BACKGROUND

This cross-sectional study was performed to determine the reference ranges for two bone turnover markers--aminoterminal propeptide of type I collagen (P1NP) and C-terminal telopeptide of type I collagen (beta-CrossLaps, beta-CTX)--in normal postmenopausal Spanish women as determined in serum by automated methods.

METHODS

A community-based population of 1080 healthy postmenopausal women was evaluated. Data regarding risk factors for osteoporosis and fractures were collected by means of a structured questionnaire. Fasting serum levels of P1NP, beta-CTX, 25-Hydroxivitamin D (25OHD), and intact parathyroid hormone (iPTH) were measured on the Elecsys 2010 automated analyzer (Roche). BMD at lumbar spine, femoral neck and total hip was determined by DXA.

RESULTS

The mean age of subjects was 63+/-9. Logarithmic transformation of both markers was performed to allow for normal distributions. Mid-95% ranges for P1NP and beta-CTX were 19-100 ng/ml and 0.112-1.018 ng/ml, respectively. Mean values of P1NP (47.7+/-19.9 ng/ml) were similar to those previously determined by the manufacturer of the assays, whereas beta-CTX mean values (0.387+/-0.197 ng/ml) were lower. Both markers were higher among osteoporotic women.

CONCLUSIONS

Values obtained from this well-characterized population study provide reference ranges for serum automated P1NP and beta-CTX in normal Spanish postmenopausal women.

OBJECTIVE

The osteoclast has been implicated in development of bone erosion in gout. The aim of this study was to determine whether zoledronate, a potent antiosteoclast drug, influences bone erosion in people with tophaceous gout.

METHODS

This was a 2-year, randomised, double-blind, placebo-controlled trial of 100 people with tophaceous gout. Participants were randomised to annual administration of 5 mg intravenous zoledronate or placebo. The primary endpoint was change in the foot CT bone erosion score from baseline. Secondary endpoint was change in plain radiographic damage scores. Other endpoints were change in bone mineral density (BMD), bone turnover markers and the OMERACT-endorsed core domains for chronic gout studies.

RESULTS

There was no change in CT erosion scores over 2 years, and no difference between the two treatment groups at Year 1 or 2 (p(treat)=0.10, p(time)=0.47, p(treat*time)=0.23). Similarly, there was no change in plain radiographic scores over 2 years, and no difference between the two groups at Year 1 or 2. By contrast, zoledronate increased spine, neck of femur, total hip and total body BMD. Zoledronate therapy also reduced the bone turnover markers P1NP and β-CTX compared with placebo. There was no difference between treatment groups in OMERACT-endorsed core domains.

CONCLUSIONS

Despite improvements in BMD and suppression of bone turnover markers, antiosteoclast therapy with zoledronate did not influence bone erosion in people with tophaceous gout. These findings suggest a disconnect between responses in the healthy skeleton and at sites of focal bone erosion in tophaceous gout.

BACKGROUND

Vitamin D and bone turnover markers (BTMs) might have an effect on the occurrence of acute hip fracture, while the current results are conflicting. The purpose of this study is to explore the relationship between serum 25(OH)D, bone turnover markers and bone mineral density in Chinese postmenopausal women with hip fracture.

METHODS

A total of 277 patients with hip fractures and 272 patients without fractures were included in this study. The serum 25(OH)D, bone formation markers, including N-terminal extension propeptide of type-I collagen (P1NP), alkaline phosphatase (ALP) and osteocalcin(OC), bone resorption markers, including C-terminal telopeptide of type-I collagen (CTX-1), and bone mineral density were collected and analyzed.

RESULTS

Women with hip fractures had significantly lower concentrations of serum 25(OH)D, higher concentrations of serum CTX-1, P1NP and OC, lower concentrations of femoral neck and total hip bone mineral density (P<0.05). After adjustment for age and other confounding factors, multiple logistic regression analysis showed that serum 25(OH)D (OR=0.878, 95%CI=0.855-0.902, P<0.001), CTX-1 (OR=4.884, 95%CI=2.419-9.861, P<0.001)and total hip BMD (OR=0.141, 95%CI=0.034-0.577, P=0.006) were independent risk factors for hip fractures in postmenopausal women. The receiver operating characteristics curves showed that serum 25(OH)D had a good AUC value (0.830).

CONCLUSIONS

In this study, lower concentrations of serum 25(OH)D and total hip bone mineral density were widely existed in Chinese postmenopausal women with hip fractures. Furthermore, bone resorption was more active than bone formation in senile postmenopausal women. Therefore, monitoring the alteration of serum CTX-1 in clinically might be useful for fracture prevention.

C-terminal telopeptide of type I collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) are bone turnover markers (BTMs) that are promising surrogate measures of fracture healing; however, it is unknown if their response is affected by other bone healing metabolites. Since 70% of fracture patients are reported to have insufficient serum vitamin D, we sought to determine if serum 25(OH)D levels are associated with differential changes in CTX and P1NP concentrations after hip fracture. This prospective cohort included hip fracture patients 65 years of age or older admitted to one of eight Baltimore-area hospitals. Serum samples were collected at baseline, 2-, 6-, and 12-month post-fracture. A mixed-effects repeated-measures analysis was used to determine the longitudinal association between vitamin D deficiency (25(OH)D < 20 ng/ml) and CTX and P1NP. Baseline lab values were obtained for 296 participants (mean age, 80.8 years; 51% male; 55% 25(OH)D < 20 ng/ml). During the acute fracture healing period P1NP concentrations increased by 14% (95%CI: 7-21%, p < 0.01) while CTX levels did not change (p = 0.07). Both CTX and P1NP decreased below baseline at 6 and 12 months. CTX levels were higher in participants with baseline 25(OH)D < 20 ng/ml (p = 0.01). There was no association between 25(OH)D < 20 ng/ml and P1NP levels over the study duration (p = 0.33). Data from this large, longitudinal cohort support claims that CTX and P1NP concentrations change during fracture healing; however, the differential response of CTX among vitamin D deficient patients highlights important questions for its utility as a reliable surrogate marker of fracture healing. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

BACKGROUND

The effect of massage therapy on bone metabolism in adults has only scarcely been explored. In a randomized crossover trial, we investigated the skeletal effect of Thai traditional massage by examining the changes in biochemical markers of bone turnover.

METHODS

Forty-eight postmenopausal women participated in the study. All volunteers were randomized to a 2-hour session of Thai traditional massage twice a week for 4 weeks and a 4-week control period after a 2-week washout, or vice versa. Twenty-one subjects were allocated to receiving Thai traditional massage first, followed by the control period, while 27 were initially allocated to the control period.

RESULTS

Serum P1NP increased significantly after Thai traditional massage (P <0.01), while there was no change in serum osteocalcin or CTX. During the control period, there was no significant change in P1NP, osteocalcin or CTX compared to baseline. When age and height were taken into account, P1NP in postmenopausal women whose ages were in the middle and higher tertiles and whose heights were in the lower and middle tertiles (n = 22) had a 14.8 ± 3.3% increase in P1NP after massage (P <0.001), while no change in P1NP was found in the rest of the women (n = 26).

CONCLUSIONS

Thai traditional massage results in an increase in bone formation as assessed by serum P1NP, particularly in postmenopausal women who are older and have a smaller body build. Future studies with larger samples and additional design features are warranted.

BACKGROUND

ClinicalTrials.gov : NCT01627028.

METHODS

Retrospective study.

OBJECTIVE

We conducted a study to investigate the time course changes in bone metabolic markers after the administration of the anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody and to assess drug compliance among osteoporotic patients.

BACKGROUND

The anti-RANKL antibody is expected to provide an improvement in those with a bone metabolism disorder. However there are only a few clinical reports available on the effect of treatment.

METHODS

We included 40 post-menopausal osteoporotic patients who received the anti-RANKL antibody. To determine the time course changes in the bone metabolic markers, we measured the serum tartrate-resistant acid phosphatase 5b (TRACP 5b; a bone resorption marker) and the serum N-terminal propeptide of type 1 collagen (P1NP; a bone formation marker) levels prior to and 1 month after administrating the anti-RANKL antibody. To evaluable drug compliance, we assessed the dropout rate during treatment and at 6 months after treatment.

RESULTS

The average TRACP 5b level significantly decreased from 574.8 mU/dL before treatment to 153.2 mU/dL 1 month after treatment (p<0.05). There was no significant difference in the average P1NP level, which was 56.9 µG/L and 35.1 µG/L before and 1 month after treatment, respectively (p>0.05). As for drug compliance, we did not have any dropouts during the treatment or after 6 months (dropout rate: 0%).

CONCLUSIONS

Our study suggests that anti-RANKL antibody treatment suppresses bone resorption and maintains bone formation.

OBJECTIVE

Thiazoledinediones increase limb fat in HIV+ patients with lipoatrophy. However, their use in the general population has been associated with bone loss and fracture. We sought to determine the effects of rosiglitazone on bone metabolism in HIV-infected patients.

METHODS

HIV+ patients with lipoatrophy were randomized to rosiglitazone versus placebo for 48 weeks in a double-blind, placebo-controlled trial. Limb fat, bone mineral density (BMD), bone formation markers (procollagen type 1 amino-terminal propeptide [P1NP], osteocalcin [OC]) and bone resorption markers (C-terminal telopeptide of type I collagen [CTX]) were measured, along with receptor activator for nuclear factor kappa β ligand (RANKL), osteoprotegerin (OPG), and inflammatory cytokines.

RESULTS

Seventy-one subjects were randomized to rosiglitazone or placebo: 17% female and 51% white. Total BMD did not change significantly in either group. In the rosiglitazone group, P1NP showed statistically significant decreases at 24 and 48 weeks; however, changes compared to placebo were only significant at 24 weeks. OC decreased significantly in the rosiglitazone group at 24 weeks, but there were no between-group differences. CTX, RANKL, or OPG did not change for either group. Multivariable regression within the rosiglitazone arm showed P1NP changes were inversely associated with limb fat changes, protease inhibitors, and tenofovir use.

CONCLUSIONS

Rosiglitazone use was associated with decreased bone formation, but it did not alter bone resorption or total BMD. The increase in limb fat that accompanies rosiglitazone use appears to be associated with decreased osteoblast activity. Further studies are needed to determine the effect of thiazoledinediones on bone health in HIV-infected persons.

This case-control study aimed to examine the effect of high serum parathyroid hormone (PTH) level, especially the effect of secondary hyperparathyroidism (SHPT) related to hypovitaminosis D, on bone metabolism and bone phenotypes. We included a total of 830 Chinese postmenopausal women aged ≥ 50 years with serum 25-hydroxyvitamin D (25(OH)D) level < 30 ng/ml, among whom 415 women had prevalent vertebral fractures (VFs) and others were age-matched controls. We measured serum levels of 25(OH)D, PTH and bone turnover markers (BTMs), which included C-terminal telopeptide of type I collagen (β-CTX), N-aminoterminal prepeptide of type I procollagen (P1NP) and osteocalcin (OC). Bone mineral densities (BMDs) at lumbar spine and femoral neck were quantified by dual-energy X-ray absorptiometry. Morphometric VFs were validated by lateral radiograph of thoracolumbar spine. Compared to fracture-free controls, women with VFs exhibited a higher serum level of PTH and a higher percentage of SHPT (both p < 0.05), but had a similar serum level of 25(OH)D (p = 0.166). Positive correlations were depicted between PTH and BTMs (all p < 0.01), and between 25(OH)D and bone formation markers (p = 0.013 for OC, p = 0.068 for P1NP), whereas no significant correlation was identified between both calciotropic hormones and BMDs or between 25(OH)D and β-CTX (all p > 0.05). Increasing PTH was associated with an increased risk of VFs independent of 25(OH)D and BMD [odds ratio (OR) per SD increase in PTH 1.016, 95% confidence interval (95% CI) 1.006-1.027]. Moreover, women with SHPT (i.e., > 68 pg/ml) had about three times odds for VF compared to women with normal PTH levels (OR 3.270, 95% CI 1.581-6.760). These data suggest that evaluated serum PTH level might promote the bone remodeling and then lead to increased risks of VFs among Chinese postmenopausal women with vitamin D insufficiency.

Polyostotic fibrous dysplasia (PFD) is a rare non-inherited genetic disorder characterized by osteolytic lesions in multiple bones causing bone pain, deformity, and pathological fracture. As an anti-osteolytic agent, the new generation bisphosphonate zoledronic acid (ZOL) restricts lesion progression by inhibiting osteoclastic activity. Although ZOL is more effective than pamidronate, its efficacy and safety in long-term therapy in PFD is unknown. We report a case of PFD advanced to extensive bone destruction in the skull and ribs and evaluate the efficacy and long-term safety of early first-line ZOL in PFD with severe bone disease, recommending possible future treatments. The annual infusion of 5 mg ZOL was intravenously administered, cumulatively 20 mg over four courses, with oral supplementation of calcium, vitamin D, and potassium. No long-term use side effect was observed, and mild transient symptoms were easily resolved. Significant radiological improvement was seen in filling of destroyed bone and cortical thickening. ZOL decreased both serum collagen type 1 cross-linked C-telopeptide and type 1 procollagen N-terminal (P1NP) from extremely high baseline levels. An unexpected direct increase in P1NP after long-term therapy could indicate discontinuation of ZOL to observe its prolonged effect. Early first-line ZOL therapy is effective in PFD with severe bone destruction and is safe for long-term therapy. The use of bisphosphonates in FD remains off-label, and regular monitoring is highly advised.

Cathepsin K (CK), a lysosomal cysteine protease, is highly expressed in mature osteoclasts and degrades type 1 collagen. Odanacatib (ODN) is a selective and reversible CK inhibitor that inhibits bone loss in preclinical and clinical studies. Although an antiresorptive, ODN does not suppress bone formation, which led us to hypothesize that ODN may display restorative effect on the osteopenic bones. In a curative study, skeletally mature New Zealand rabbits were ovarectomized (OVX) and after induction of bone loss were given a steady-state exposure of ODN (9 mM/d) for 14 weeks. Sham-operated and OVX rabbits treated with alendronate (ALD), 17b-estradiol (E2), or parathyroid hormone (PTH) served as various controls. Efficacy was evaluated by assessing bone mineral density (BMD), bone microarchitecture (using micro-computed tomography), fluorescent labeling of bone, and biomechanical strength. Skeletal Ca/P ratio was measured by scanning electron microscopy (SEM) with X-ray microanalysis, crystallinity by X-ray diffraction, and bone mineral density distribution (tissue mineralization) by backscattered SEM. Between the sham and ODN-treated osteopenic groups, lumbar and femur metaphyseal BMD, Ca/P ratio, trabecular microstructure and geometric indices, vertebral compressive strength, trabecular lining cells, cortical parameters (femoral area and thickness and periosteal deposition), and serum P1NP were largely comparable. Skeletal improvements in ALD-treated or E2-treated groups fell significantly short of the sham/ODN/PTH group. However, the ODN group displayed reduced ductility and enhanced brittleness of central femur, which might have been contributed by higher crytallinity and tissue mineralization. Rabbit bone marrow stromal cells expressed CK and when treated with ODN displayed increased formation of mineralized nodules and decreased apoptosis in serum-deficient medium compared with control. In vivo, ODN did not suppress remodeling but inhibited osteoclast activity more than ALD. Taken together, we show that ODN reverses BMD, skeletal architecture, and compressive strength in osteopenic rabbits; however, it increases crystallinity and tissue mineralization, thus leading to increased cortical bone brittleness.

Anabolic actions of PTH in bone involve increased deposition of mineralizing matrix. Regulatory feedback of the process may be important to maintain calcium homeostasis and, in turn, calcium may inform the process. This investigation clarified the role of calcium availability and the calcium sensing receptor (CaSR) in the anabolic actions of PTH. CaSR function promoted osteoblastic cell numbers, with lower cell numbers in post-confluent cultures of primary calvarial cells from Col1-CaSR knock-out (KO) mice, and for calvarial cells from wild-type (WT) mice treated with a calcilytic. Increased apoptosis of calvarial cells with calcilytic treatment suggested CaSR is critical for protection against stage-dependent cell death. Whole and cortical, but not trabecular, bone parameters were significantly lower in Col1-CaSR KO mice versus WT littermates. Intact Col1-CaSR KO mice had lower serum P1NP levels relative to WT. PTH treatment displayed anabolic actions in WT and, to a lesser degree, KO mice, and rescued the lower P1NP levels in KO mice. Furthermore, PTH effects on whole tibiae were inhibited by osteoblast-specific CaSR ablation. Vertebral body implants (vossicles) from untreated Col1-CaSR KO and WT mice had similar bone volumes after 4 weeks of implantation in athymic mice. These findings suggest that trabecular bone formation can occur independently of the CaSR, and that the CaSR plays a collaborative role in the PTH anabolic effects on bone. J. Cell. Biochem. 117: 1556-1567, 2016. © 2015 Wiley Periodicals, Inc.

BACKGROUND

Polymyalgia rheumatica (PMR) is a common condition in the elderly. A previous study demonstrated that it is associated with an increase in bone resorption. This effect was ameliorated by steroids, implying that inflammation is the cause of increased bone resorption and that this can be reduced by steroids. This is in keeping with accumulating evidence that systemic inflammation is associated with bone resorption and bone loss. We studied bone formation and resorption markers in 53 patients with PMR prior to any therapeutic intervention.

METHODS

Bone resorption was measured by estimating urinary free pyridinoline (fPYD) and deoxypyridinoline (fDPD). Bone formation was estimated by measuring serum concentrations of procollagen type 1 N-terminal propeptide (P1NP). Disease activity was assessed using inflammatory markers (erythrocyte sedimentation rate and C-reactive protein). Patients had a baseline dual-energy X-ray absorptiometer scan to assess bone mineral density.

RESULTS

Bone resorption markers were significantly increased and bone formation markers significantly decreased in PMR patients prior to treatment, compared with a control population matched for gender and age.

CONCLUSIONS

This implies that bone turnover is uncoupled in PMR. This may lead to a decrease in skeletal mass in the long term due to the disease process alone. However, no significant loss of bone mineral density was detected. It is possible that, due to the acute onset of PMR, increased bone resorption is not present long enough to result in a detectable decrease in bone mineral density. The effects of steroid treatment on bone metabolism and the subsequent long-term outcome need to be investigated.

OBJECTIVE

The ZOTECT study assesses the effect of zoledronic acid (ZOL) on bone-marker levels and potential correlations with disease outcomes in bisphosphonate-naive patients.

METHODS

This prospective, single-arm, open-label study in bisphosphonate-naive (≥6 months) patients with bone metastases from prostate cancer (PC; n=301) or breast cancer (BC; n=99) enrolled at 98 German sites (May 2006 to July 2008) investigated the effect of ZOL (4 mg intravenously every 4 weeks×4 months, with a final follow-up at 12 months) on bone-marker levels. Secondary assessments: skeletal-related event (SRE) rate, pain, quality of life (QoL), and prostate-specific antigen levels. Endpoints were assessed using summary statistics by visit/tumor type and Kaplan-Meier analyses.

RESULTS

ZOL treatment significantly decreased bone-marker levels (amino-terminal propeptide of type I collagen [P1NP], C-terminal cross-linking telopeptide of type I collagen [CTX]; P<0.0001), and this decrease was maintained through the final 1-year follow-up visit. Baseline P1NP and CTX levels correlated with extent of bone disease (P<0.0001, each) and on-treatment decreases in marker levels. Skeletal disease burden and bone-marker levels were similar between PC and BC patients, and ZOL did not significantly influence osteoprotegerin/receptor activator of nuclear factor-κB ligand levels. Only 13 SREs occurred in 11 patients, supporting the known ZOL-mediated reduction in SREs. On-treatment bone-marker level changes did not correlate with SRE rate, pain scores, or QoL. Generally, ZOL was well tolerated and adverse events were consistent with its known safety profile.

CONCLUSIONS

This study confirms that ZOL therapy significantly reduces bone turnover (measured as P1NP and CTX levels) in patients with bone metastases from PC or BC.

OBJECTIVE

The aim of this study was to evaluate differences in outcomes of denosumab for a year with or without bisphosphonate (BP) pre-treatment in patients with glucocorticoid-induced osteoporosis (GIO).

METHODS

Forty-eight female patients with GIO and low bone mineral density (BMD) (T score of BMD; less than -3.0 SD) were, retrospectively, enrolled and classified into the following two groups: (1) GIO with BP pre-treatment (BP pre-treated group; n = 24) and (2) GIO without BP treatment (BP pre-untreated group; n = 24). We measured serum bone alkaline phosphatase (BAP), N-terminal propeptide of type 1 procollagen (P1NP), and tartrate-resistant acid phosphatase (TRACP)-5b at baseline, and at 3, 6, and 12 months. We also assessed BMD of the lumbar 1-4 vertebrae BMD (L-BMD) and bilateral hip BMD (H-BMD) at baseline, and at 6 and 12 months.

RESULTS

TRACP-5b was significantly inhibited at 3 months in both groups and at 6 and 12 months in the BP pre-untreated group compared with pre-treatment levels. Both BAP and P1NP were significantly suppressed at 3, 6, and 12 months in both groups compared with baseline values. L-BMD and H-BMD were significantly increased at 6 (4.2% and 3.4%, respectively) and 12 months (4.7% and 4.7%, respectively) in the BP pre-untreated group over pre-treatment levels. There were no significant differences between the groups during the observational period.

CONCLUSIONS

Denosumab significantly improved both L-BMD and H-BMD in the BP pre-untreated group, but not in the BP pre-treated group, suggesting it to be a good option for GIO patients without BP pre-treatment.

OBJECTIVE

Diets rich in animal protein, such as the typical American diet, are thought to create a high acid load. An association between acid load and bone loss has led to the idea that providing positive alkaline salt therapy could have beneficial effects on bone metabolism. The objective of this study was to investigate the effects of potassium citrate (K-citrate), 40 mEq daily, over 1 year on bone resorption and formation.

METHODS

A randomized, double-blind, placebo-controlled trial of 83 women with postmenopausal osteopenia. Levels of bone turnover markers, specifically urinary N-telopeptide of collagen type 1 (u-NTX), amino-terminal propeptide of type 1 procollagen (P1NP), bone-specific alkaline phosphatase (BSAP), and osteocalcin (OC) were compared. Changes in bone mineral density (BMD) were also examined.

RESULTS

K-citrate decreased both u-NTX (P = .005) and serum P1NP (P<.001) starting at month 1 and continuing through month 12. No significant change was seen in BSAP or OC. No significant change was seen in lumbar or hip BMD between the 2 groups.

CONCLUSIONS

In women with postmenopausal osteopenia, treatment with K-citrate for 1 year resulted in a significant decrease in markers of turnover. The effect on markers of bone formation was not consistent. K-citrate may serve as a potential treatment for bone loss that is well tolerated and without any significant known long-term consequences.

Vitamin D (VD) plays an important role in bone mineralization. The present study investigates the effect of VD supplementation alone on bone turnover markers in younger postmenopausal women. It has been shown that VD supplementation in postmenopausal women with hypovitaminosis D is associated with a reduction in bone turnover markers.

The purpose of this study is to evaluate the effect of VD supplementation alone on bone turnover markers in younger postmenopausal women.

In this double-blind, placebo-controlled trial, 160 women were randomized into the VD group (supplementation with 1000 IU of vitamin D3/day, orally; n = 80) or placebo group (n = 80). Women aged 50-65 years with amenorrhea ≥ 12 months and normal bone mineral density were included. The intervention lasted 9 months, and the participants were assessed at the beginning and end of treatment. Serum levels of total calcium, parathormone (PTH), alkaline phosphatase (AP), and 24-h urine calcium were determined. Serum C-terminal telopeptide of type I collagen (s-CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured by immunoassay as markers of bone resorption and formation, respectively. Plasma 25-hydroxyvitamin-D [25(OH)D] concentrations were measured by HPLC. Intention-to-treat analysis was performed using ANOVA, Student's t test, Tukey's test, and gamma distribution.

Over the period of 9 months, 25(OH)D concentrations increased from 15.0 ± 7.5 to 27.5 ± 10.4 ng/mL (+ 45.4%) in the VD group and decreased from 16.9 ± 6.7 to 13.8 ± 6.0 ng/mL (- 18.5%) in the placebo group (p < 0.001). There was a decrease (- 21.3%) of PTH levels in the VD group with a significant difference between groups at the end of the study (p < 0.001). No significant differences were observed in the other laboratory parameters (total calcium, AP, and calciuria) in either group (p>> 0.05). A comparison of bone turnover markers showed a significant reduction in of s-CTX (- 24.2%, p < .0001) and P1NP (- 13.4%, p = 0.003) levels in the VD group. No significant variations in bone turnover markers were observed in the placebo group (s-CTX, - 6.9%, p = 0.092 and P1NP, - 0.6%, p = 0.918).

In younger postmenopausal women with VD deficiency, isolated supplementation with 1000 IU of vitamin D3 for 9 months is associated with a reduction in bone turnover markers. However, any between-group differences was not observed in bone turnover markers.

Changes of bone remodeling markers reflect bone growth and bone turnover. Information on bone metabolism can be attained by blood and urine laboratory tests. Recently developed bone specific markers are categorized by bone remodeling process, i.e. bone formation and resorption. The formation markers include bone-specific alkaline phosphatase (BAP), osteocalcin (OC), undercarboxylated osteocalcin (ucOC), procollagene type I C- and N-terminal peptides (P1CP and P1NP). Bone resorption markers include deoxypyridinoline, collagen I C- and N-terminal telopeptides (CTX and NTX) , and tartrate resistent acid phosphatase (TRACP) isoform 5b. These laboratory tests offer lots of advantages for the diagnosis of bone metabolic disorders and for the evaluation of clinical states of primary osteoporosis and other metabolic skeletal diseases.

Cbl and Cbl-b are E3 ubiquitin ligases and adaptor proteins, which perform regulatory roles in bone remodeling. Cbl-/- mice have delayed bone development due to decreased osteoclast migration. Cbl-b-/- mice are osteopenic due to increased bone resorbing activity of osteoclasts. Unique to Cbl, but not present in Cbl-b, is tyrosine 737 in the YEAM motif, which upon phosphorylation provides a binding site for the regulatory p85 subunit of PI3K. Substitution of tyrosine 737 with phenylalanine (Y737F, CblYF/YF mice) prevents Y737 phosphorylation and abrogates the Cbl-PI3K interaction. We have previously reported that CblYF/YF mice had increased bone volume due to defective bone resorption and increased bone formation. Here we show that the lumbar vertebra from CblYF/YF mice did not have significant bone loss following ovariectomy. Our data also suggests that abrogation of Cbl-PI3K interaction in mice results in the loss of coupling between bone resorption and formation, since ovariectomized CblYF/YF mice did not show significant changes in serum levels of c-terminal telopeptide (CTX), whereas the serum levels of pro-collagen type-1 amino-terminal pro-peptide (P1NP) were decreased. In contrast, following ovariectomy, Cbl-/- and Cbl-b-/- mice showed significant bone loss in the tibiae and L2 vertebrae, concomitant with increased serum CTX and P1NP levels. These data indicate that while lack of Cbl or Cbl-b distinctly affects bone remodeling, only the loss of Cbl-PI3K interaction protects mice from significant bone loss following ovariectomy.

Glucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent. Short-term treatment (7-14 days) with oral prednisone is used for many acute inflammatory and allergic conditions. This study was conducted to characterize the safety and pharmacodynamic (PD) dose-response of a 7-day course of oral prednisone on biomarkers of GC receptor agonism.

In this randomized, single-blind, placebo-controlled, crossover study (A9001309), 37 healthy subjects received placebo or a prednisone dose from 2.5-60 mg daily over 7 days in each of three treatment periods. White blood cell counts and plasma samples for measuring cortisol, osteocalcin and procollagen type 1 N-propeptide (P1NP) were obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Days 0 and 8. Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) were collected on Days 0, 1, 2, 4, and 8. Serum samples for adiponectin were obtained prior to dosing on days 0, 1, 4 and 8.

Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin, plasma P1NP, serum cortisol, and absolute blood eosinophil counts. Absolute blood neutrophil counts increased, while blood lymphocyte counts rebounded to an increased level following an initial rapid decrease after dosing. An increase was observed for uNTX and adiponectin. The incidence of adverse effects with prednisone was not dose related, and nervous system disorders, mainly headache, were the most frequently reported adverse effects.

This characterization provides important and relevant information on safety and PD responses of short-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for early clinical development of dissociated agents targeting a differentiated PD profile.

NCT02767089 (retrospectively registered: 21 April 2016).

Osteocalcin (OC) is a vitamin K-dependent bone protein used as a marker of bone formation. Mouse models have demonstrated a role for the uncarboxylated form of OC (ucOC) in energy metabolism, including energy expenditure and adiposity, but human data are equivocal. The purpose of this study was to determine the associations between changes in measures of OC and changes in body weight and percent body fat in obese, but otherwise healthy post-menopausal women undergoing a 20-week weight loss program. All participants received supplemental vitamins K and D and calcium. Body weight and body fat percentage (%BF) were assessed before and after the intervention. Serum OC [(total (tOC), ucOC, percent uncarboxylated (%ucOC)], and procollagen type 1N-terminal propeptide (P1NP; a measure of bone formation) were measured. Women lost an average of 10.9 ± 3.9 kg and 4 %BF. Serum concentrations of tOC, ucOC, %ucOC, and P1NP did not significantly change over the twenty-week intervention, nor were these measures associated with changes in weight (all p>> 0.27) or %BF (all p>> 0.54). Our data do not support an association between any serum measure of OC and weight or %BF loss in post-menopausal women supplemented with nutrients implicated in bone health.

Aim: To develop a practical model for classification bone turnover status and evaluate its clinical usefulness. Methods: Our classification of bone turnover status is based on internationally recommended biomarkers of both bone formation (N-terminal propeptide of type1 procollagen, P1NP) and bone resorption (beta C-terminal cross-linked telopeptide of type I collagen, bCTX), using the cutoffs proposed as therapeutic targets. The relationships between turnover subtypes and clinical characteristic were assessed in1223 hospitalised orthogeriatric patients (846 women, 377 men; mean age 78.1±9.50 years): 451(36.9%) subjects with hip fracture (HF), 396(32.4%) with other non-vertebral (non-HF) fractures (HF) and 376 (30.7%) patients without fractures. Resalts: Six subtypes of bone turnover status were identified: 1 - normal turnover (P1NP)32 μg/L, bCTX≤0.250 μg/L and P1NP/bCTX>100.0[(median value]); 2- low bone formation (P1NP ≤32 μg/L), normal bone resorption (bCTX≤0.250 μg/L) and P1NP/bCTX>100.0 (subtype2A) or P1NP/bCTX<100.0 (subtype 2B); 3- low bone formation, high bone resorption (bCTX>0.250 μg/L) and P1NP/bCTX<100.0; 4- high bone turnover (both markers elevated ) and P1NP/bCTX>100.0 (subtype 4A) or P1NP/bCTX<100.0 (subtype 4B). Compared to subtypes 1 and 2A, subtype 2B was strongly associated with nonvertebral fractures (odds ratio [OR] 2.0), especially HF (OR 3.2), age>75 years and hyperparathyroidism. Hypoalbuminaemia and not using osteoporotic therapy were two independent indicators common for subtypes 3, 4A and 4B; these three subtypes were associated with in-hospital mortality. Subtype 3 was associated with fractures (OR 1.7, for HF OR 2.4), age>75 years, chronic heart failure (CHF), anaemia, and history of malignancy, and predicted post-operative myocardial injury, high inflammatory response and length of hospital stay (LOS) above10 days. Subtype 4A was associated with chronic kidney disease (CKD), anaemia, history of malignancy and walking aids use and predicted LOS>20 days, but was not discriminative for fractures. Subtype 4B was associated with fractures (OR 2.1, for HF OR 2.5), age>75 years, CKD and indicated risks of myocardial injury, high inflammatory response and LOS>10 days. Conclusions: We proposed a classification model of bone turnover status and demonstrated that in orthogeriatric patients altered subtypes are closely related to presence of nonvertebral fractures, comorbidities and poorer in-hospital outcomes. However, further research is needed to establish optimal cut points of various biomarkers and improve the classification model.

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To understand the paradox of an increased fracture risk despite increased bone mineral density (BMD) in persons with type 2 diabetes (DM2).

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We studied 80 old persons with DM2. Mineral metabolism, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), bone turnover - osteocalcin, procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) - were measured and BMD was assessed at the lumbar spine (LS) and femoral neck (FN). Data was analyzed with the Statistical Package for the Social Sciences Program.

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Low levels of 25OHD (84%) and high values of PTH (20%) were found. Osteocalcin was directly related to CTX, p < 0.001, with increased bone formation and increased BMD (z-score) at LS and FN. PTH was directly related to osteocalcin and CTX and inversely related to BMD at the FN, p < 0.05. Patients with dyslipidemia presented higher P1NP, p < 0.05 and patients with hypertension presented higher BMD at LS and FN, p < 0.01.

UNASSIGNED

Old type 2 diabetics present increased bone formation, PTH-driven. Low grade secondary hyperparathyroidism may explain the paradox of an increased fracture risk despite increased BMD.