Terminal Telopeptide Research Articles

Enhanced Osteogenic Differentiation in Zoledronate-Treated Osteoporotic Patients.

Bisphosphonates are well known inhibitors of osteoclast activity and thus may be employed to influence osteoblast activity. The present study was designed to evaluate the in vivo effects of zoledronic acid (ZA) on the proliferation and osteoblastic commitment of mesenchymal stem cells (MSC) in osteoporotic patients. We studied 22 postmenopausal osteoporotic patients. Densitometric, biochemical, cellular and molecular data were collected before as well as after 6 and 12 months of ZA treatment. Peripheral blood MSC-like cells were quantified by colony-forming unit fibroblastic assay; their osteogenic differentiation potential was evaluated after 3 and 7 days of induction, respectively. Circulating MSCs showed significantly increased expression levels of osteoblastic marker genes such as Runt-related transcription factor 2 (RUNX2), and Osteonectin (SPARC) during the 12 months of monitoring time. Lumbar bone mineral density (BMD) variation and SPARC gene expression correlated positively. Bone turnover marker levels were significantly lowered after ZA treatment; the effect was more pronounced for C terminal telopeptide (CTX) than for Procollagen Type 1 N-Terminal Propeptide (P1NP) and bone alkaline phosphatase (bALP). Our findings suggest a discrete anabolic activity supported by osteogenic commitment of MSCs, consequent to ZA treatment. We confirm its anabolic effects in vivo on osteogenic precursors.

Influence of telopeptides on the structural and physical properties of polymeric and monomeric acid-soluble type I collagen

Currently two factors hinder the use of collagen as building block of regenerative devices: the limited mechanical strength in aqueous environment, and potential antigenicity. Polymeric collagen is naturally found in the cross-linked state and is mechanically tougher than the monomeric, acid-soluble collagen ex vivo. The antigenicity of collagen, on the other hand, is mainly ascribed to inter-species variations in amino acid sequences of the non-helical terminal telopeptides. These telopeptides can be removed through enzymatic treatment to produce atelocollagen, although the effect of this cleavage on triple helix organization, amino acidic composition and thermal properties is often disregarded. Here, we compare the structural, chemical and physical properties of polymeric and monomeric type I collagen with and without telopeptides, in an effort to elucidate the influence of either mature covalent crosslinks or telopeptides. Circular dichroism (CD) was used to examine the triple helical conformation and quantify the denaturation temperature (Td) of both monomeric collagen (36.5°C) and monomeric atelocollagen (35.5°C). CD measurements were combined with differential scanning calorimetry (DSC) in order to gain insight into the triple helix-to-coil thermal transition and shrinkage temperature (Ts) of polymeric atelo collagen (44.8°C), polymeric collagen (62.7°C), monomeric atelo collagen (51.4°C) and monomeric collagen (66.5°C). Structural and thermal analysis was combined with high pressure liquid chromatography (HPLC) to determine the content of specific collagen amino acidic residues used as markers for the presence of telopeptides and mature crosslinks. Hydroxylamine was used as the marker for polymeric collagen, and had a total content of 9.66% for both polymeric and polymeric atelo collagen; tyrosine was used as the marker for telopeptide cleavage, was expressed as 0.526% of the content of polymeric collagen and the partially-reduced content of 0.39% for atelocollagen.

Bone alkaline phosphatase as a surrogate marker of bone metastasis in gastric cancer patients.

BackgroundBone metastasis is relatively uncommon in gastric cancer patients, but its incidence has been rising. Early detection of bone metastasis is important in preventing complications related to bone metastasis such as pain, fracture and the compromise of chemotherapy. In this pilot study, we investigated the feasibility of bone turnover markers as surrogate markers of bone metastasis in gastric cancer patients.MethodsFifty-eight patients with gastric cancer were included in this study. Serum levels of bone alkaline phosphatase (ALP), parathyroid hormone (PTH), 25(OH) D, osteocalcin (OC) and C terminal telopeptide were measured and compared between patients with bone metastasis and those without. Student’s t-test and Mann-Whitney U test were used in comparing two groups, and Spearman’s rank order correlation coefficient was calculated to quantify the strength of the associations.ResultsFifty eight age- and sex-matched patients were evaluated for bone turnover markers, among whom 29 patients had bone metastasis and 29 patients with no bone metastasis. The median age was 62 and there were 20 (68.9 %) males and 9 (31.1 %) females in each group. Bone ALP was significantly higher in the patient group (57.32 ± 46.83 vs. 34.57 ± 21.57, P = 0.037) than control group. Bone ALP was positively associated with ALP, osteocalcin, CA19-9, CA 72–4 and negatively associated with 25(OH) D. According to ROC-curve analysis, at the threshold value of 29.60 μg/L, the sensitivity of bone ALP was 76.7 % and the specificity was 59.4 %.ConclusionBone ALP may be a surrogate marker of bone metastasis in gastric cancer patients. More prospective studies are warranted to determine the optimal bone turnover markers in the evaluation of bone metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2415-x) contains supplementary material, which is available to authorized users.

Effect of Atorvastatin on Bone biochemical markers in dyslipidemic patients, Basra, Iraq


 
 
 
 
 Objective: The aim of the study was to estimate the action atorvastatin(20mg/day) on bone biochemical markers dyslipidemic men. Methodology: This study was conducted between May 2015 and November 2015 in Al-Basrah General hospital in Basra, Iraq, to evaluate important role of atorvastatin (20mg/day)(Lipitor® Pfizer Pharma GmbH.Germany) on bone biochemical markers. Thirty men patients who had been admitted for a variety of medical problems included in the study. All the patients had previously been diagnosed with Dyslipidemia by specialist physician in internal medicine and all patients age below 55 years . the inclusion criteria for the experimental group was use of atorvastatin for at least three months; the study group was then compared to age-matched healthy men .bone biochemical markers were compared between groups. Results are expressed mean ± SD; statistically Student’s t test was used to compare variables. Results: The mean age of the statin group was 44.5 ± 5.9 and control group was 45.7 ± 4.4.After 3 months treatment with atorvastatin, as in table (1) and figures (1-8) Surprisely level of serum total cholesterol remain significantly higher than value of normal healthy group. LDL value significantly reduced by treatment but still significantly higher than values of normal group. HDL value were significantly higher than that of its initial values, but level of HDL ;after treatment; was not significantly different from that of normal group. Triglycerides was not significantly changed by treatment and its value still significantly higher than normal group. Vit D level was not significantly change by treatment and its value was significantly lower than normal group. Osteocalcin was elevated significantly by treatment; and this elevation was significantly as compared with its initial value and with that of normal group. Amino Terminal telopeptide procollagen type I (NTX-I) was not significantly change by treatment and its value still significantly higher than normal group and before treatment values. Also body mass index value was not significantly changed by treatment. Recommendations: Further studies are recommended to confirm the positive effects of atorvastatin and other statins on bone biochemical markers with larger number of patients and longer period of follow up. Also other bone formation and resorption markers are recommended to determine the expected mechanisms of action of statins on bone remodeling processes.
 
 
 
 
 
 
 
 

ICTP as a Diagnostic Marker of Bone Resorption and Its Relation to Disease Progression and Treatment Response in Multiple Myeloma

1 MD Clinical Pathology, Professor of Clinical Pathology, Clinical Pathology Dept, Ain Shams University 2 MD Clinical Pathology, Lecturer of Clinical Pathology, Clinical Pathology Dept, Ain Shams University Corresponding Author Gehan Mostafa Hamed 67 El Nasr St, Sheraton Heliopolis, Cairo, Egypt Email: gehanzeina@yahoo.com Mobile no.: 00202 01224954542 Abstract Aim: To assess the significance of collagen type I carboxy terminal telopeptide (ICTP) as a diagnostic marker of osteolysis, as well as its relation to disease progression and response to treatment in multiple myeloma (MM). Subject and methods: ICTP was measured in 40 newly diagnosed MM patients (including 22 patients with osteolytic lesion), and 20 ageand sexmatched controls. Patients were followed up for detection of their response to treatment. Results: The median and IQR levels of ICTP were significantly elevated in MM patients compared with controls (0.65 [0.15-0.8] ng/mL versus 0.05 [0.04-0.07] ng/mL, p<0.001), with significant higher median levels among patients with osteolytic lesion compared with myeloma patients without osteolytic lesion (0.7 [0.65 – 1.0] ng/mL versus 0.1 [0.1 -0.2] ng/mL, p<0.001). According to ROC curve analysis, ICTP at a cutoff 0.3 ng/mL could detect osteolytic lesion with high sensitivity and specificity. ICTP was positively correlated with markers of renal impairment, hypercalcemia, anemia, thrombocytopenia and poor prognostic factors; lactate dehydrogenase (LDH), C reactive protein (CRP), hypoalbuminaemia, and β2-microglobulin (β2M) (p<0.05). Using logistic regression analysis, ICTP was found to be a significant predictor of osteolysis. Moreover, initial ICTP levels were higher in progressive/relapsed myeloma patients compared with responsive/stable patients (p<0.001). Conclusion: We suggest that ICTP is a reliable marker that can be used in the diagnosis and prediction of osteolytic lesion and prediction of treatment response in MM.

Response of bone turnover markers to raloxifene treatment in postmenopausal women with osteopenia.

We used two methods of identifying women who reached the target for raloxifene treatment with bone turnover markers. Both approaches identified women that responded to treatment but did not fully agree and may be complementary. The change in bone turnover markers (BTMs) in response to osteoporosis therapy can be assessed by a decrease beyond the least significant change (LSC) or below the mean of the reference interval (RI). We compared the performance of these two approaches in women treated with raloxifene. Fifty postmenopausal osteopenic women (age 51-72years) were randomised to raloxifene or no treatment for 2years. Blood samples were collected for the measurement of BTM. The LSC for each marker was calculated from the untreated women and the RI obtained from healthy premenopausal women (age 35-40years). Bone mineral density (BMD) was measured at the spine and hip. There was a decrease in BTM in response to raloxifene treatment, percentage change at 12weeks: C terminal telopeptide of type I collagen (CTX) -39% (95% CI -48 to -28) and N terminal propeptide of type I procollagen (PINP) -32% (95% CI -40 to -23) P < 0.001. The proportion of women classified as responding to treatment using LSC at 12weeks was as follows: CTX 38% and PINP 52% and at 48weeks CTX 60% and PINP 65%. For the RI approach, the proportion of women classified as responding to treatment at 12 weeks was CTX and PINP 38 % and at 48 weeks CTX 40% and PINP 45%. There was a significant difference in the change in spine BMD in the raloxifene-treated group compared to the no-treatment group at week 48: difference 0.031g/cm(2) (95% CI 0.016 to 0.046, P < 0.001). The two approaches identified women that reached the target for treatment using BTM. Both LSC and RI criteria appear useful in identifying treatment response, but the two approaches do not fully overlap and may be complementary.

Bone turnover increases during supervised treadmill walking in Thai postmenopausal women

IntroductionTreadmill walking is a cheap and attainable form of exercise, which carries a low injury risk and confers other health benefit. The aim of this study is to investigate the effects of 3-month treadmill walking on biochemical bone markers in Thai postmenopausal women. Material and methodsThai postmenopausal women participated in a 3-month supervised treadmill walking program. The program consisted of treadmill walking, the intensity of which was 55–70% of maximal heart rate, with duration of 30 min per day, at a frequency of 3 days a week. Crosslinked C–terminal telopeptides of type I collagen (CTX–I) and N–terminal propeptides of type I procollagen (PINP) level were measured at baseline and at 1 week after 3-month training. ResultsEighteen women completed the training program. The average age of patients was 59.39 ± 4.18 years. The average period after menopause was 9.28 ± 6.52 years. CTX–I and PINP levels at baseline were 0.43 ± 0.14 and 52.15 ± 13.43 ng/ml. CTX–I and PINP levels after 3-month training were 0.80 ± 0.26 and 66.77 ± 22.82 ng/ml. Bone resorption and formation markers were significantly increased after treadmill walking (p < 0.01). ConclusionBone turnover increases after 3-month supervised treadmill walking in Thai postmenopausal women.

Effects of zoledronic acid on bone fusion in osteoporotic patients after lumbar fusion.

Treatment with zoledronic acid in osteoporotic patients with spinal fusion shortens the duration of time to fusion, improves the fusion rate, prevents the subsequent adjacent vertebral compression fractures, improves the clinical outcomes, and prevents immobilization-induced bone loss in the hip. The objective of the study was to explore the effects of zoledronic acid on the healing process in osteoporotic patients following spinal fusion in a randomized, placebo-controlled, and triple-blinded study. Seventy-nine osteoporotic patients with single-level degenerative spondylolisthesis were randomly assigned to receive either zoledronic acid infusion (zoledronic acid group) or saline infusion (controls) after spinal fusion. Functional radiography and CT scans were used to evaluate fusion status. Bone formation was graded into three categories: Grade A (bridging bone bonding with adjacent vertebral bodies), Grade B (bridging bone bonding with either superior or inferior vertebral body), or Grade C (incomplete bony bridging). A solid fusion was defined as less than 5° of angular motion with Grade A or B bone formation. Adjacent vertebral compression fractures (VCF) were assessed on MRI at 12months after surgery. Serum level of carboxy terminal cross-linked telopeptide of type I collagen (β-CTX) and amino-terminal propeptide of type I procollagen (PINP) was measured. Bone mineral density (BMD) was measured by DXA. Oswestry Disability Index (ODI) was used to assess the clinical outcomes. Grade A or B bridging bone was more frequently observed in zoledronic acid group at 3, 6, and 9months post-operation compared to the control group (p < 0.05). At 12 -months post-operation, bridging bone and solid fusion were not significantly different between groups. No patients in zoledronic acid group showed aVCF, whereas six patients (17%) in the control group did (p < 0.05). Both β-CTX and PINP were suppressed in zoledronic acid group. BMD at the femoral neck decreased rapidly and did not return to the preoperative level in the controls at 3 (-1.4%), 6 (-2.5%), and 12 (-0.8%) months after surgery. Zoledronic acid prevented this immobilization-induced bone loss and increased BMD. ODI showed the improved clinical outcomes compared with controls at 9 and 12months post-surgery. Treatment with zoledronic acid in osteoporotic patients with spinal fusion shortens the time to fusion, improves the fusion rate, prevents subsequent aVCFs, and improves clinical outcomes.

Acute effect of a supplemented milk drink on bone metabolism in healthy postmenopausal women is influenced by the metabolic syndrome.

BackgroundDietary factors acutely influence the rate of bone resorption, as demonstrated by changes in serum bone resorption markers. Dietary calcium exerts its effect by reducing parathyroid hormone levels while other components induce gut incretin hormones both of which reduce bone resorption markers. The impact of dietary calcium on bone turnover when energy metabolism is modulated such as in metabolic syndrome has not been explored. This study was designed investigate whether metabolic syndrome or a greater amount of visceral fat influences the impact of dietary calcium on bone turnover.MethodsThe influence of the metabolic syndrome on effects of dietary calcium on bone turnover in community dwelling postmenopausal women was studied. Twenty five volunteers consumed 200 mL of low fat milk with additional 560 mg calcium (one serve of Milo®) in the evening on one occasion. Fasting morning serum biochemistry before and after the milk drink with lumber spine bone density, bone mineral content, fat and lean mass using dual energy X-ray absorptiometry (DXA) and waist circumference were measured. The women were divided into 2 groups using the waist measurement of 88 cm, as a criterion of metabolic syndrome. Student’s t tests were used to determine significant differences between the 2 groups.ResultsThe lumbar spine mineral content was higher in women with metabolic syndrome. After consuming the milk drink, serum bone resorption marker C terminal telopeptide (CTX) was suppressed to a significant extent in women with metabolic syndrome compared to those without.ConclusionsThe results suggests that dietary calcium may exert a greater suppression of bone resorption in post-menopausal women with metabolic syndrome than healthy women. Despite substantial evidence for close links between energy metabolism and bone metabolism this is the first report suggesting visceral fat or metabolic syndrome may influence the effects of dietary calcium on bone metabolism.

Atrial fibrillation and biomarkers of myocardial fibrosis in heart failure

Objectives. Alterations of collagen metabolism present in heart failure promote the fibrotic substrate for the development of atrial fibrillation (AF). Myocardial collagen I synthesis and degradation can be assessed indirectly by circulating biomarkers such as the carboxy terminal propeptide (PICP) and carboxy-terminal telopeptide (CITP), respectively. Design. We examined myocardial collagen type-I metabolism in 143 patients with systolic heart failure (New York Heart Association Class 2–4) in relation to coexisting AF. Results. Mean age was 75 years, blood pressure 134/80 mm Hg, ejection fraction 34%, serum PICP 81 μg/L and CITP 8.3 μg/L, and median plasma brain natriuretic peptide 215 pg/L; 77 were in AF. PICP and CITP were related to left atrial diameter (r = 0.22, P = 0.013, and r = 0.26, P = 0.003) and CITP to pulmonary capillary wedge pressure and C-reactive protein (r = 0.19, P = 0.044, and r = 0.29, P = 0.003). A logistic regression suggested that PICP (odds ratio per 1 μg/L change 1.01, P = 0.012) and left ventricular end-diastolic volume (odds ratio per 1 mL change 0.98, P < 0.001) were independently associated with coexisting AF. Conclusion. Collagen type-I metabolism is associated to left atrial size. Heart failure patients with coexisting AF exhibit more altered collagen type-I metabolism than patients in sinus rhythm. This might represent more severe atrial and ventricular fibrosis.Trial registration: ClinicalTrials.gov identifier: NCT01671995.

Smoking is a significant determinant of low serum vitamin D in young and middle-aged healthy males.

We aimed to determine the prevalence of 25(OH)D (D2 and D3 independently) inadequacy in healthy young/middle-aged men and to investigate its relationship with BMD, bone markers, demographic and lifestyle parameters such as age, BMI, smoking, alcohol consumption and dietary calcium intake. We determined 25(OH)D levels using LC-MS/MS, a robust method for measurement of both 25(OH)D3 and 25(OH)D2, iPTH, osteocalcin, beta C terminal cross-linked telopeptides of type I collagen (b-CTXs), procollagen type 1 amino-terminal propeptide (PINP), BMD at L2-L4 and proximal femur, smoking habits, daily dietary calcium intake and alcohol consumption in 181 randomly selected healthy men aged 20-50y. The prevalence of vitamin D deficiency (25(OH)D < 20 ng/ml) was 50.3%. Only 8.8% of the participants had vitamin D sufficiency (25(OH)D ≥ 30 ng/ml). We found a strong correlation between 25(OH)D and smoking in the totality of participants (p<0.001). 25(OH)D level was lower by approximately 4.3 ng/dl (p<0.001) in a smoker compared to a non-smoker among the totality of participants, while this value increased to 9.2 ng/ml in the 40-50y subgroup (p=0.003). A multinomial logistic regression model demonstrated that a young smoker (20-29y) had 58% increased likelihood of having vitamin D deficiency compared to a non-smoker of the same age group (p=0.041). A high prevalence of vitamin D deficiency was identified in a young and middle-aged male population. Smoking is a significant determinant of serum 25(OH)D, while it increases significantly the likelihood of having vitamin D deficiency. In our hands, vitamin D levels are not a determinant of bone turnover and BMD in this population.

Low bone density in achondroplasia

To the editor, A 39-year-old female achondroplastic patient was admitted to our outpatient clinic for her back and lower extremity pain. Her height and weight were 125 cm and 38 kg, respectively (Fig. 1). She had a body mass index of 24.3 kg/m. She had undergone leg lengthening on bilateral tibias when she was 12. On physical examination, she had bilateral paravertebral muscle spasm at her back. She also had painful hip internal rotation and knee flexion on both sides with bilateral positive Clarke’s sign. Her physical examination was otherwise noncontributory. X-ray examination revealed early degenerative changes, especially at the hip joints and strikingly osteopenia. On detailed questioning, it was understood that she had been advised to receive 300,000 IU vitamin D3 (the form of vitamin D available in our country) once a year and to exercise regularly for low bone density 2 years ago. The past two bone mineral density (BMD) measurements, performed by a single technician using dual-energy X-ray absorptiometry (DEXA) on a Lunar DPX-IQ scanner in our center, were analyzed, and a new BMD measurement was performed under similar conditions with the ones referred above (Table 1, Fig. 2). The laboratory tests was as follows: serum total calcium, 9.3 mg/dl (8.2–10.6); inorganic phosphate, 3.2 mg/dl (2.5–4.5); alkaline phosphatase (ALP), 47 U/l (30–126); type 1 collagen C terminal telopeptide (CTX), 0.253 (25–573); osteocalcin, 3.46 ng/ml (3.1–13.7); parathormone, 34.23 pg/ml (15–65), and vitamin D3, 20.1 ng/ml (>30). Risk factor examination for low bone density yielded no results. Low bone density was considered as a consequence of altered bone metabolism due to achondroplasia. She was prescribed 300,000 IU oral vitamin D3 and recommended to continue on her exercises. She was also included in a physical therapy program for her symptoms due to degenerative changes. Achondroplasia is the most common form of skeletal dysplasias. A spontan or inherited mutation in the fibroblast growth factor receptor 3 (FGFR3) gene on the fourth chromosome brings out the disease [1]. The primary defect is abnormal endochondral ossification [2]. It has a number of wellknown neuromusculoskeletal manifestations [3]. Recently, Arita et al. reported low bone density, diagnosed with spinal BMD analysis and panoramic radiographic measurements, in 5 of 11 achondroplastic patients for the first time in the literature [4]. To the best of our knowledge, our report is the second one referring the relationship between

Preeclampsia – a risk factor for osteoporosis? Analysis of maternal Sclerostin levels and markers of bone turnover in patients with pre-eclampsia

Introduction: The role of preeclampsia (PE) in affecting bone metabolism could not be clarified in the past years. Recently Sclerostin, a new marker of bone metabolism which is known to have an inhibitory effect on bone formation causing osteoporosis, was discovered. Objective: To investigate serum levels of Sclerostin and markers of bone turnover in women with normotensive pregnancies and pregnancies complicated by PE. Methods: In this prospective study we enrolled 22 women with PE and 22 healthy pregnant women to observe serum levels of carboxyterminal propeptide of type I collagen (PICP), cross-linked carboxyl terminal telopeptide of the type I collagen (ICTP), calcium, phosphate, 25-hydroxyvitamin D and parathyroid hormone. In 16 preeclamptic and 16 healthy pregnant women, serum Sclerostin levels were analyzed. Results: Serum levels of Sclerostin (mean ± standard deviation: healthy 10.5 ± 8.1 pmol/l versus PE 11.5 ± 9.4 pmol/l, p = 0.768), ICTP (healthy 0.3 ± 0.2 ng/ml versus PE 0.4 ± 0.1 ng/ml, p = 0.462), PICP (healthy 59.9 ± 49.9 ng/ml versus PE 89.0 ± 62.0 ng/ml, p = 0.094), phosphate (healthy 1.1 ± 0.2 mmol/l versus PE 1.2 ± 0.4 mmol/l, p = 0.162) and parathyroid hormone (healthy 26.9 ± 14 pg/ml versus PE 35.3 ± 17.6 pg/ml, p = 0.08) showed no significant differences between the groups. Significantly lower serum calcium (healthy 2.3 ± 0.1 mmol/l versus PE 2.2 ± 0.2 mmol/l, p < 0.005) and serum 25-Hydroxyvitamin D (healthy 39.3 ± 16.7 nmol/l versus PE 23.9 ± 16.9 nmol/l, p < 0.005) were observed in preeclamptic women. Conclusion: Pregnancies complicated by PE show no signs of high bone turnover and may not lead to a higher risk of osteoporosis in later life.

Comparing Tolerability and Efficacy of Generic versus Brand Alendronate: A Randomized Clinical Study in Postmenopausal Women with a Recent Fracture

IntroductionAn increasing number of generic alendronate formulations have become available. Although expected to have the same tolerability and efficacy, head-to head comparison of generic and brand alendronate was never performed. Therefore, we compared the tolerability and efficacy of generic and brand alendronate.MethodsIn a randomized double-blinded single centre cross-over study in 37 postmenopausal women (mean age 65.4±6.4 years) with osteoporosis were treated with generic and branded alendronate during 24 (2x12) weeks. Tolerance was evaluated by the Gastro intestinal Symptom Rating Scale (GSRS) and self-reported side effects. Efficacy was assessed by serum bone turnover markers, carboxy terminal telopeptide (CTX) and procollagen type I N-terminal propeptide (PINP). No wash out period was allowed (ethical reasons). Because of possible carry over effect only data of the first 12 weeks were analyzed using linear mixed models.ResultsThere were no significant differences in overall tolerance (GSRS) between treatment groups. However, for subscale abdominal pain, patients using generic had a significantly higher mean GSRS score at week 4 (estimated mean difference (B): 0.40; 95%CI: 0.05 to 0.74, p = 0.024). The level of bone turnover markers significantly decreased over 12 weeks of follow-up for generic and branded alendronate (p < 0.001). Mean level of CTX was significantly lower with branded at week 4 (B: 121.3; 95%CI: 52.0 to 190.5), but not at week 12 (B: 53.6; 95%CI:-3.7 to 110.9). No significant differences were found for PINP at week 4 or 12.ConclusionsBone turnover markers were significantly reduced with branded and generic alendronate. With branded, CTX was significantly lower at 4 weeks. Generic caused significantly higher abdominal pain scores in the first 4 weeks of treatment. Therefore, generic alendronate may not have the same tolerability and efficacy as branded alendronate in the first weeks after starting treatment in patients with a recent fracture.Trial RegistrationDutch Trial Register NTR number 1867 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1867

Biologicals and bone loss

Inflammatory joint diseases like rheumatoid arthritis (RA), as well as other rheumatic conditions such as ankylosing spondylitis and systemic lupus erythematosus, comprise a heterogeneous group of joint disorders that are all associated with extra-articular side effects, including bone involvement. Disease activity, immobility and treatment with glucocorticoids are the main factors that increase the risk of osteoporotic fractures, on top of the background fracture risk based on, amongst others, age, body mass index and gender. It is thought that the pathogenesis of both peri-articular and generalized osteoporosis and local bone erosions share common pathways. This hypothesis has been strengthened by the discovery that osteoclasts, stimulated mostly by the receptor activator of nuclear factor kappa B ligand (RANKL) pathway, play a central role in all of these processes. Generalized bone loss has been documented in cross-sectional studies: a 2-fold increase in osteoporosis, defined as a T-score <-2.5 in females and Z-score <-1 was found in 394 postmenopausal RA-patients and 192 male RA-patients [1]. Before the introduction of biologicals, a high bone loss was also observed in a longitudinal study in early RA: -2.4% at the spine and -4.3% at the trochanter [2]. Against that background, it is relevant that we investigated whether treatment with anti-TNF-α prevents loss of bone mineral density at the spine and hip (generalized) and in the hands (local) in patients with rheumatoid arthritis (RA) and during anti-TNF treatment [3]. 102 patients with active RA, who were treated with infliximab during one year, were included into this open cohort study. The BMD of the spine and hip was unchanged during treatment with infliximab, whereas BMD of the hand decreased significantly by 0.8% (p < 0.001). The BMD of the hip in patients with an EULAR good response showed a favorable change compared with patients not achieving such a response. This is a proof that the usually occurring generalized bone loss in patients with RA can be arrested by the use of aggressive antirheumatic drugs, such as anti-TNF. Next to BMD changes upon anti-TNF, we investigated the changes in bone markers, to elucidate the underlying mechanism of the favourable effect of anti-TNF. Bone formation was measured by osteocalcin (OC) and bone resorption was determined by b-isomerized carboxy terminal telopeptide of type 1 collagen (b-CTx); osteoclast regulating proteins including the soluble receptor activator of Nfκb (s-RANKL) and osteoprotegerin (OPG) were determined in serum using an ELISA from Immun-diagnostik. Serum β-CTx and RANKL were both significantly decreased compared to baseline at all time points. The decrease in β-CTx was associated to the decrease in DAS-28 and CRP during the 0 to 14 weeks interval. No changes were observed in serum osteocalcin and OPG. These data on bone mineral density emphasizes that the arrested bone loss at the spine and hips can be described to a large extent to a decrease in disease activity. Later on, it was also shown that bone loss could be arrested in RA-patient treated with adalimumab [4], and the favourable effects of anti-TNF on bone markers were also observed during treatment with rituximab [5].

Changes in Cytokines, Biomarkers of Bone Turnover and Hormones are Associated with Bone Loss in Postmenopausal Indian Women

: Background: The pro-inflammatory cytokines that are associated with the decline in ovarian function during menopause are involved in the pathophysiology of postmenopausal bone loss, which has not been examined in Indian postmenopausal women.Objectives: This study assessed the extent of changes in pro-inflammatory cytokines in relation to bone turnover markers, hormones, and bone mineral density (BMD) during menopausal transition in Indian women. Material/Patients and Methods: Levels of interleukin 1 (IL1 β), interleukin 6 (IL6), and tumor necrosis factor (TNF α); the bone markers osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), carboxy terminal telopeptide (CTX), and deoxypyridoniline (DPD); and the hormones parathyroid hormone (PTH), follicle-stimulating hormone (FSH), and estrone glucuronide (E1G) were measured by enzyme linked immunosorbant assay (ELISA) in blood and urine samples of premenopausal (age: 21-40 years, n=124) and menopausal women (41-70 years, n=256) without fractures. Bone mineral density (BMD) in the femur and spine was measured by dual energy x-ray absorptiometry (DXA).Results: Of the cytokines that were measured, only IL6 increased significantly in all 3 groups of menopausal women (compared with premenopausal healthy women. The changes in IL6 paralleled changes in markers of bone resorption and correlated positively with bone turnover markers and negatively with BMD and E1G levels. In menopausal women, the rise in IL6, CTX, and DPD was high ( > 100%) and was associated with a decline in E1G ( > 75%) and BMD levels ( > 22%) during the first 5 years of menopause, indicating that bone loss is confined to the first decade of menopause. Conclusions: IL6 correlates negatively with estrogens and BMD and positively with bone resorption markers. Thus, IL6 levels, in conjunction with CTX, DPD, and estrogen levels, improve the prediction of bone loss in menopausal women. Implication for health policy/practice/research/medical education: The article will be help Clinicians in predicting and planning correct strategies for postmenopausal bone loss. Please cite this paper as: Desai M, Khatkhatay MI, Taskar V, Ansari Z. Changes in Cytokines, Biomarkers of Bone Turnover and Hormones Are Associated With Bone Loss in Postmenopausal Indian Women. Int J Endrocrinol Metab. 2012:10(1): 399-403. DOI: 10.5812/ijem.3339 Copyright©2012 Kowsar M. P. Co. All rights reserved

Current Recommendations for Laboratory Testing and Use of Bone Turnover Markers in Management of Osteoporosis

Osteoporosis is a major health problem worldwide, and is projected to increase exponentially due to the aging of the population. The absolute fracture risk in individual subjects is calculated by the use of algorithms which include bone mineral density (BMD), age, gender, history of prior fracture and other risk factors. This review describes the laboratory investigations into osteoporosis which include serum calcium, phosphate, creatinine, alkaline phosphatase and 25-hydroxyvitamin D and, additionally in men, testosterone. Parathyroid hormone (PTH) is measured in patients with abnormal serum calcium to determine its cause. Other laboratory investigations such as thyroid function testing, screening for multiple myeloma, and screening for Cushing's syndrome, are performed if indicated. Measurement of bone turnover markers (BTMs) is currently not included in algorithms for fracture risk calculations due to the lack of data. However, BTMs may be useful for monitoring osteoporosis treatment. Further studies of the reference BTMs serum carboxy terminal telopeptide of collagen type I (s-CTX) and serum procollagen type I N-terminal propeptide (s-PINP) in fracture risk prediction and in monitoring various treatments for osteoporosis may help expedite their inclusion in routine clinical practice.

Comment on Rogers et al. “Acute response of plasma markers of bone turnover to a single bout of resistance training or plyometrics”

to the editor: We read with interest the paper by Rogers et al. ([11][1]) and were surprised by the choice of bone turnover markers. β-COOH terminal telopeptide of type I collagen (CTX) is highly responsive to nutrient ingestion (2–4, 8), which the authors acknowledge. However, they subsequently

The Effect of Oral Glucose Tolerance Test on Serum Osteocalcin and Bone Turnover Markers in Young Adults

Osteocalcin (OC) is an osteoblast-derived protein implicated in the regulation of glucose tolerance and energy metabolism. This endocrine function has been suggested to be exerted via its undercarboxylated form, which has been shown to induce expression of adiponectin, insulin, and islet cell proliferation in mice. Furthermore, insulin has recently been shown to regulate the biological activity of OC in bone. Our aim was to explore the association between glucose and bone metabolism by evaluating the effect of a standard 75g oral glucose tolerance test (OGTT) on serum OC, carboxylated OC (cOC) and bone-turnover markers (BTMs) C terminal telopeptide (βCTX-I) and N terminal propeptide (PINP) of type I collagen and tartrate-resistant acid phosphatase 5b (TRACP5b). Serum samples collected at 0 and at 120min were analyzed in a cohort of normoglycemic young adults (n=23, mean age 23.6years). During OGTT a significant decrease was observed in all BTMs (P<0.001 for all variables). The median decreases from 0 to 120min for OC, cOC, βCTX-I, PINP, and TRACP5b were -32.1% (-37.9 to -19.6), -34.4% (-39.8 to -22.2), -61.4% (-68.5 to -53.0), -26.8% (-33.2 to -19.2), and -44.5% (-48.3 to -40.2), respectively. A strong association between the changes in OC and cOC was observed (r=0.83, P<0.001). The decrease in PINP was associated with changes in OC, whereas the changes in βCTX-I and TRACP5b were not associated with decreases in OC or cOC. The observed OGTT-induced changes in bone-derived proteins were partially independent of each other and potentially mediated by different mechanisms.

Bone Turnover, Osteoprotegerin/Rankl and Inflammation with Antiretroviral Initiation: Tenofovir versus Non-Tenofovir Regimens

Bone mineral density decreases with antiretroviral therapy (ART) initiation, although the pathogenesis, including the role of tenofovir (TDF), is unclear. This study assessed changes in bone-turnover markers, osteoprotegerin (OPG), soluble receptor activator for nuclear factor-κβ ligand (sRANKL), and inflammation in subjects initiating TDF- versus non-TDF-containing regimens, and determined the relationship between bone turnover, OPG/sRANKL and inflammation. This was a longitudinal observational study comparing levels of bone turnover markers (C-terminal telopeptide of type I collagen [CTX] and osteocalcin [OC]), OPG, sRANKL and inflammatory cytokines (soluble tumour necrosis factor [TNF]-α receptor [sTNFR]-I, sTNFR-II and interleukin-6) prior to ART and 6-12 months after ART initiation with a TDF- versus non-TDF-containing regimen in HIV-infected subjects 18-50 years old. A total of 87 subjects were enrolled (TDF n=44 and non-TDF n=43). Groups were similar except subjects on TDF had a lower CD4(+) T-cell nadir (P<0.01) and were more likely to receive a protease inhibitor (PI; P=0.03). At pre-ART, 35% and 1% of subjects had CTX and OC above the normal range, respectively. Both increased with ART initiation, whereas OPG, sRANKL and inflammatory markers significantly decreased. In multivariate models, increases in OC were associated with TDF use, PI use and pre-ART levels of sTNFR-I, whereas increases in CTX were associated with CD4(+) T-cell nadir <50 cell/mm³. Increases in bone markers were unrelated to pre-ART levels of OPG/sRANKL and changes in OPG/sRANKL after ART initiation. TDF use, PI use, TNF-α activity and advanced HIV disease are associated with changes in bone turnover markers, underscoring the complicated interaction between ART, bone turnover, inflammation and immune status, which extend beyond the OPG/RANKL system.