Levels Of Bone Resorption Markers Research Articles

Increased Bone Resorption Is Associated With Higher Mortality in Community-Dwelling Men ≥50 Years of Age: The MINOS Study

Low BMD, high concentration of 17beta-estradiol (17betaE2), and decreased level of 25-hydroxycholecalciferol [25(OH)D] predict mortality. Our hypothesis is that high levels of biochemical bone turnover markers (BTMs) are independent predictors of mortality in home-dwelling men. In 781 men >or=50 yr of age followed up prospectively for 10 yr, we studied the association of BTMs with mortality after adjustment for confounders including BMD, major osteoporotic fractures, and concentrations of 17betaE2 and 25(OH)D. Men who died had lower BMD and higher BTM levels. In multivariate models, mortality was higher in men with low BMD (lowest quartile) at the total hip, whole body, and ultradistal radius (HR = 1.49-1.70, p < 0.05). After exclusion of the first 3 yr, higher levels (fourth quartile) of bone resorption markers (free and total deoxypyridinoline and urinary and serum type I collagen C-telopeptide) predicted mortality in multivariate models adjusted for age, BMI, smoking habits, alcohol intake, physical performance and activity, comorbidities, total hip BMD, major osteoporotic fractures, creatinine clearance, season, and concentrations of 17betaE2 and 25(OH)D (HR = 1.58-2.44, p < 0.05-0.001). In conclusion, in older community-dwelling men, increased bone resorption markers levels predicted mortality regardless of age and other confounders. Thus, in older men, high bone resorption may reflect poor current health status and poor aging.

Major Depression Is a Risk Factor for Low Bone Mineral Density: A Meta-Analysis

The role of depression as a risk factor for low bone mineral density (BMD) and osteoporosis is not fully acknowledged, mainly because the relevant literature is inconsistent and because information on the mechanisms mediating brain-to-bone signals is rather scanty. Searching databases and reviewing citations in relevant articles, we identified 23 studies that quantitatively address the relationship between depression and skeletal status, comparing 2327 depressed with 21,141 nondepressed individuals. We subjected these studies to meta-analysis, assessing the association between depression and BMD as well as between depression and bone turnover markers. Overall, depressed individuals displayed lower BMD than nondepressed subjects, with a composite weighted mean effect size (d) of -.23 (95% confidence interval: -.33 to -.13; p < .001). The association between depression and BMD was similar in the spine, hip, and forearm. It was stronger in women (d = -.24) than men (d = -.12) and in premenopausal (d = -.31) than postmenopausal (d = -.12) women. Only women individually diagnosed for major depression by a psychiatrist with DSM criteria displayed significantly low BMD (d = -.36); women diagnosed by self-rating questionnaires did not (d = -.06). Depressed subjects had increased urinary levels of bone resorption markers (d = .52). The present findings portray depression as a significant risk factor for low BMD. Premenopausal women who are psychiatrically diagnosed with major depression are particularly at high-risk for depression-associated low BMD. Hence, periodic BMD measurements and antiosteoporotic prophylactic and curative measures are strongly advocated for these patients.

Serum bone turnover markers may be involved in the metastatic potential of lung cancer patients

The aim of this study was to investigate several bone markers in Non-Small Cell Lung (NSCLC) and Small Cell Lung (SCLC) patients experiencing or not secondary bony disease. Fasting serum levels of bone formation, bone resorption, and osteoclastogenesis markers were determined in 22 NSCLC patients with bone metastases, 18 without bone metastasis, and 28 SCLC patients. A total of 29 healthy volunteers were also included in the study. Decreased osteocalcin (OC) serum levels and increased osteopontin and ligand of the receptor of nuclear factor kB (RANKL) serum levels were detected in NCSLC patients with bone metastases while increased C-terminal cross-linking telopeptide of type I collagen and increased RANKL/OPG (osteoprotegerin) ratio were detected in SCLC patients. Increased serum levels of OPG were observed in all lung cancer patients. OPG may be actively involved in the development of lung cancer metastasis. Furthermore, OC, OPN, and RANKL in NSCLC and CTX and RANKL in SCLC patients may also have a broader role in the pathogenesis and spread of lung cancer. They also provide useful information in identifying the group of patients that may benefit from a more rigorous treatment.

The impact of an osteoporosis clinical guideline on rates of referral to an osteoporosis clinic

ing to the superoxide group. Our own previous studies have shown that P. sarmentosum has the ability to inhibit the 11-β-hydroxysteroid dehydrogenase (11-βHSD) enzyme, an enzyme important in the synthesis of cortisol. Based on this and also its antioxidant property, we hypothesize that P. sarmentosum will be able to prevent osteoporosis in a rat model of excess glucocorticoids. Forty male Sprague–Dawley rats, aged 3 months and weighing between 200 and 250 g were used. Twenty-four animals were adrenalectomized and replaced with intramuscular dexamethasone 120 μg/kg/day. They were simultaneously given either P. sarmentosum 0.125 g/kg/day, glycyrrhizic acid (GCA) 240 μg/kg/day or vehicle distilled water (adrx-control group) daily by oral gavage. A group of eight animals were sham-operated and given vehicle daily, i.e. intramuscular olive and oral distilled water. The treatment was given for 8 weeks. The group given GCA was used as a comparison since GCA had been proven to inhibit 11-βHSD enzyme, therefore reducing serum cortisol levels. A baseline control group was used to determine whether any significant stress was induced in the sham-control group. The results after eight weeks showed increased serum cortisol levels in the adrx-control group compared to the sham-control group. However, in the groups treated with P. sarmentosum and GCA, the serum cortisol levels were maintained at sham-control levels. Plasma pyridinoline (bone resorption marker) levels were lower in the P. sarmentosum and GCA groups compared to the adrx-control group. No difference in serum osteocalcin levels were detected between all the groups. In conclusion, the results showed that P. sarmentosum was as effective as GCA in preventing the increased cortisol levels seen in adrenalectomised rats treated with dexamethasone. This was associated with reduced bone resorption activity. Therefore, this suggests that P. sarmentosum is potentially useful in prevention of osteoporosis induced by long-term glucocorticoid therapy.

Effect of Intermittent Systemic Corticosteroid on Bone Metabolism in Bronchial Asthma Patients

The purpose of this study was to assess the effect on bone mineral density (BMD) of systemic corticosteroid (SCS) intermittently administered for rescue from asthmatic exacerbation. Through digital image processing and calculation of four other indices, BMD was compared in groups of asthmatic patients receiving inhaled corticosteroid (ICS) alone or ICS plus intermittent SCS. We defined SCS as intermittent administration of the equivalent of 1 mg/day prednisolone in the management of asthma exacerbations during the previous 1 year. Serum NTX, a bone resorption marker, was significantly higher (p = 0.02) in the SCS group than the ICS group. SCS had no effect on BMD, although the frequency of patients at “high-risk” for osteoporosis according to the Female Osteoporosis Self-assessment Tool for Asia (FOSTA) tended to be higher in the SCS group (35%) than in the ICS (28%) or control (10%) group. Because patients in the ICS group already had impaired respiratory function due to repeated asthma exacerbations, it was difficult to determine whether it was asthma itself or SCS that is the risk factor for osteoporosis. In addition, the response of biochemical markers of bone turnover to intermittent SCS remains unclear and likely differs from that elicited by high-dose, short-term, or continuous SCS. That said, relatively low-dose intermittent administration of SCS raised levels of bone resorption markers, which likely reflects altered bone metabolism. Taken together, these findings suggest that, without consideration of its effects on bone, SCS administration should be avoided.

Disruption of BMP Signaling in Osteoblasts Through Type IA Receptor (BMPRIA) Increases Bone Mass

Bone morphogenetic proteins (BMPs) are known as ectopic bone inducers. The FDA approved BMPs (BMP2 and BMP7) for clinical use. However, direct effects of BMPs on endogenous bone metabolism are not yet well known. We conditionally disrupted BMP receptor type IA (BMPRIA) in osteoblasts during weanling and adult stages to show the impact of BMP signaling on endogenous bone modeling and remodeling. Cre recombination was detected in immature osteoblasts in the periosteum, osteoblasts, and osteocytes but not in chondrocytes and osteoclasts after tamoxifen administration. Bmpr1a conditional knockout mice (cKO) showed increased bone mass primarily in trabecular bone at P21 and 22 wk as determined by H&E staining. Vertebrae, tails, and ribs showed increased radiodensity at 22 wk, consistent with a significant increase in BMD. Both muCT and histomorphometry showed an increase in trabecular BV/TV and thickness of cKO adult bones, whereas osteoclast number, bone formation rate, and mineral apposition rate were decreased. Expression levels of bone formation markers (Runx2 and Bsp), resorption markers (Mmp9, Ctsk, and Tracp), and Rankl were decreased, and Opg was increased in adult bones, resulting in a reduction in the ratio of Rankl to osteoprotegerin (Opg). The reduction in osteoclastogenesis through the RANKL-OPG pathway was also observed in weanling stages and reproduced in newborn calvaria culture. These results suggest that Bmpr1a cKO increased endogenous bone mass primarily in trabecular bone with decreased osteoclastogenesis through the RANKL-OPG pathway. We conclude that BMPRIA signaling in osteoblasts affects both bone formation and resorption to reduce endogenous bone mass in vivo.

Increased Levels of Serum Tissue Inhibitor of Metalloproteinase-1 Correlate with Advanced Stage, Increased Bone Resorption, Lytic Bone Disease and Poor Survival in Newly-Diagnosed Myeloma Patients

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a natural metalloproteinase (MMP) inhibitor that binds to and inactivates mainly MMP-9. TIMP-1 has multifunctional roles in tumorigenesis: inhibition of the catalytic activity of metalloproteinases, growth promotion, inhibition of apoptosis, and regulation of angiogenesis. Increased TIMP-1 has been associated with an unfavorable prognosis in many cancers including breast, colorectal, gastric, head and neck, lung cancer, and lymphomas. In vitro studies have revealed that TIMP-1 is overexpressed in myeloma cell lines. Furthermore, TIMP-1 promotes myeloma cell invasion across basement membranes. The aim of this study was to evaluate the serum levels of TIMP-1 in newly-diagnosed, previous untreated myeloma patients and explore possible correlations with clinical and laboratory data, including survival. Fifty-five patients with newly-diagnosed myeloma (25M/30F, median age: 69 years) were evaluated. Eleven patients had stage 1 disease according to ISS, while 27 had stage 2 and 17 stage 3 myeloma. Serum TIMP-1 was determined before the administration of any therapy, including bisphosphonates, using ELISA methodology (Oncogene Science/Siemens HealthCare Diagnostics, Cambridge, MA, USA) along with a series of serum markers of bone metabolism:osteoclast regulators [soluble receptor activator of nuclear factor-κB ligand (sRANKL), and osteoprotegerin (OPG)],osteoblast inhibitor dickkopf-1 (Dkk-1),bone resorption markers (N- & C-telopeptide of collagen type-I: NTX, CTX and ICTP; and tartrate-resistant acid phosphatase-isoform 5b, TRACP-5b), andbone formation markers (bone-specific alkaline phosphatase, bALP; and osteocalcin, OC).The above bone markers were also evaluated in 27 healthy controls of similar age and gender. The mean serum TIMP-1 level of all patients was 431.9 ng/ml (SD 198.1 ng/ml). Twenty-six patients (17M/9F; 47%) had elevated values of TIMP-1 (upper normal limit 324 ng/ml for males and 454 ng/ml for post-menopausal women). Patients had also increased levels of Dkk-1, sRANKL, sRANKL/OPG ratio and bone resorption markers (NTX, CTX, ICTP and TRACP-5b) (p<0.01 compared with healthy controls). TIMP-1 serum levels correlated with ICTP (r=0.514, p<0.001), beta2-microglobulin (r=0.414, p<0.01), albumin (r=-0.416, p<0.01), osteocalcin (r=0.325, p=0.01), CTX (r=0.314, p=0.01), NTX (r=0.306, p=0.02), and LDH (r=0.295, p=0.03). More importantly, TIMP-1 correlated with ISS (ANOVA p=0.005). Patients with ISS 3 disease had higher levels of TIMP-1 (mean±SD 557.8±234 ng/ml) compared with those who had ISS 1 (311±90.6 ng/ml; p=0.001) or ISS 2 disease (405.5±165.6 ng/ml; p=0.021). Furthermore, patients with lytic disease (n=43) had increased levels of TIMP-1 (457.7±205 ng/ml) compared with all others (313.6±107.6 ng/ml; p=0.05). The median follow-up was 31 months and 16/55 patients have died. The median survival has not been reached yet. Patients who had TIMP-1 level of above the mean value had a median survival of 37 months, while in all others the median survival has not been reached yet (p=0.04). Our study provides evidence for the first time that increased serum levels of TIMP-1 correlate with advanced myeloma, with increased bone resorption and with increased number of osteolytic lesions. Furthermore, elevated TIMP-1 was associated with inferior survival of MM patients. These results suggest that TIMP-1 may participate in myeloma pathogenesis and support that serum TIMP-1 deserves further study to determine its predictive and prognostic potential in a larger cohort of myeloma patients.

Biochemical markers of bone turnover: potential use in the investigation and management of postmenopausal osteoporosis

The aim was to analyse data on the use of biochemical bone turnover markers (BTM) in postmenopausal osteoporosis. We carried out a comparative analysis of the most important papers concerning BTM in postmenopausal osteoporosis that have been published recently. The BTM levels are influenced by several factors. They are moderately correlated with BMD and subsequent bone loss. Increased levels of bone resorption markers are associated with a higher risk of fracture. Changes in the BTM during the anti-osteoporotic treatment (including combination therapy) reflect the mechanisms of action of the drugs and help to establish their effective doses. Changes in the BTM during the anti-resorptive treatment are correlated with their anti-fracture efficacy. Biological samples should be obtained in a standardised way. BTM cannot be used for prediction of the accelerated bone loss at the level of the individual. BTM help to detect postmenopausal women who are at high risk of fracture; however, adequate practical guidelines are lacking. BTM measurements taken during the anti-resorptive therapy help to identify non-compliers. They may improve adherence to the anti-resorptive therapy and the fall in the BTM levels that exceeds the predefined threshold improves patients' persistence with the treatment. There are no guidelines concerning the use of BTM in monitoring anti-osteoporotic therapy in postmenopausal women.

Rapid Suppression of Bone Resorption Marker Levels With Ibandronate Therapy in a Bisphosphonate-Naïve Population

This 6-mo open-label study assessed the pattern of bone turnover marker (BTM) level changes in bisphosphonate-naïve women with postmenopausal osteoporosis treated with monthly oral ibandronate 150 mg and the correlation between month 1 and month 6 serum C-terminal cross-linking telopeptide of type I collagen (sCTX) levels. The following BTMs were monitored: sCTX, urinary N-terminal telopeptide of type I collagen (uNTX), serum procollagen type 1 N-terminal propeptide (PINP), serum osteocalcin (OC), and serum bone-specific alkaline phosphatase (bALP). BTM levels were measured immediately before dosing at baseline and months 1, 2, 3, and 6, and 7 d after dosing at baseline and month 4. A multiple regression model was applied to determine whether month 1 sCTX response predicted month 6 sCTX change. sCTX levels declined 70% 7 d after dosing at baseline and month 4. Predosing sCTX declined 55% at month 6. The pattern of uNTX reduction was similar to sCTX. Bone formation markers PINP, OC, and bALP declined gradually over time. Month 1 sCTX change was a significant predictor of Month 6 change ( p = 0.0001). Once monthly 150 mg oral ibandronate treatment reduced BTMs in women with osteoporosis. sCTX reduction occurred within 7 d and was sustained over 6 mo. Month 1 sCTX predicted month 6 sCTX.

Biomarkers for Osteoporosis Management

Osteoporosis is a systemic disease characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in an increased risk of fracture. While the level of bone mass can be estimated by measuring bone mineral density (BMD) using dual X-ray absorptiometry (DXA), its measurement does not capture all the risk factors for fracture. Quantitative changes in skeletal turnover can be assessed easily and non-invasively by the measurement of serum and urinary biochemical markers; the most sensitive markers include serum osteocalcin, bone specific alkaline phosphatase, the N-terminal propeptide of type I collagen for bone formation, and the crosslinked C- (CTX) and N- (NTX) telopeptides of type I collagen for bone resorption. Advances in our knowledge of bone matrix biochemistry, most notably of post-translational modifications in type I collagen, are likely to lead to the development of new biochemical markers that reflect changes in the material property of bone, an important determinant of bone strength. Among those, the measurement of the urinary ratio of native (alpha) to isomerized (beta) CTX - an index of bone matrix maturation - has been shown to be predictive of fracture risk independently of BMD and bone turnover. In postmenopausal osteoporosis, levels of bone resorption markers above the upper limit of the premenopausal range are associated with an increased risk of hip, vertebral, and nonvertebral fracture, independent of BMD. Therefore, the combined use of BMD measurement and biochemical markers is helpful in risk assessment, especially in those women who are not identified as at risk by BMD measurement alone. Levels of bone markers decrease rapidly with antiresorptive therapies, and the levels reached after 3-6 months of therapy have been shown to be more strongly associated with fracture outcome than changes in BMD. Preliminary studies indicate that monitoring changes of bone formation markers could also be useful to monitor anabolic therapies, including intermittent parathyroid hormone administration and, possibly, to improve adherence to treatment. Thus, repeated measurements of bone markers during therapy may help improve the management of osteoporosis in patients.

Reduction of urinary levels of pyridinoline and deoxypyridinoline and serum levels of soluble receptor activator of NF-kappaB ligand by etanercept in patients with rheumatoid arthritis

The effects of soluble TNF-alpha receptor, etanercept, on bone metabolism were investigated in patients with rheumatoid arthritis (RA). Thirty RA patients were administered etanercept once or twice a week for more than 6 months. We evaluated clinical and laboratory parameters and measured urinary excretion levels of pyridinoline (PYD), deoxypyridinoline (DPD), cross-linked N-telopeptides of type I collagen (NTX), and serum levels of bone alkaline phosphatase (BAP), osteoprotegerin (OPG), and soluble receptor activator of NFkappaB ligand (sRANKL) at the baseline and at 3 and 6 months after initial treatment with etanercept. Etanercept treatment resulted in an improvement of symptoms due to RA and in a reduction of urinary excretion levels of PYD and DPD as well as serum sRANKL levels, with a significant difference at 6 months, and an increase of serum BAP levels at 3 and 6 months after the initial treatment with etanercept. Urinary NTX and serum OPG levels did not show a significant change at 3 and 6 months after the initial treatment, but serum OPG levels did show a reverse correlation with serum CRP levels, suggesting that the regulation of inflammation in RA may result in an induction of OPG production. Etanercept may have the ability to reduce the levels of bone resorption markers and to increase the levels of a bone formation marker while reducing sRANKL formation in RA patients.

Celiac disease in children: Impact on bone health

Celiac disease is a chronic enteropathy caused by permanent intolerance to gluten and similar proteins found in wheat, barley and rye. The intestinal mucosa of susceptible individuals is crossed by undigested gluten, which leads to a marked inflammatory response. The clinical features may vary from overt intestinal symptoms to silent disease. Bone health has been found to be markedly affected in children and adolescents with untreated celiac disease, regardless of clinical presentation. Bone mass measurements are greatly reduced compared to healthy youth. As indicated by surrogate markers of bone turnover, bone formation rates are depressed and bone resorption rates enhanced in untreated patients. The causes underlying alterations in bone metabolism are still under investigation, but are attributed to non-intestinal factors. Increased production of inflammatory cytokines and presence of specific autoantibodies may together disrupt bone metabolism equilibrium in children and adolescents with celiac disease. Gluten withdrawal is able to restore bone mass quite rapidly, with a normalization of levels of bone formation and bone resorption markers. Good adherence to gluten-free diet is mandatory to maintain optimal bone health. Monitoring of dietary compliance is important to ensure appropriate bone mass accrual through childhood and puberty in these patients, to maximize peak bone mass and reduce fracture risk later in life.

Link between obstructive sleep apnea and increased bone resorption in men

The bone metabolic abnormalities in patients with obstructive sleep apnea (OSA) were examined. Severity-dependent increases in the serum/urinary levels of bone resorption markers and their attenuation following continuous positive airway pressure therapy in subjects with OSA provide the first evidence of a link between OSA and abnormal bone metabolism. Hypoxia, microinflammation and oxidative stress, well-known pathophysiological features of obstructive sleep apnea (OSA), are also known to affect bone metabolism. We examined the bone metabolic abnormalities in patients with OSA and also the effects of continuous positive airway pressure (CPAP) therapy on these abnormalities. A cross-sectional and prospective study was conducted in 50 consecutive male subjects visiting a sleep clinic and 15 age-matched control subjects without OSA. Plasma concentrations of IL-1beta, IL-6, TNF-alfa, 3-nitrotyrosine, osteocalcin, bone-specific alkaline phosphatase (BAP), and urinary concentrations of cross-linked C-terminal telopeptide of type I collagen (CTX) were examined before and after 3 months' CPAP in subjects with OSA. The plasma levels of the cytokines as well as the urinary CTX levels were higher in subjects with severe OSA than in those with mild OSA or control subjects. Significant decrease of the urinary excretion of CTX (before: 211+/-107 vs. after: 128+/-59 microg/mmol/creatinine; p<0.01) as well as of the plasma levels of the cytokines was observed following 3 months' CPAP. Severity-dependent increases in the serum/urinary levels of bone resorption markers and their reversal following CPAP in subjects with OSA provide the first evidence of a link between OSA and abnormal bone metabolism.

Teriparatide

Recombinant teriparatide (Forteo; Forsteo) is an anabolic (bone forming) agent. Studies have shown that subcutaneous teriparatide 20 microg/day is effective in women with postmenopausal osteoporosis, men with idiopathic or hypogonadal osteoporosis and patients with glucocorticoid-induced osteoporosis. Teriparatide improves bone mineral density (BMD) and alters the levels of bone formation and resorption markers; histomorphometric studies showed teriparatide-induced effects on bone structure, strength and quality. Subcutaneous teriparatide 20 microg/day administered over a treatment period of 11-21 months was effective in reducing the risk of fractures in and in improving BMD in men with idiopathic or hypogonadal osteoporosis, women with postmenopausal osteoporosis and patients with glucocorticoid-induced osteoporosis. Furthermore, the beneficial effects of teriparatide on vertebral fracture prevention and BMD appear to persist following treatment cessation. Teriparatide is generally well tolerated and treatment compliance rates are favourable. However, current limitations on the length of treatment and the high acquisition cost mean that teriparatide is best reserved for the treatment of patients with osteoporosis at high risk of fracture, or for patients with osteoporosis who have unsatisfactory responses to or intolerance of other osteoporosis therapies.

ASSESSMENT OF BONE MINERAL DENSITY AND MARKERS OF BONE TURNOVER IN CHILDREN UNDERGOING LONG-TERM ORAL ANTICOAGULANT THERAPY

INTRODUCTION: Oral anticoagulants antagonize vitamin K action and potentially impair the carboxylation of osteocalcin, a protein that is essential for normal bone matrix formation. OBJECTIVE: Our aim was to evaluate bone mineral density (BMD) and bone-turnover markers in 23 children who were undergoing long-term oral anticoagulant therapy (median age: 4 years) and 25 age- and gender-matched controls. METHODS: BMD (characterized as a z score) of the lumbar spine was assessed by using dual energy radiograph absorptiometry. Osteoblast (bone alkaline phosphatase, osteocalcin, and amino-terminal procollagen 1 extension peptide) and osteoclast (urinary calcium and deoxypyridinoline and serum cross-linked C telopeptide) activity markers were measured. Vitamin D (25-hydroxy vitamin D, parathyroid hormone, whole and ionized calcium, phosphorus, and magnesium) and vitamin K (factors II, VII, IX, and X, protein C, protein S, and undercarboxylated osteocalcin [Glu-Oc]) statuses were determined. RESULTS: Patients presented with higher levels of Glu-Oc, parathyroid hormone, and bone-resorption markers and lower levels of bone-formation markers and 25-hydroxy vitamin D; 52% of them showed signs of osteopenia (−1.0 &amp;gt; BMD z score &amp;gt; −2.5). Statistical analysis demonstrated that anticoagulant therapy was an independent predictor of alterations in Glu-OC, osteocalcin, bone alkaline phosphatase, amino-terminal procollagen 1 extension peptide, and serum cross-linked C telopeptide levels. CONCLUSIONS: Long-term use of coumarin derivatives may cause osteopenia in children with the risk of developing osteoporosis later in life.

Biochemical Markers of Bone Turnover in Percutaneous Vertebroplasty for Osteoporotic Compression Fracture

To evaluate relationships between biochemical markers of bone turnover, bone mineral density, and new compression fractures following vertebroplasty. Initially, we enrolled 30 consecutive patients with vertebral compression fractures caused by osteoporosis. Twenty-three of the 30 patients visited our hospital for follow-up examinations for more than 4 weeks after vertebroplasty. The patients were divided into two groups: patients with new fractures (group F) and patients with no new fractures (group N). We analyzed differences in the following parameters between these two groups: serum bone alkaline phosphatase, urinary crosslinked N-telopeptide of type I collagen, urinary deoxypyridinoline, and bone mineral density. Next, the patients were divided into another two groups: patients with higher risk (group H: urinary crosslinked N-telopeptide of type I collagen >54.3 nmol BCE/mmol Cr or urinary deoxypyridinoline >7.6 nmol/mmol Cr, and serum bone alkaline phosphatase <29.0 U/l) and patients with lower risk (group L). We analyzed the difference in the rate of new fractures between these two groups. We identified 9 new fractures in 7 patients. There were no significant differences between groups F and N. We identified 5 new fractures in 3 of the 4 patients in group H, and 4 new fractures in 4 of the 19 patients in group L. There was a significant difference in the rate of new fractures between groups H and L. A combination of high levels of bone resorption markers and normal levels of bone formation markers may be associated with increased risk of new recurrent fractures after percutaneous vertebroplasty.

Effects of Thiazolidinediones on Bone Loss and Fracture

To examine the evidence regarding the effects of thiazolidinediones on bone loss and fracture. Published studies assessing the effects of thiazolidinediones on bone and/or fracture risk in humans were selected for review. A MEDLINE (1950-April 2007) and International Pharmaceutical Abstracts (1970-April 2007) search was performed. Search terms included thiazolidinediones, rosiglitazone, pioglitazone, troglitazone, bone, bone mineral density, fracture, and osteoporosis. The literature search retrieved 5 English-language studies evaluating the effects of thiazolidinediones on bone in humans. These consisted of 2 small, uncontrolled studies using troglitazone; 1 prospective, randomized controlled study and 1 retrospective cohort study using rosiglitazone; and a post hoc analysis of an observational cohort study in subjects taking various thiazolidinediones. All of the studies assessed markers of bone metabolism and/or bone mineral density (BMD). No studies were identified that addressed rate of fractures in subjects taking thiazolidinediones. The first troglitazone study demonstrated a decrease in levels of bone formation markers (10%; p < 0.05) and resorption markers (12%; p < 0.01), and authors determined that troglitazone produces a protective effect on bone through decreased bone turnover. The second troglitazone study did not demonstrate a significant change in BMD or levels of bone turnover markers. The 2 rosiglitazone studies demonstrated decreases in BMD of 1.19-1.9% with rosiglitazone use (p < 0.05). The post hoc analysis with various thiazolidinediones indicated a 2.5-fold greater decrease in BMD in women reporting thiazolidinedione use. Few studies have assessed the effects of thiazolidinediones on bone in humans. Studies available suggest that treatment with thiazolidinediones, primarily rosiglitazone, contributes to bone loss. The effect appears to be most prominent in postmenopausal women. More studies are needed to better understand the effects of thiazolidinediones on bone and fracture rates.

Predictors for Skeletal-Related Events in Patients with Advanced Multiple Myeloma.

Most patients with advanced multiple myeloma (MM) develop bone lesions during their disease course. Myeloma bone disease can result in potentially debilitating and life threatening skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, the need for palliative radiotherapy (RT) or surgery to bone, and hypercalcemia of malignancy. Bone-targeted therapies that prevent or delay SRE onset may maintain quality of life (QOL) and functional independence in patients with advanced MM. Yet, the risk factors for SREs in this patient population are not fully understood. Exploratory analyses were conducted to identify potential SRE risk factors in patients with bone lesions from MM who received either zoledronic acid or pamidronate every 3 to 4 weeks for up to 24 months in a large, randomized trial. Patients with complete baseline demographics, disease characteristics, and markers of bone metabolism information available were included (n=282). Dichotomous variables included sex, race (white/other), narcotic analgesics (yes/no), Eastern Cooperative Oncology Group performance status (active/impaired), prior SRE (yes/no), and values with a defined upper limit of normal (creatinine, lymphocyte %, hemoglobin, serum glutamic oxaloacetic transaminase, albumin, lactate dehydrogenase [LDH], and calcium). Continuous variables included age, weight, cancer duration, Functional Assessment of Cancer Therapy-General score, Brief Pain Inventory (BPI) score, and bone markers (eg, urinary N-telopeptide of type I collagen [NTX], deoxypyridinoline [DPD]). Paraprotein type was also included. Univariate and multivariate analyses to determine relative risks (RR) for reduced time to first SRE associated with baseline variables using Cox regression models were developed, and those that were not significant at the 5% level were removed by backward elimination to generate a reduced model. In the reduced multivariate model, lower weight (RR=0.94 per 5-kg increase; P=.021), higher BPI scores (RR=1.16 per 1-unit increase; P < .001), race other than white (RR=0.60; P=.028), need for narcotic analgesics (RR=1.61; P=.017), and high levels of NTX (RR=1.68 per 100-nmol/mmol creatinine increase; P=.005) significantly correlated with reduced time to first SRE. Pathologic fracture and RT to bone were the most common SREs; in multivariate models, lower weight and higher BPI scores were associated with increased RRs of both fractures and RT to bone. Race and DPD levels were also significant covariates for fractures, whereas high levels of LDH correlated significantly with need for RT. Because bone resorption marker levels were significant covariates, the correlation between baseline NTX and time to first SRE was assessed. High baseline NTX (≥ 50 nmol/mmol creatinine) was associated with increased risk of shorter time to first SRE: by a significant 67% in the zoledronic acid group (n=210; P=.015) and by a 57% trend in the pamidronate group (n=108; P=.114). Taken together, lower weight and pain parameters (eg, BPI or narcotic analgesics) correlated consistently with skeletal morbidity risks in patients with advanced MM. Treatments that facilitate the restoration of bone homeostasis, as evidenced by bone marker normalization, may reduce the risk of SREs, thus maintaining QOL in this patient population.

304 ORAL Early normalization of elevated baseline bone resorption marker levels by zoledronic acid and improved survival in patients with bone metastases from solid tumors

304 ORAL Early normalization of elevated baseline bone resorption marker levels by zoledronic acid and improved survival in patients with bone metastases from solid tumors

Enhancement of graft bone healing by intermittent administration of human parathyroid hormone (1–34) in a rat spinal arthrodesis model

Bone grafting is commonly used to treat skeletal disorders associated with large bone defect or unstable joint. It can take several months, however, to achieve a solid union and bony fusion sometimes delays or fails especially in osteoporosis patients. Therefore, we used a rat spinal arthrodesis model to examine whether intermittent administration of human PTH(1–34) accelerates bone graft healing. Eighty-two male Sprague–Dawley rats underwent posterolateral spinal arthrodesis surgery using autologous bone grafts. Animals were given daily subcutaneous injections of hPTH(1–34) (40 μg/kg/day PTH group) or 0.9% saline vehicle (control group) from immediately after surgery till death. Five rats each were killed 2, 4, 7, and 14 days after the surgery, and mRNA expression analysis was performed on harvested grafted bone. Seven rats each were killed 14, 28, and 42 days after the surgery, and the lumbar spine, which contained the grafted spinal segment, was subjected to fusion assessment, microstructural analysis using three-dimensional micro-computed tomography, and histologic examination. Serum bone metabolism markers were analyzed. The results indicated that PTH administration decreased the time required for graft bone healing and provided a structurally superior fusion mass in the rat spinal arthrodesis model. PTH administration increased the fusion rate on day 14 (14% in the control group and 57% in the PTH group), accelerated grafted bone resorption, and produced a larger and denser fusion mass compared to control. mRNA expression of both osteoblast- and osteoclast-related genes was upregulated by PTH treatment, and serum bone formation and resorption marker levels were higher in the PTH group than in the control group. Histologically calculated mineral apposition rate, mineralized surface and osteoclast surface were also higher in the PTH group than in the control group. These findings suggest that intermittent administration of PTH(1–34) enhanced bone turn over dominantly on bone formation at the graft site, leading to the acceleration of the spinal fusion. Based on the results of this study, intermittent injection of hPTH(1–34) might be an efficient adjuvant intervention in spinal arthrodesis surgery and all other skeletal reconstruction surgeries requiring bone grafts.