Bone-specific Alkaline Phosphatase Levels Research Articles

Effects of Radiation Therapy on Established Neurogenic Heterotopic Ossification

Heterotopic ossification (HO) is frequently seen on rehabilitation units after spinal cord injuries, fractures, brain injuries, and limb amputations. Currently, there is no effective treatment for HO other than prophylaxis with anti-inflammatory medications, irradiation, and bisphosphonate administration. These prophylactic treatments are not effective for managing ectopic bone once it has formed. Here we describe three cases of established neurogenic HO treated with radiation therapy (RT). All patients had decreased serum alkaline phosphatase (ALP) and bone-specific ALP levels with decreased pain but increased range of motion immediately after RT. Post-treatment X-rays revealed no further growth of the HO. All patients maintained clinical and laboratory improvements 4 or 6 months after the RT. Our results suggest that RT is safe and effective in decreasing pain and activity of neurogenic HO.

The Clinical Utility of Bone Resorption and Bone Formation Markers in Multiple Myeloma

Introduction: While bone resorption markers such as urinary N-terminal telopeptide (NTx) have long been used in research, serum C-terminal telopeptide (CTx) has become the preferred marker of bone status in multiple myeloma (MM). A full understanding of the clinical utility of CTx, as well as the bone formation markers osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP), in MM is still lacking. In this study, we evaluated levels of CTx, OC, and BSAP in a cohort of MM patients to better understand their roles.Methods: One set of CTx, OC, and BSAP data was obtained by random sampling in patients during a 60-day window at the Weill Cornell Medical College Myeloma Center. Bone marker changes were assessed with respect to type of myeloma therapy, response status, use of anti-resorptive therapy, and presence of osteolytic lesions or fractures. Additionally, we tested the ability of the bone markers to isolate a high fracture risk group, as defined by radiologic evidence of impending fracture. The Wilcoxon-Mann-Whitney test was used to assess clinical variables, and a 2-sided t value of less than 0.05 indicated statistical significance.Results: 50 patients were identified with bone marker data, of which 47 had MM and 3 had MM precursor diseases. The mean age was 64 years, with 25 males and 25 females. All three markers CTx (p=0.001), OC (p=0.004), and BSAP (p<0.001) significantly decreased with myeloma therapy initiation. Only CTx, however, was significantly lower in patients who achieved a partial response or greater, compared to non-responders (p=0.010). Moreover, only CTx decreased significantly in patients using anti-resorptive therapy within one year of bone marker date (p=0.006). Both CTx (p=0.011) and BSAP (p=0.005) were significantly higher in patients with more than 5 osteolytic lesions compared to those without such lesions. Additionally, only CTx predicted which patients were at risk for impending fracture (p<0.001). Of 8 patients in this high-risk group for fractures, 2 developed new pathological fractures within 1 month of the CTx test. CTx values were significantly higher in patients who were taking both proteasome inhibitor (PI) and alkylating agents compared to those only taking PIs (p<0.001). Choice of PI also affected levels of bone markers, with patients receiving bortezomib having significantly higher levels of CTx (p=0.019) than those on carfilzomib. BSAP levels were similarly higher, with a trend toward significance (p=0.064).Discussion: Of the evaluated bone markers, only CTx correlated with response to anti-MM therapy and risk of impending fracture. Additionally, CTx reflects the extent of bone disease. CTx levels decreased with use of anti-resorptive therapy within one year of bone marker date, but not with longer time points. This suggests the clinical benefit of at least annual dosing of anti-resorptive therapy and indicates the dynamic nature of this marker. The high CTx values in the PI plus alkylating group may also suggest that PI alone is more effective in addressing bone disease in such patients. Differences in CTx between individual proteasome inhibitors points to agent-specific effects of PI on bone remodeling, which warrant further investigation. The potential increase in BSAP with bortezomib versus carfilzomib treatment is consistent with recent findings, which show that bortezomib promotes osteoblastic differentiation and bone formation. As opposed to our CTx data, OC and BSAP did not prognosticate disease response or future fractures or correlate with use of anti-resorptive therapy, suggesting limited utility of these bone formation markers in MM.Table 1Bone MarkerCategoryMM Therapy InitiationMM Therapy RespondersART Use Within 1 YearART Use Before 1 YearLytic Lesions Present5+ lytic Lesions PresentRisk of Future FracturePI Plus AlkylatorCTxBone Resorption↓↓↓↓↓NS↑↑↑↑↑↑↑↑OCBone Formation↓↓NSNSNSNSNSNSNSBSAPBone Formation↓↓NSNSNS↑↑↑NS↑Abbreviations: CTx, C-terminal telopeptide; OC, osteocalcin; BSAP, bone-specific alkaline phosphatase; MM, multiple myeloma; ART, anti-resorptive therapy; NS, not significant; PI, proteasome inhibitor. Single arrow represents a change by a factor of less than 2. Double arrows represent a change by a factor of greater than 2. Triple arrows represent a change by a factor of greater than 3. DisclosuresPearse:Celegen: Consultancy. Rossi:Calgene: Speakers Bureau. Mark:Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Niesvizky:Celgene: Consultancy, Speakers Bureau. Lane:Agnovos Healthcare, LLC: Consultancy; Bone Therapeutics: Membership on an entity's Board of Directors or advisory committees; CollPlant Holdings, Ltd.: Consultancy; D'Fine, Inc.: Consultancy; Gradtys: Membership on an entity's Board of Directors or advisory committees; ISTO Technologies, Inc: Membership on an entity's Board of Directors or advisory committees; Kuros: Membership on an entity's Board of Directors or advisory committees; Royal Consulting & Marketing: Consultancy.

25-Hydroxyvitamin-D and Bone Turnover Marker Levels in Patients with Distal Radial Fracture.

Fragility fractures are a major public health issue with substantial socioeconomic cost. Vitamin-D deficiency and increased bone turnover are associated with higher rates of bone loss and an increased risk of fracture. We hypothesized that patients with a distal radial fracture would have lower levels of 25-hydroxyvitamin D (25[OH]D) and increased levels of serum bone turnover markers than controls without a fracture. Postmenopausal women with a recent distal radial fracture (fracture group, n = 105) were prospectively recruited and were compared with individuals without a fracture (control group, n = 150). Outcome variables included serum levels of 25(OH)D and markers of bone formation, including N-terminal extension propeptide of type-I collagen (P1NP), parathyroid hormone (PTH), bone-specific alkaline phosphatase (BSAP), and osteocalcin, as well as a marker of resorption (C-terminal telopeptide of type-I collagen [CTX-1]). Bone mineral density was measured with dual x-ray absorptiometry. The fracture group was slightly older than the control group (mean and standard deviation [SD], 66.8 ± 10.8 years versus 63.3 ± 9.0 years, p = 0.008), had a lower body mass index (26.4 ± 5.9 kg/m(2) versus 28.0 ± 6.2 kg/m(2), p = 0.05), and more commonly had had a prior fracture (52% versus 31%, p < 0.001). Bone mineral density at the hip was lower in the fracture group than in the control group (0.831 ± 0.130 g/cm(2) versus 0.917 ± 0.139 g/cm(2), p < 0.001). The mean 25(OH)D levels were similar in the fracture and control groups (44.4 ± 14.6 ng/mL versus 41.3 ± 14.5 ng/mL, p = 0.08). Levels of serum markers of bone formation were significantly higher in the fracture group than in the control group (P1NP: 70.4 ± 33.2 ng/mL versus 53.2 ± 25.6 ng/mL, p < 0.001; osteocalcin: 22.3 ± 9.9 ng/mL versus 20.2 ± 9.2 ng/mL, p = 0.017). Levels of BSAP, PTH, and CTX-1 were similar in the two groups. Multivariable logistic regression showed independent associations between a distal radial fracture and low total hip bone mineral density (odds ratio [OR] = 2.02 for each decrease of 1 SD, 95% confidence interval [CI] = 1.38 to 3.01, p < 0.001) and a high P1NP level (OR = 2.17 for each 1-SD increase, 95% CI = 1.52 to 3.06, p < 0.001). In this cohort, 25(OH)D levels were not associated with distal radial fracture and do not appear to affect the risk assessment for distal radial fracture in postmenopausal women. Patients with a distal radial fracture, however, had increased bone turnover as evidenced by high P1NP and osteocalcin levels. Women with both a high P1NP level and low bone mineral density were at particularly high risk for fracture.

Increase in circulating sclerostin at the early stage of menopausal transition in Japanese women

ObjectiveWe examined the change in circulating sclerostin level during the menopausal transition and we investigated the associations of sclerositin with hormones and bone turnover markers according to each menopausal stage in cross-sectional and longitudinal studies. MethodsWe conducted a cross-sectional study in 200 healthy Japanese women and divided them into 4 stages (reproductive, menopausal transition, early postmenopause and late postmenopause) by menstrual regularity, follicle-stimulating hormone level and years since menopause. Serum levels of sclerostin, bone turnover markers and reproductive hormones were measured. In addition, we examined changes in sclerostin level from the reproductive stage to menopausal transition and from menopausal transition to early postmenopause in a longitudinal study. ResultsIn the cross-sectional study, sclerostin level gradually increased with progression of menopausal stages and showed a significant change during the menopausal transition. Sclerostin levels significantly increased from the reproductive stage to menopausal transition and from menopausal transition to early postmenopause in the longitudinal study. A negative correlation of sclerostin with estradiol was found in early postmenopause. Sclerostin levels were negatively correlated with bone-specific alkaline phosphatase levels in the reproductive stage and menopausal transition and with tartrate-resistant acid phosphatase-5b in menopausal transition. ConclusionThe change in sclerostin has already occurred in the early stage of menopausal transition and sclerostin level increases with progression of menopausal stages. Elevated sclerostin levels during the menopausal transition may be involved in relative decline in bone formation against increase in bone resorption.

Serbian

The aim of this work was to study the effect of two modalities of antiosteoporotic therapy in postmenopausal women at the level of biochemical markers of bone turnover such as bone specific alkaline phosphatase (BALP) and deoxypiridinoline (Dpd) as well as bone mineral density (BMD). The study included 87 patients with postmenopausal osteoporosis (OP). Group A consisted of 48 patients treated with alendronate (AL), whereas group B included 39 patients treated with hormone replacement therapy (HRT). BMD was measured by Lunar DPX 2000 device, on the lumbar spine and the femur, and bone markers (BM) were measured by commercial ELISA assays. There was a statistically significant decrease in the levels of BALP and Dpd after 6 weeks and 8 months of both types of therapy compared to the level of these markers before therapy. There was a statistically significant increase of BMD on both locations after 8 months of both therapies. In addition, there was a statistically significantly higher degree of changes of Dpd values in the group treated with AL than in the group treated with HRT. On the other hand, the changes in the level of BALP were significantly higher in the group treated with HRT. We concluded that the early effect of the two studied antiosteoporotic medications can be monitored by changes in the levels of BM. Dpd as bone resorption marker proved to be a better indicator of the efficiency of applied medications compared to bone formation markers such as BALP. Acta Medica Medianae 2015;54(3):5-11.

Randomized, Double-blind, Placebo-controlled Trial of the Effects of Polycan, β-glucan Originating from Aureobasidium Pullulans, on Bone Biomarkers in Healthy Women

Polycan originating from Aureobasidium pullulans is mostly composed of β-1, 3/1, 6 glucans and possesses an anti-osteoporotic effect. We conducted a randomized, double-blind, placebo-controlled trial to examine the efficacy and safety of the polycan on bone biochemical markers in healthy perimenopausal women. Sixty subjects were randomly allocated to 2 groups?group 1 received 400 mg of polycan and group 2 received placebo?these were administered once daily for 28 days. Fasting blood and urine samples were collected at baseline and 4 weeks after treatment. The primary outcome was change in osteocalcin (OSC) and bone-specific alkaline phosphatase (BALP). Changes in calcium (Ca), phosphorus (P), C-telopeptide of collagen cross-links (CTx), N-telopeptide of collagen cross-links (NTx), and deoxypyridinoline (DPYR) were the secondary outcomes. A safety assessment was performed using adverse event (AE) and laboratory data. After 4 weeks of polycan treatment, OSC, DPYR, and BALP levels changed (P 0.05) significantly from baseline in both groups. However, no significant differences were observed in any markers between the 2 groups, except for P (P 0.05). Interestingly, group 2 showed a significant increase in CTx (65.2%, P 0.05), while CTx in group 1 slightly increased (17.2%). Both groups showed no significant differences in AE. Although 4 weeks of polycan treatment did not have a statistically significant effect on bone metabolism biomarkers, increases in CTx were modestly inhibited by polycan. Further studies in a large population and longer treatment periods are needed to confirm the effect of polycan on bone turnover.

α2-Antiplasmin is involved in bone loss induced by ovariectomy in mice

The mechanism of postmenopausal osteoporosis is not fully understood. α2-Antiplasmin (α2-AP) is the primary inhibitor of plasmin in the fibrinolytic system, but is known to have activities beyond fibrinolysis. However, its role in bone metabolism and the pathogenesis of osteoporosis remains unknown. In the current study, we therefore examined the effects of α2-AP deficiency on ovariectomy (OVX)-induced bone loss by using wild-type and α2-AP-deficient mice. Quantitative computed tomography analysis revealed that α2-AP deficiency blunted OVX-induced trabecular bone loss in mice. Moreover, α2-AP deficiency significantly blunted serum levels of bone-specific alkaline phosphatase, cross-linked C-telopeptide of type I collagen, and interleukin (IL)-1β elevated by OVX. α2-AP treatment elevated the levels of IL-1β and tumor necrosis factor (TNF)-α mRNA in RAW 264.7 cells, although it suppressed osteoclast formation induced by receptor activator of nuclear factor-κB ligand. α2-AP treatment activated ERK1/2 and p38 MAP kinase pathways in RAW 264.7 cells, and these MAP kinase inhibitors antagonized the levels of IL-1β mRNA elevated by α2-AP. The data demonstrate that α2-AP is linked to bone loss due to OVX, through a mechanism that depends in part on the production of IL-1β and TNF-α in monocytes.

Abstract P1-09-33: Weight loss and bone health in postmenopausal breast cancer survivors

Abstract Background: The importance of bone health among postmenopausal breast cancer survivors cannot be overemphasized. In addition to bone loss due to aging, secondary bone loss resulting from treatment is a major concern. Although weight loss has adverse effects on bone health in postmenopausal women without cancer, the impact of weight loss on bone health in postmenopausal women with breast cancer is not known. Our objective in this study was to evaluate the effect of weight loss on bone health among overweight/obese postmenopausal breast cancer survivors participating in a weight loss trial. Methods: We conducted this study in a subset of women (postmenopausal, N=81) enrolled in the multi-site Exercise and Nutrition to Enhance Recovery and Good health for You (ENERGY) study. The ENERGY study is a randomized controlled clinical trial designed to achieve a sustained ≥7% loss in body weight among overweight/obese breast cancer survivors with stage I, II or IIIA disease. Weight loss was achieved largely through dietary modification with the addition of physical activity. Bone health was assessed in a subset of women at a single site using bone turnover markers (BTMs) and dual energy X-ray absorptiometry (DXA). Markers of bone formation: osteocalcin, bone-specific alkaline phosphatase (BALP), procollagen type I N-terminal propeptide (PINP) and bone resorption: N-telopeptides of type-I collagen (NTX), C-terminal telopeptide (CTX) were quantified in blood samples collected at baseline, 6 month and 12-month follow-up. DXA T-score was used to measure bone mineral density at baseline and at 12-month follow-up. Generalized estimating equations were used to assess differences in mean values over time as well as from baseline to 6- and 12-month follow-up. Data from intervention and control arm women were used and treated as a cohort. Results: The mean age and body mass index (BMI) of women enrolled in our sub-study were 56 years and 31.6kg/m2, respectively. Majority (54.3%) had stage 2 disease. Mean weight decreased by 5.6 pounds between baseline and 6-month follow-up and 4.3 pounds between baseline and 12-month follow-up. There were statistically significant decreases in mean osteocalcin (2.0ng/ml, p-value&amp;lt;0.001), PINP (7.9ng/ml, p-value&amp;lt;0.001) and NTx (3.65nM BCE/L, p-value&amp;lt;0.001), but not BALP and CTX-1 levels between baseline and 12-month follow-up. No significant changes were observed in mean T-scores, pelvis and lumbar spine bone mineral densities between baseline and 12-month follow-up. Weight change from baseline to 12-month follow-up was weakly inversely associated with changes in DXA T-score (r=-0.25, p-value=0.04) and CTX (r=-0.22, p-value=0.07) but not with other BTMs over the same time period. Conclusion: Weight loss over a 12-month period was associated with decreases in markers of bone formation and resorption but no changes in BMD in overweight/obese postmenopausal women with stage I, II or IIIA breast cancer. Further studies on the association of weight loss and the possible modifying effect of physical activity are needed in order to personalize weight control strategies in overweight/obese breast cancer survivors. Citation Format: Adetunji T Toriola, Jingxia Liu, Patricia A Ganz, Graham A Colditz, Lin Yang, Sonya Izadi, Anna L Schwartz, Kathleen Y Wolin. Weight loss and bone health in postmenopausal breast cancer survivors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-09-33.

Dried pomegranate potentiates anti-osteoporotic and anti-obesity activities of red clover dry extracts in ovariectomized rats.

Red clover (RC) shows potential activity against menopausal symptoms and pomegranates have antioxidative and beneficial effects on postmenopausal symptoms; thus, we investigated whether the anti-climacteric activity of RC could be enhanced by the addition of dried pomegranate concentrate powder (PCP) extracts in ovariectomized (OVX) rats. Regarding the anti-osteoporotic effects, bone mineral density increased significantly in OVX induced rats treated with 60 and 120 mg/kg of an RC:PCP 2:1 mixture, respectively, compared with OVX control rats. Additionally, femoral, tibia, and L4 bone resorption was decreased in OVX induced control rats treated with the RC:PCP 2:1 mixture (60 and 120 mg/kg), respectively, compared with OVX control rats. Regarding anti-obesity effects, the OVX induced rats treated with 60 and 120 mg/kg of the RC:PCP 2:1 mixture showed a decrease in total fat pad thickness, the mean diameters of adipocytes and the body weights gain compared with OVX induced control rats. The estradiol and bone-specific alkaline phosphatase levels were significantly increased in OVX induced rats treated with the RC:PCP 2:1 mixture (120 mg/kg) compared with OVX induced control rats, also, the uterine atrophy was significantly inhibited in 60 and 120 mg/kg of the RC:PCP 2:1 mixture treatment compared with OVX control rats. In conclusion, our results indicate that PCP enhanced the anti-climacteric effects of RC in OVX rats. The RC:PCP 2:1 mixture used in this study may be a promising new potent and protective agent for relieving climacteric symptoms.

Prospective Evaluation of Zoledronic Acid in the Treatment of Bone Metastases from Differentiated Thyroid Carcinoma.

The objectives of this study were to prospectively delineate the efficacy and safety of zoledronic acid for treating bone metastases (BM) from differentiated thyroid carcinoma (DTC), and to evaluate the relationships between levels of bone metabolic markers and occurrence of skeletal-related events (SREs). This was a prospective, single-arm, single-center study. Nineteen patients with BM from DTC were assigned to receive zoledronic acid therapy every 4-5 weeks. Imaging studies for sites of BM were conducted every 6 months, and levels of bone metabolic markers, including serum bone-specific alkaline phosphatase (BAP) and urinary N-telopeptide of type I collagen (NTx), were assessed every 3 months. To evaluate the efficacy of zoledronic acid use, data of SREs were compared with those of 16 historical controls. SREs developed in eight patients (42 %), but metastatic spinal cord compression (MSCC) appeared in only one patient. Pain scores were ameliorated in five patients, but aggravated in six patients. Ten patients had stable disease, six showed progressive disease, and none showed partial or complete response during the observation period. Decreases in levels of bone metabolic markers were observed in ten patients for BAP and 15 for NTx. However, no significant correlations were identified between changes in bone metabolic marker levels and development of SREs. Zoledronic acid may offer a mainstay of multidisciplinary treatment for patients with BM for the purpose of reducing SREs. Levels of serum BAP and urinary NTx do not appear reliable as indicators of amelioration of BM symptoms.

Bone metabolism biomarkers in men with advanced prostate cancer (PC) and bone metastases treated with denosumab versus zoledronic acid (ZA).

267 Background: Denosumab, compared with ZA, has recently demonstrated significant benefits in preventing skeletal-related events (SREs) in a double-blind phase 3 study of men with castration-resistant PC and bone metastases (N=1901). This post hoc analysis was performed to determine if key bone metabolism biomarker levels correlated with time-to-first SRE. Methods: Time-to-Grade ≥2 increase in total serum alkaline phosphatase (ALP) was assessed for correlation with time-to-first SRE. Levels of urinary N-telopeptide (uNTX) and serum bone-specific alkaline phosphatase (BSAP) markers were measured at baseline and study week 13, and correlations with time-to-first SRE were assessed. Covariate analyses were performed using a Cox proportional hazards model, stratified by treatment group or (for baseline analyses) with treatment group as the independent variable. Results: Analysis of the relationship between time-to-Grade ≥2 increase in total ALP and time-to-first SRE demonstrated that Grade ≥2 increases in ALP of PC patients were associated with a higher risk of first SRE (hazard ratio [HR] 1.838, 95% confidence interval [CI] 1.559, 2.167; P&lt;0.0001). In dichotomized analyses (&lt; vs ≥ median), a higher level of uNTX and BSAP (at baseline or week 13) was correlated with an increased risk of first SRE (Table). In baseline covariate analyses, treatment benefit for denosumab was maintained after adjusting for either baseline uNTX (HR 0.818, 95% CI 0.703, 0.951; P=0.0091) or BSAP (HR 0.813, 95% CI 0.700, 0.943; P=0.0061). Conclusions: Higher levels of uNTX or BSAP at baseline or week 13 were associated with worse SRE outcomes in men with advanced PC and bone metastases. Denosumab was more efficacious for preventing or delaying SREs compared with ZA, regardless of bone-related biomarker levels. Relationship of covariate to time-to-first SRE Clinical trial information: NCT00321620. [Table: see text]

Advanced Oxidation Protein Products as a Novel Marker of Oxidative Stress in Postmenopausal Osteoporosis.

BackgroundAdvanced oxidation protein products (AOPPs) are acknowledged as a novel marker of oxidation-mediated protein damage. This study aimed to investigate the plasma levels of AOPPs in postmenopausal osteoporotic women, and to determine the relationship between AOPPs accumulation and lumbar bone mineral destiny (BMD) or bone turnover markers.Material/MethodsLumbar BMD was measured by dual-energy X-ray absorptiometry. Plasma AOPPs levels as a marker of protein oxidation damage and malondialdehyde (MDA) levels as a marker of lipid peroxidation were measured by spectrophotometry. The concentrations of 2 specific markers of bone turnover, bone-specific alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase5b, (TRACP 5b) were quantified using ELISA kits.ResultsWe recruited 60 postmenopausal women meeting osteoporosis (OP) diagnostic criteria of World Health Organization (WHO) and 60 postmenopausal women without OP. Plasma levels of AOPPs (P<0.001), BALP (P<0.001) and TRACP 5b (P<0.001) were statistically significantly increased in the postmenopausal osteoporotic women compared with controls, but there was no statistically significant difference in MDA (P=0.124) between the 2 groups. Plasma AOPPs levels were negatively correlated with lumbar BMD and positively correlated with bone turnover markers both in postmenopausal osteoporotic women and in all subjects. However, plasma MDA levels were not correlated with lumbar BMD or bone turnover markers.ConclusionsIn postmenopausal osteoporotic women elevated AOPPs is associated with reduced BMD and increased bone turnover markers. Because AOPPs is stable and easy to detect it may be used as a simple plasma marker to predict the severity of postmenopausal OP.

Serum sclerostin levels in type 2 diabetes mellitus patients: possible correlations with bone metabolism parameters and thrombocytosis

Introduction Type 2 diabetes mellitus (T2DM) is a group of pandemic debilitating metabolic diseases featuring chronic hyperglycemia that results from defective insulin secretion and/or insulin actions. Dame and Sutor reported that diabetic patients are prone to thrombocytosis through a complex interplay of mechanisms. Therefore, the aim of our work is to evaluate serum sclerostin levels in patients with T2DM and to analyze the relationships among sclerostin, bone mineral density (BMD), bone metabolism, and thrombocytosis. Objective This study aimed to evaluate serum sclerostin in T2DM and its correlations with bone metabolism and thrombocytosis. Patients and methods Fifty male T2DM patients were enrolled; they were divided into two groups according to existing thrombocytosis. Forty age-matched men were included as controls. Clinical tests of physical mobility, fasting blood glucose, glycated hemoglobin, calcium, creatinine, parathormone (PTH), 25-hydroxyvitamin D, bone-specific alkaline phosphatase (BALP), serum carboxy-terminal cross-linked telopeptide of type I collagen (sCTX-I), serum sclerostin, and BMD were performed. Results There were insignificant increases in BMD in diabetic patients versus controls. There were significantly lower levels of PTH, BALP, and sCTX-I in the diabetes mellitus (DM) patient groups compared with the controls (P Conclusion Sclerostin plays a role in the pathogenesis of bone changes in T2DM. The interplay between vitamin D, PTH, and blood glucose highlights the possibility of an existing endocrine axis. Finally, the role of osteocytes in regulating hematopoiesis and association with DM and osteoporosis should be investigated further.

A Prospective Study on Inflammatory Cytokines and Bone Metabolism Mediators in Patients Affected by Rheumatoid and Psoriatic Arthritis treated with Adalimumab

Rheumatoid (RA) and Psoriatic arthritis (PsA) are characterized by extensive synovitis resulting in bone destruction in both diseases and new bone formation in PsA. Objective: This prospective study analyzed interleukin (IL)-6, IL-17, IL-23, tumor necrosis factor (TNF)-α serum and synovial fluid (SF) levels and osteoprotegerin (OPG), bone-specific alkaline phosphatase (BAP) and D-vitamin (D-Vit) serum levels in RA and PsA patients before and after anti-TNF-α. Methods: 15 RA and 15 PsA patients with knee effusion and starting adalimumab (ADA) treatment were enrolled. Serum and SF from inflamed knee joint samples were obtained at baseline and after 24 weeks of treatment. Statistical analysis was performed using Graph Pad 5.0 statistical software. Results: In RA and PsA, SF IL-6, IL-17, and TNF-α were higher than serum levels while higher serum IL-23 was detected than in SF. Higher serum/SF IL-6, IL-23 and SF TNF-α were observed in RA than PsA, while serum IL-17 was higher in PsA than RA. Positive feedback among IL-6, IL-23, IL-17 and CRP and negative correlation between IL-17 and TNF-α in RA were found. In PsA, IL-23 correlated positively with IL-6. OPG correlated positively with ESR/CRP in RA and PsA. D-Vit correlated negatively with OPG and ESR in PsA. Higher BAP in RA than PsA and positive correlation with IL-6 in RA and with OPG in PsA were noticed. In PsA, IL-6 and OPG serum levels decreased significantly after 24 weeks ADA treatment. Conclusions: Distinct distribution of inflammatory cytokines and correlations with bone mediators were detected in RA and PsA. ADA affected inflammatory cytokines and bone mediators in PsA patients.

Effects of raloxifene on bone metabolism in postmenopausal women on chronic hemodialysis.

Postmenopausal women with end-stage renal failure are at an increased risk of fracture because of the effects of secondary hyperparathyroidism and postmenopausal osteoporosis. In the present study, we investigated the feasibility of using raloxifene to prevent fractures in postmenopausal women with end-stage renal failure on hemodialysis. This study was conducted using a multicenter, single-arm, prospective design. Raloxifene was administered to postmenopausal women aged ≥50 years who were on maintenance hemodialysis and met any of the following criteria after a 24-week run-in period: an alkaline phosphatase level (bone formation marker) of ≥6.18 µkat/L (≥370 U/L), a bone-specific alkaline phosphatase (BAP; bone formation marker) level of ≥0.59 µkat/L (≥35.4 U/L), or a bone-derived tartrate-resistant acid phosphatase (TRACP-5b; bone resorption marker) level of ≥4.2 U/L. A total of 48 individuals were eligible for study inclusion. Of them, 30 individuals participated in this study. The BAP levels were significantly decreased at week 4, but returned to the baseline levels at week 24. Similarly, the TRACP-5b levels were significantly decreased at week 4, but returned to the baseline levels at week 24. The serum calcium value decreased consistently after the start of raloxifene therapy. The intact parathyroid hormone (iPTH) levels were likely increased at week 4. The ratio of BAP to iPTH levels and the ratio of TRACP-5b to iPTH levels both showed significant decreases over time. During the raloxifene therapy, no thrombosis or other drug-related adverse events developed. The study results indicated that raloxifene can transiently reduce the levels of bone metabolism markers and might be useful for preventing fractures in postmenopausal women with end-stage renal failure, although raloxifene use over the long term may not have adequate efficacy in the absence of appropriate concomitant active vitamin D therapy.

Efficacy of a Once-Monthly Pill Containing Ibandronate and Cholecalciferol on the Levels of 25-Hydroxyvitamin D and Bone Markers in Postmenopausal Women with Osteoporosis.

BackgroundThe present study evaluated the efficacy of a combination of ibandronate and cholecalciferol on the restoration of the levels of 25-hydroxyvitamin D (25[OH]D) and various bone markers in postmenopausal women with osteoporosis.MethodsThis was a randomized, double-blind, active-controlled, prospective 16-week clinical trial conducted in 20 different hospitals. A total of 201 postmenopausal women with osteoporosis were assigned randomly to one of two groups: the IBN group, which received a once-monthly pill containing 150 mg ibandronate (n=99), or the IBN+ group, which received a once-monthly pill containing 150 mg ibandronate and 24,000 IU cholecalciferol (n=102). Serum levels of 25(OH)D, parathyroid hormone (PTH), and various bone markers were assessed at baseline and at the end of a 16-week treatment period.ResultsAfter 16 weeks of treatment, the mean serum levels of 25(OH)D significantly increased from 21.0 to 25.3 ng/mL in the IBN+ group but significantly decreased from 20.6 to 17.4 ng/mL in the IBN group. Additionally, both groups exhibited significant increases in mean serum levels of PTH but significant decreases in serum levels of bone-specific alkaline phosphatase and C-telopeptide of type 1 collagen (CTX) at 16 weeks; no significant differences were observed between the groups. However, in subjects with a vitamin D deficiency, IBN+ treatment resulted in a significant decrease in serum CTX levels compared with IBN treatment.ConclusionThe present findings demonstrate that a once-monthly pill containing ibandronate and cholecalciferol may be useful for the amelioration of vitamin D deficiency in patients with postmenopausal osteoporosis. Moreover, this treatment combination effectively decreased serum levels of resorption markers, especially in subjects with a vitamin D deficiency, over the 16-week treatment period.

Bone-Specific Alkaline Phosphatase Levels among Patients with Multiple Myeloma Receiving Various Therapy Options.

Objective: This study aimed to investigate the impact of the different therapy regimens used in multiple myeloma (MM) on bone-specific alkaline phosphatase (BALP) levels.Materials and Methods: One hundred and thirteen patients with MM were included in the study. Patients were grouped according to the regimens they received, as follows: group 1, melphalan and prednisolone (MP); group 2, vincristine, adriablastin, and dexamethasone (VAD); group 3, thalidomide plus dexamethasone; and group 4, bortezomib plus dexamethasone. BALP levels were measured before treatment and at the third and sixth months of treatment. A fifth group consisted of patients in the post-treatment remission period at study entry (no-treatment group). Results: The BALP levels at the third and sixth months of the treatment were significantly higher than the pre-treatment levels in the bortezomib and the no-treatment groups, whereas no significant difference was observed in the MP, VAD, and thalidomide groups.Conclusion: Considering that BALP is a surrogate marker of bone formation, our study suggests that bortezomib more efficiently leads to the improvement of bone disease in myeloma than other treatment options.

The Relationship Between Bone Formation and Functional Status in Symptomatic Lumbar Spinal Stenosis

Objective: The aim of the present study was to investigate the relationship between bone formation and functional status in patients with symptomatic lumbar spinal stenosis (LSS). Material and Methods: Sixty patients (range 45 to 65 years) diagnosed with symptomatic lumbar spinal stenosis and 30 ageand gendermatched healthy controls were included in this study. Bone mineral density (BMD) of the subjects included in the study was measured from the lumbar vertebra and proximal femur. Bone-specific alkaline phosphatase, osteocalcin, and 24-hour urinary calcium (Ca) and phosphorus (P) levels were tested to assess bone metabolism. The functional status of patients was evaluated with the modified Oswestry disability index (mODI) and Swiss spinal stenosis questionnaire (SSSQ). Results: The mean age of the patient and control groups was different but not significant. No statistically significant difference was found between the patient and the control groups in bone-specific alkaline phosphatase, osteocalcin, and 24-hour urinary Ca and P values. Mean BMD values measured from the lumbar vertebra and proximal femur were significantly lower in patients with LSS. In the patient group, the mean mODI score was 42.28±3.1. Mean SSSQ pain scale score was 3.34±0.2, whereas the mean functional status score was 2.35±0.2. There was no statistically significant relationship of mODI with bone-specific alkaline phosphatase and osteocalcin levels. The pain and functional status scales of the SSSQ had no significant correlation with bone-specific alkaline phosphatase and osteocalcin. Conclusion: In this study, we determined that LSS has a negative impact on the functional status of patients, does not influence bone metabolism, and decreases BMD.

Development, in vitro and in vivo characterization of zoledronic acid functionalized hydroxyapatite nanoparticle based formulation for treatment of osteoporosis in animal model

We investigated the potential of using novel zoledronic acid (ZOL)-hydroxyapatite (HA) nanoparticle based drug formulation in a rat model of postmenopausal osteoporosis. By a classical adsorption method, nanoparticles of HA loaded with ZOL (HNLZ) drug formulation with a size range of 100–130nm were prepared. 56 female Wistar rats were ovariectomized (OVX) or sham-operated at 3months of age. Twelve weeks post surgery, rats were randomized into seven groups and treated with various doses of HNLZ (100, 50 and 25μg/kg, intravenous single dose), ZOL (100μg/kg, intravenous single dose) and HA nanoparticle (100μg/kg, intravenous single dose). Untreated OVX and sham OVX served as controls. After three months treatment period, we evaluated the mechanical properties of the lumbar vertebra and femoral mid-shaft. Femurs were also tested for trabecular microarchitecture. Sensitive biochemical markers of bone formation and bone resorption in serum were also determined. With respect to improvement in the mechanical strength of the lumbar spine and the femoral mid-shaft, the therapy with HNLZ drug formulation was more effective than ZOL therapy in OVX rats. Moreover, HNLZ drug therapy preserved the trabecular microarchitecture better than ZOL therapy in OVX rats. Furthermore, the HNLZ drug formulation corrected increase in serum levels of bone-specific alkaline phosphatase, procollagen type I N-terminal propeptide, osteocalcin, tartrate-resistant acid phosphatase 5b and C-telopeptide of type 1 collagen better than ZOL therapy in OVX rats. The results strongly suggest that HNLZ novel drug formulation appears to be more effective approach for treating severe osteoporosis in humans.

Clinical efficacy of oral risedronate therapy in Japanese patients with Paget's disease of bone.

Paget's disease of bone (PDB) is a chronic disorder characterized by localized bone regions with excessive bone turnover. Although oral risedronate (17.5mg daily for 8weeks) was recently approved in Japan, its efficacy is not well understood. We retrospectively examined the efficacy of oral risedronate in PDB patients in a clinical setting. Eleven patients whose serum alkaline phosphatase (ALP) level exceeded the upper limit of the normal range were treated. Patients whose ALP levels normalized and remained so for 12months after therapy initiation were defined as responders. Treatment was repeated if bone pain recurred or if serum ALP levels increased at least 25% above the nadir. Six patients (55%) were responsive to the therapy. A higher prevalence of skull lesions, higher serum calcium levels at treatment initiation and antecedent treatments of bisphosphonates were predictors of resistance against the therapy. Fresh frozen serum samples obtained from some treatment sessions were evaluated for metabolic bone markers such as bone-specific ALP (BAP), type I procollagen N-terminal pro-peptide (PINP), N-treminal crosslinking telopeptide of type I collagen and C-treminal crosslinking telopeptide of type I collagen (CTX). A significant reduction of P1NP preceded that of serum ALP levels in the responders, which was followed by a similar occurrence for BAP and osteocalcin (BGP) levels. A temporary decrease in CTX levels was noted. No significant changes in markers (including ALP level) were observed in non-responder and repeat-treatment groups. P1NP levels may be more useful than ALP levels in assessing treatment efficacy. Repeat treatment effectiveness for the repeat-treatment group was limited.