP isoforms 5a and 5b as disease markers of inflammation and bone destruction in RA. One hundred eighteen patients were recruited including 50 with RA (25 with nodules), 26 with osteoarthritis (OA), and 42 with other rheumatic diseases. Twenty‐six healthy adults served as controls. Serum TRACP 5a activity, TRACP 5a protein, and TRACP 5b activity were determined by in‐house immunoassays. C‐reactive protein (CRP) was determined by in‐house immunoassay using commercial antibodies and CRP. Other commercial markers included bone‐specific alkaline phosphatase (BALP), C‐telopeptides of type‐I collagen (ICTP), cartilage glycoprotein‐39 (YKL‐40), and IgM rheumatoid factors (IgM‐RF). Mean TRACP 5a protein was significantly elevated only in RA compared with healthy controls and other disease groups. TRACP 5a protein correlated significantly only with IgM‐RF in RA. Among RA patients, mean TRACP 5a protein and IgM RF were significantly higher in nodule formers. In contrast, TRACP 5b activity was slightly elevated in RA and correlated with BALP, ICTP, and YKL‐40 but not with IgM‐RF or CRP. Mean TRACP 5b activity was no different in RA patients with or without nodules. TRACP isoforms could be useful disease markers in RA; TRACP 5a protein may be a measure of systemic inflammatory macrophage burden and disease severity. TRACP 5b activity is a marker for osteoclast number and perhaps local or systemic bone destruction.     

血清ICTP与TRACP 5b联合检测在乳腺癌骨转移诊断中的价值

目的:探讨溶骨性骨代谢标志物血Ⅰ型胶原交联羧基末端肽(ICTP)和血抗酒石酸酸性磷酸酶5b(TRACP 5b)的检测对诊断乳腺癌骨转移的价值.方法:用ELISA法测定78例乳腺癌患者及40例乳腺良性肿瘤患者血清ICTP和TRACP 5b水平,比较两者水平在骨转移、非骨转移乳腺癌患者及良性乳腺肿瘤患者中的差异及其相关性.结果:乳腺癌骨转移患者血清ICTP和TRACP 5b水平均明显高于无骨转移及乳腺良性肿瘤患者(均P＜0.001),而后两者间无统计学差异(均P＞0.05).乳腺癌患者血清ICTP与TRACP 5b浓度表达呈正相关(r=0.63,P＜0.01).血清ICTP和TRACP诊断乳腺癌骨转移的敏感性、特异性和准确性分别为55.3％,92.5％,81.4％和84.2％,83.8％,83.9％,两者联合检测分别为94.7％,81.3％,85.6％.结论:血清ICTP和TRACP 5b对乳腺癌骨转移的诊断均有重要价值,两者联合检测有助于提高诊断的敏感性和准确性.     

Correlations of new markers of bone formation and resorption in kidney transplant recipients

Renal osteodystrophy is a common complication of chronic renal failure and renal replacement therapy. Successful kidney transplantation reverses many of these abnormalities, but the improvement is often incomplete. The evaluation of renal osteodystrophy in everyday practice is based on noninvasive measurements. Taking this into consideration the aim of the present study was to assess new markers of bone metabolism: serum CrossLaps degradation products of C-terminal telopeptides of type I collagen tartrate-resistant acid phosphatase (TRAP) and bone-specific alkaline phosphatase (bALP), as well as their correlations with bone mineral disease (BMD) in kidney transplant recipients. Twenty-six patients (aged 26 to 54 years) receiving a triple immunosuppressive regimen with stable graft function were enrolled in the study. Serum parathormone (PTH) osteocalcin type collagen C-terminal peptides (ICTP), and procollagen type I carboxyterminal extension peptide (PICP) concentrations were measured by radioimmunoassay (RIA), Serum CrossLaps, bALP, beta2-microglobulin, TRAP 5b by enzyme-linked immunoassay (ELISA), and deoxypyridinoline (DPD) in urine immunochemiluminescence. BMD, as measured by dual-energy X-ray absorptiometry (DEXA), correlated negatively with markers of bone formation (bALP, osteoclacin, and PICP) and resorption (TRAP, ICTP, and beta2-microglobulin). The only positive correlation was between urine DPD and BMD at the femoral neck. Interestingly, BMD correlated negatively with CsA concentration. TRAP 5b correlated positively with serum creatinine, ALP, bALP, osteocalcin, iPTH, ICTP, and serum beta2-microglobulin, and negatively with CsA concentration, and azathioprine and prednisone dose. DPD did not correlate with any parameters. Serum CrossLaps correlated with markers of both bone formation and resorption. Because TRAP and serum CrossLaps correlated with markers of both bone formation and or resorption, additional studies are needed to establish the value of these markers of bone resorption to assess renal osteodystrophy.     

Serum Levels of TRAP5b,a New Bone Resorption Marker Unaffected by Renal Dysfunction,as a Useful Marker of Cortical Bone Loss in Hemodialysis Patients

Tartrate-resistant acid phosphatase (TRAP) 5b is a new marker of bone resorption that is unaffected by renal dysfunction. The significance of TRAP5b was assessed in hemodialysis (HD) patients. Serum concentrations of TRAP5b and cross-linked N-telopeptide of type I collagen (NTX) were determined as bone resorption markers, and those of bone alkaline phosphatase (BAP) and intact osteocalcin (OC) were measured as bone formation markers in 58 HD patients. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry twice in the distal third of the radius, with a 2-year interval between measurements. Serum TRAP5b correlated significantly with BAP, intact OC, intact parathyroid hormone (PTH), and especially serum NTX. TRAP5b, NTX, BAP, and intact OC all correlated significantly with BMD at the time of the second measurement; and TRAP5b, NTX, and intact OC, but not BAP and intact PTH, correlated significantly with the annual change in BMD during the 2-year period. Among the bone markers, patients in the highest tertile for serum TRAP5b and intact OC showed the fastest rate of cortical bone loss. The sensitivity and specificity for detection of rapid bone loss were 57.9% and 76.9%, respectively, for serum TRAP5b. Measurement of serum TRAP5b, as well as intact OC, may be a clinically relevant assay for estimation of bone metabolic status in HD patients, although serum intact OC accumulates in uremic serum.     

Clinical performance of immunoreactive tartrate-resistant acid phosphatase isoform 5b as a marker of bone resorption

Previous immunoassays developed for the measurement of serum tartrate-resistant acid phosphatase (TRACP) have lacked specificity for osteoclastic TRACP, TRACP 5b, or have not shown satisfactory clinical performance. The aim of this study was to evaluate the clinical performance of a novel immunocapture activity assay for TRACP 5b, in comparison to telopeptide fragments of type I collagen. Within-subject variability and the effect of feeding on TRACP 5b and telopeptides of type I collagen were assessed in 20 healthy premenopausal women. Diurnal variation of TRACP 5b and serum beta C-terminal cross-linked telopeptide of type I collagen (sbetaCTX) was assessed in 12 healthy postmenopausal women. Renal clearance was assessed in 19 end stage renal failure patients undergoing routine haemodialysis. Response to antiresorptive treatment and calcium supplementation was assessed in osteoporotic postmenopausal women treated with alendronate and calcium (n = 16) or with calcium alone (n = 7) for 24 weeks.Within-subject variability (CVi) of TRACP 5b was 6.6%, lower than CVi of urinary and serum telopeptides. TRACP 5b decreased by 2.4 +/- 0.8%, in response to feeding (P < 0.05) compared to 7.0 +/- 2.6% to 7.9 +/- 3.7% for urinary telopeptides (P < 0.05 to < 0.01) and 8.5 +/- 1.7% to 17.8 +/- 2.6% for serum telopeptides (P < 0.0001). The amplitude of the diurnal rhythm for TRACP 5b was small compared to that of sbetaCTX, 14 +/- 4% vs. 137 +/- 14%. Haemodialysis did not have a significant effect on TRACP 5b but reduced sbetaCTX by 46 +/- 4% (P < 0.0001). In response to alendronate, TRACP 5b decreased by 39 +/- 4% compared to 49 +/- 4% to 69 +/- 5% for urinary telopeptides and 75 +/- 8% for sbetaCTX.We conclude that TRACP 5b shows an attenuated response to antiresorptive therapy in comparison with other markers of bone resorption, but that this may be offset by lower biological variability. TRACP 5b may provide useful additional information about bone resorption.     

妊娠妇女性激素、骨密度、骨代谢生化指标的变化及相关性研究

目的：探讨妊振妇女骨密度和骨代谢的变化及其与性激素的关系。方法：随机选取63例健康脑力劳动孕妇和21例健康脑力劳动妇女分别测定骨密度,血清Ca、P、ALP、BGP和E2、P、FSH、LH、PRL以及尿HP/Cr、Ca/Cr比值。结果：孕期骨密度虽有下降但无显变化（P＞0.05),ALP和BGP在晚孕期有显变化（P＜0.05)且此变化与E2成正相关（r=0.61、0.36)。结论：妊娠期骨密度虽无明显变化,但晚孕期骨转换率明显增加且与E2呈正相关。提示可通过测定E2了解孕期骨代谢情况,并及时予以补钙等措施可能有益。     

跑台运动对阿霉素联合醋酸戈舍瑞林诱导骨质疏松大鼠骨密度和骨代谢的影响

目的研究阿霉素(doxorubicin,DOX)和醋酸戈舍瑞林(goserelin acetate,GA)联合作用对大鼠骨密度和骨代谢的影响,以及跑台运动对DOX联合GA诱导的大鼠骨质疏松的防治效果。方法 8周龄雌性SD大鼠64只,被随机分为8组,每组8只:安静对照组(SED)、DOX干预组(SED+DOX)、GA干预组(SED+GA)、DOX和GA联合干预组(SED+DOX+GA)、跑台运动对照组(EX)、跑台运动结合DOX干预组(EX+DOX)、跑台运动结合GA干预组(EX+GA)、跑台运动结合DOX和GA联合干预组(EX+DOX+GA)。药物和跑台运动干预周期均为8周,8周后测试所有大鼠左侧股骨骨密度和血清骨代谢指标。结果与其相对应的非药物干预各组相比较,药物干预各组大鼠骨密度显著降低、骨形成指标ALP和BGP显著降低而骨吸收指标Ca2+和TRACP5b显著升高;与DOX单独干预组及GA单独干预组相比较,DOX和GA联合干预组大鼠骨密度显著降低、骨形成指标ALP和BGP显著降低而骨吸收指标Ca2+和TRACP5b显著升高;与其相对应的安静组相比较,跑台运动各组大鼠骨密度显著升高、骨形成指标ALP和BGP显著升高而骨吸收指标Ca2+和TRACP5b显著降低。结论 DOX和GA单独或联合作用均可导致大鼠骨质疏松症的发生,且DOX和GA联合作用诱导大鼠骨质疏松的程度显著大于DOX或GA单独作用的结果;跑台运动可以有效降低DOX和GA单独或联合作用诱导的大鼠骨质疏松。     

血清镁浓度与绝经后骨质疏松症患者骨转换指标和骨密度的相关性研究

目的确定绝经后骨质疏松骨密度(bone mineral density,BMD)和血清骨代谢标志物(bone turnover marker,BTM)酒石酸抗性酸性磷酸酶-5b(tartrate-resistant acid phosphatase-5b,TRAP-5b)、骨特异性碱性磷酸酶(bone-specific alkaline phosphatase,BSAP)、雌二醇(E_2)和镁(Mg~(2+))离子浓度的相关性。方法选取123例绝经后骨质疏松症妇女和97名无骨质疏松症的健康绝经后妇女作为研究对象。采用双能X射线吸收测量扫描评估不同骨骼部位的BMD。通过酶联免疫吸附测定法测量E_2、BSAP和TRAP-5b的血清水平。使用比色光谱技术测定血清Mg~(2+)水平。结果骨质疏松女性血清BTM水平显著高于对照组。BSAP具有中等敏感性(76. 8%)和特异性(84. 7%)(截止点为21. 27 U/L)。在3. 46 U/L的截止点,TRAP-5b的灵敏度为86. 8%,特异性为90. 8%。骨质疏松症患者血清Mg~(2+)浓度显著低于对照组。Mg~(2+)水平与BMD值呈正相关。此外,Mg~(2+)浓度与E_2水平呈正相关。脊柱骨密度与BSAP水平呈负相关。结论本研究表明,BMD与BTM呈负相关,与E_2和Mg~(2+)呈正相关。     

One year prospective open study of the effect of high dose inhaled steroids, fluticasone propionate, and budesonide on bone markers and bone mineral density

BACKGROUND: Inhaled corticosteroids are recognised as the most effective agents in the treatment of asthma. However, concerns have been expressed about the effects of high doses of inhaled corticosteroids on safety in relation to bone resorption and formation. This study measures the effects of two inhaled corticosteroids on bone markers and bone mineral density (BMD) over one year. METHODS: A one year randomised, prospective, open parallel study comparing inhaled fluticasone propionate (FP), 500 micrograms twice daily in 30 patients, and budesonide (BUD), 800 micrograms twice daily in 29 patients, delivered by metered dose inhaler and large volume spacers was performed in adults with moderate to severe asthma. Biochemical markers of bone turnover (osteocalcin, procollagen type 1 C-terminal propeptide (PICP), immunoreactive free deoxypyridinoline (iFDpd), N-terminal crosslinked telopeptides of type I collagen (NTx)), BMD at the spine and femoral neck, and serum cortisol concentrations were measured at baseline and 12 months later. RESULTS: There were no significant differences between the inhaled steroids on bone markers of bone resorption and formation or bone mineral density. Bone mineral density of the spine increased slightly in both groups over the 12 month period. Serum osteocalcin levels increased from baseline in both treatment groups (FP 16.9%, p = 0.02; BUD 14.3%, p = 0.04). PICP did not differ significantly from baseline. Both markers of bone resorption (iFDpd, NTx) varied considerably with no significant changes after one year. There was a significant correlation in percentage change from baseline between BMD of the spine and osteocalcin at 12 months (r = 0.4, p = 0.017). Mean serum cortisol levels remained within the normal range in both groups following treatment. CONCLUSION: There was no evidence of a decrease in BMD during 12 months of treatment with high doses of either FP or BUD. The change in spine BMD correlated with the increase in osteocalcin. Studies extending over several years are needed to establish whether these findings persist.     

阿仑膦酸钠对2型糖尿病合并骨质疏松患者骨代谢标志物的影响

目的 观察阿仑膦酸钠对2型糖尿病合并骨质疏松症患者骨代谢标志物的影响,以评价该药的治疗效果。方法 收集2011年1月至2012年6月门诊及住院患者共103例。对所有患者均早晨空腹采血。测量空腹血糖(FPG)、血钙、血磷、碱性磷酸酶(ALP)、糖化血红蛋白(HbA1c)、血清抗酒石酸酸性磷酸酶-5b（TRACP-5b）、血清Ⅰ型胶原C末端肽（s-CTX）、血清骨源性碱性磷酸酶（BAP）和血清骨钙素（OC）。利用双能X线吸收法进行腰椎和髋骨的骨密度检测。使用阿仑膦酸钠治疗6个月后复查上述各项生化指标和骨密度。将每例样本治疗前后的检测结果进行对比分析,统计学方法为配对t检验。结果 治疗前后血钙、血磷、碱性磷酸酶的差异无统计学意义;TRACP-5b、s-CTX治疗后较治疗前升高, BAP与OC较治疗前降低。治疗后腰椎和髋部的骨密度较治疗前均有不同程度升高。结论 阿仑膦酸钠对2型糖尿病合并骨质疏松症的治疗效果明显,其机制可能与抑制骨吸收,促进骨形成有关。     

COL1A1 Sp1 polymorphism associates with bone density in early puberty

Optimal acquisition of bone mass in puberty is a key determinant of the lifetime risk of osteoporosis and has a strong genetic basis. We investigated the relationship between the COL1A1 Sp1 polymorphism and BMD in early puberty, and how the genotypes relate to bone size and geometry as well as bone turnover and material properties in 247 10- to 13-year-old girls. Bone properties were measured using DXA, pQCT, and ultrasound. Also, serum P1NP, OC, B-ALP, and TRACP 5b were assessed. Our results showed that girls with the TT genotype had significantly lower BMC and BMD of the total body, lumbar spine, and proximal femur, as well as BUA at the calcaneus, than those with the GT and GG genotype. They also had significantly lower B-ALP, as well as P1NP/TRACP 5b and (OC + B-ALP)/TRACP 5b, compared to the others. These findings indicate that the COL1A1 polymorphism is associated with low bone properties in early puberty and suggest a possible physiological effect on collagen metabolism and bone turnover. This information may contribute to the identification of children at risk for suboptimal acquisition of peak bone mass and may ultimately be of value in the planning of early preventive strategies for osteoporosis.     

Cholesterol-sensing receptors, liver X receptor alpha and beta, have novel and distinct roles in osteoclast differentiation and activation.

The liver X receptor (alpha,beta) is responsible for regulating cholesterol homeostasis in cells. However, our studies using the LXRalpha-/-, LXRbeta-/-, and LXRalpha-/-beta-/- mice show that both LXRalpha and beta are also important for bone turnover, mainly by regulating osteoclast differentiation/activity. Introduction: The liver X receptors (alpha,beta) are primarily responsible for regulating cholesterol homeostasis within cells and the whole body. However, as recent studies show that the role for this receptor is expanding, we studied whether the LXRs could be implicated in bone homeostasis and development. MATERIALS AND METHODS: pQCT was performed on both male and female LXRalpha-/-, LXRbeta-/-, LXRalpha-/-beta-/-, and WT mice at 4 months and 1 year of age. Four-month-old female mice were additionally analyzed with reference to qPCR, immunohistochemistry, histomorphometry, transmission electron microscopy, and serum bone turnover markers. RESULTS: At the mRNA level, LXRbeta was more highly expressed than LXRalpha in both whole long bones and differentiating osteoblast-like MC3T3-E1 and osteoclast-like RAW 264.7 cells. Four-month-old female LXRalpha-/- mice had a significant increase in BMD because of an increase in all cortical parameters. No difference was seen regarding trabecular BMD. Quantitative histomorphometry showed that these mice had significantly more endosteal osteoclasts in the cortical bone; however, these cells appeared less active than normal cells as suggested by a significant reduction in serum levels of cross-linked carboxyterminal telopeptides of type I collagen (CTX) and a reduction in bone TRACP activity. Conversely, the female LXRbeta-/- mice exhibited no change in BMD, presumably because a significant decline in the number of the trabecular osteoclasts was compensated for by an increase in the expression of the osteoclast markers cathepsin K and TRACP. These mice also had a significant decrease in serum CTX, suggesting decreased bone resorption; however, in addition presented with an increase in the expression of osteoblast associated genes, bone formation markers, and serum leptin levels. CONCLUSIONS: Our findings show that both LXRs influence cellular function within the bone, with LXRalpha having an impact on osteoclast activity, primarily in cortical bone, whereas LXRbeta modulates trabecular bone turnover.     

Impaired bone metabolism following augmentation cystoplasties in growing rats

OBJECTIVE: The aim of this study was to evaluate the possible risk of impaired bone metabolism following augmentation cystoplasties with different gastrointestinal segments. METHOD: 60 young rats underwent augmentation cystoplasties using gastric, ileal or sigma segments, or sham operations. An additional group undergoing sigma-cystoplasty received the bisphosphonate ibandronate to inhibit osteoclast-mediated bone resorption. Bone mass in the lumbar spine and tibia was analyzed monthly by in vivo densitometry. Bone turnover was assessed monthly using current bone metabolism markers for a period of 16 weeks. Bone ashing and serum analyses of the osteotropic hormones parathyroid hormone (PTH), and 25-OH vitamin D3 were performed at study conclusion. RESULTS: Following ileocystoplasty, reduced bone mineral density (BMD) was seen throughout the observation period; this was pronounced in the trabecular bone. The decline in BMD was associated with decreased serum 25-OH vitamin D3 levels. Following sigmacystoplasty, bone calcium content was significantly decreased; this could be prevented by ibandronate. No skeletal changes occurred in the gastrocystoplasty group. Serum pH was not altered in any group, and markers of bone resorption indicated normal bone resorption rates. CONCLUSION: There is a significant correlation between impaired bone metabolism and the type of segment used for bladder augmentation. While the use of the ileum (and probably the colon too) causes osteopenia, gastrocystoplasties seem to have little influence on bone turnover.     

Premenopausal women with idiopathic low-trauma fractures and/or low bone mineral density

Introduction

In men, idiopathic osteoporosis (IOP) is often associated with low serum insulin-like growth factor (IGF-1) and reduced bone formation. The characteristics of premenopausal women with IOP are not well defined. We aimed to define the clinical, reproductive, and biochemical characteristics of premenopausal women with unexplained osteoporosis.

Methods

This is a cross-sectional study of 64 women with unexplained osteoporosis, 45 with fragility fractures, 19 with low bone mineral density (BMD; Z-score less than or equal to ?2.0) and 40 normal controls. The following are the main outcome measures: clinical and anthropometric characteristics, reproductive history, BMD, gonadal and calciotropic hormones, IGF-1, and bone turnover markers (BTMs).

Results

Subjects had lower BMI and BMD than controls, but serum and urinary calcium, serum estradiol, vitamin D metabolites, IGF-1, and most BTMs were similar. Serum parathyroid hormone (PTH) and the resorption marker, tartrate-resistant acid phosphatase (TRAP5b), were significantly higher in both groups of subjects than controls and directly associated in all groups. Serum IGF-1 and all BTMs were directly associated in controls, but the association was not significant after controlling for age. There was no relationship between serum IGF-1 and BTMs in subjects. There were few differences between women with fractures and low BMD.

Conclusions

Higher serum TRAP5b and PTH suggest that increased bone turnover, possibly related to subclinical secondary hyperparathyroidism could contribute to the pathogenesis of IOP. The absence of differences between women with fractures and those with very low BMD indicates that this distinction may not be clinically useful to categorize young women with osteoporosis.