Histone deacetylase (Hdac) inhibitors are used clinically to treat cancer and epilepsy. Although Hdac inhibition accelerates osteoblast maturation and suppresses osteoclast maturation in vitro, the effects of Hdac inhibitors on the skeleton are not understood. The purpose of this study was to determine how the pan-Hdac inhibitor, suberoylanilide hydroxamic acid (SAHA; a.k.a. vorinostat or Zolinza(TM)) affects bone mass and remodeling in vivo. Male C57BL/6J mice received daily SAHA (100mg/kg) or vehicle injections for 3 to 4weeks. SAHA decreased trabecular bone volume fraction and trabecular number in the distal femur. Cortical bone at the femoral midshaft was not affected. SAHA reduced serum levels of P1NP, a bone formation marker, and also suppressed tibial mRNA levels of type I collagen, osteocalcin and osteopontin, but did not alter Runx2 or osterix transcripts. SAHA decreased histological measures of osteoblast number but interestingly increased indices of osteoblast activity including mineral apposition rate and bone formation rate. Neither serum (TRAcP 5b) nor histological markers of bone resorption were affected by SAHA. P1NP levels returned to baseline in animals which were allowed to recover for 4weeks after 4weeks of daily SAHA injections, but bone density remained low. In vitro, SAHA suppressed osteogenic colony formation, decreased osteoblastic gene expression, induced cell cycle arrest, and caused DNA damage in bone marrow-derived adherent cells. Collectively, these data demonstrate that bone loss following treatment with SAHA is primarily due to a reduction in osteoblast number. Moreover, these decreases in osteoblast number can be attributed to the deleterious effects of SAHA on immature osteoblasts, even while mature osteoblasts are resistant to the harmful effects and demonstrate increased activity in vivo, indicating that the response of osteoblasts to SAHA is dependent upon their differentiation state. These studies suggest that clinical use of SAHA and other Hdac inhibitors to treat cancer, epilepsy or other conditions may potentially compromise skeletal structure and function.

Odanacatib (ODN) is a selective and reversible inhibitor of cathepsin K (CatK) currently being developed as a once-weekly treatment for osteoporosis. In this study, we evaluated the effects of ODN on bone turnover, bone mineral density (BMD), and bone strength in the lumbar spine of estrogen-deficient, skeletally mature rhesus monkeys. Ovariectomized (OVX) monkeys were treated in prevention mode for 21 months with either vehicle, ODN 6 mg/kg, or ODN 30 mg/kg (p.o., q.d.) and compared with intact animals. ODN treatment persistently suppressed the bone resorption markers (urinary NTx [75% to 90%] and serum CTx [40% to 55%]) and the serum formation markers (BSAP [30% to 35%] and P1NP [60% to 70%]) versus vehicle-treated OVX monkeys. Treatment with ODN also led to dose-dependent increases in serum 1-CTP and maintained estrogen deficiency-elevated Trap-5b levels, supporting the distinct mechanism of CatK inhibition in effectively suppressing bone resorption without reducing osteoclast numbers. ODN at both doses fully prevented bone loss in lumbar vertebrae (L₁ to L₄) BMD in OVX animals, maintaining a level comparable to intact animals. ODN dose-dependently increased L₁ to L₄ BMD by 7% in the 6 mg/kg group (p < 0.05 versus OVX-vehicle) and 15% in the 30 mg/kg group (p < 0.05 versus OVX-vehicle) from baseline. Treatment also trended to increase bone strength, associated with a positive and highly significant correlation (R = 0.838) between peak load and bone mineral content of the lumbar spine. Whereas ODN reduced bone turnover parameters in trabecular bone, the number of osteoclasts was either maintained or increased in the ODN-treated groups compared with the vehicle controls. Taken together, our findings demonstrated that the long-term treatment with ODN effectively suppressed bone turnover without reducing osteoclast number and maintained normal biomechanical properties of the spine of OVX nonhuman primates.

BACKGROUND

Those receiving tenofovir/emtricitabine (TDF-FTC) had greater bone loss compared with abacavir/lamivudine (ABC-3TC) in a randomized simplification trial (STEAL study). Previous studies associated increased bone turnover and bone loss with initiation of antiretroviral treatment, however it is unclear whether change in bone mineral density (BMD) was a result of specific drugs, from immune reconstitution or from suppression of HIV replication. This analysis determined predictors of BMD change in the hip and spine by dual-energy x-ray absorptiometry in virologically suppressed participants through week 96.

RESULTS

Bone turnover markers (BTMS) tested were: formation [bone alkaline phosphatase, procollagen type 1 N-terminal propeptide (P1NP)]; resorption (C-terminal cross-linking telopeptide of type 1 collagen [CTx]); and bone cytokine-signalling (osteoprotegerin, RANK ligand). Independent predictors of BMD change were determined using forward, stepwise, linear regression. BTM changes and fracture risk (FRAX®) at week 96 were compared by t-test. Baseline characteristics (n = 301) were: 98% male, mean age 45 years, current protease-inhibitor (PI) 23%, tenofovir/abacavir-naïve 52%. Independent baseline predictors of greater hip and spine bone loss were TDF-FTC randomisation (p ≤ 0.013), lower fat mass (p-trend ≤ 0.009), lower P1NP (p = 0.015), and higher hip T score/spine BMD (p-trend ≤ 0.006). Baseline PI use was associated with greater spine bone loss (p = 0.004). TDF-FTC increased P1NP and CTx through Wk96 (p<0.01). Early changes in BTM did not predict bone loss at week 96. No significant between-group difference was found in fracture risk.

CONCLUSIONS

Tenofovir/emtricitabine treatment, lower bone formation and lower fat mass predicted subsequent bone loss. There was no association between TDF-FTC and fracture risk.

BACKGROUND

In recent years the interest on the relationship of gut hormones to bone processes has increased and represents one of the most interesting aspects in skeletal research. The proportion of bone mass to soft tissue is a relationship that seems to be controlled by delicate and subtle regulations that imply "cross-talks" between the nutrient intake and tissues like fat. Thus, recognition of the mechanisms that integrate a gastrointestinal-fat-bone axis and its application to several aspects of human health is vital for improving treatments related to bone diseases. This work analysed the effects of gut hormones in cell cultures of three osteoblastic cell lines which represent different stages in osteoblastic development. Also, this is the first time that there is a report on the direct effects of glucagon-like peptide 2, and obestatin on osteoblast-like cells.

METHODS

mRNA expression levels of five gut hormone receptors (glucose-dependent insulinotropic peptide [GIP], glucagon-like peptide 1 [GLP-1], glucagon-like peptide 2 [GLP-2], ghrelin [GHR] and obestatin [OB]) were analysed in three osteoblastic cell lines (Saos-2, TE-85 and MG-63) showing different stages of osteoblast development using reverse transcription and real time polymerase chain reaction. The responses to the gut peptides were studied using assays for cell viability, and biochemical bone markers: alkaline phosphatase (ALP), procollagen type 1 amino-terminal propeptides (P1NP), and osteocalcin production.

RESULTS

The gut hormone receptor mRNA displayed the highest levels for GIP in Saos-2 and the lowest levels in MG-63, whereas GHR and GPR39 (the putative obestatin receptor) expression was higher in TE-85 and MG-63 and lower in Saos-2. GLP-1 and GLP-2 were expressed only in MG-63 and TE-85. Treatment of gut hormones to cell lines showed differential responses: higher levels in cell viability in Saos-2 after GIP, in TE-85 and MG-63 after GLP-1, GLP-2, ghrelin and obestatin. ALP showed higher levels in Saos-2 after GIP, GHR and OB and in TE-85 after GHR. P1NP showed higher levels after GIP and OB in Saos-2. Decreased levels of P1NP were observed in TE-85 and MG-63 after GLP-1, GLP-2 and OB. MG-63 showed opposite responses in osteocalcin levels after GLP-2.

CONCLUSIONS

These results suggest that osteoblast activity modulation varies according to different development stage under different nutrition related-peptides.

Osteoporosis mainly affects postmenopausal women and older men. Gastrointestinal hormones released after meal ingestion, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-2, have been shown to regulate bone turnover. However, whether GLP-1, another important gastrointestinal hormone, and its analogues also have antiosteoporotic effects, especially in aged postmenopausal situation, has not been confirmed. In the present study, we evaluated the effects of the GLP-1 receptor agonist exendin-4 on ovariectomy (OVX)-induced osteoporosis in old rats. Twelve-month-old female Sprague-Dawley rats were subjected to OVX, and exendin-4 was administrated 4 weeks after the surgery and lasted for 16 weeks. Bone characters and related serum and gene biomarkers were analyzed. Sixteen weeks of treatment with exendin-4 slowed down body weight gain by decreasing fat mass and prevented the loss of bone mass in old OVX rats. Exendin-4 also enhanced bone strength and prevented the deterioration of trabecular microarchitecture. Moreover, exendin-4 decreased the urinary deoxypyridinoline (DPD)/creatinine ratio and serum C-terminal cross-linked telopeptides of type I collagen (CTX-I) and increased serum alkaline phosphatase (ALP), osteocalcin (OC), and N-terminal propeptide of type 1 procollagen (P1NP) levels, key biochemical markers of bone turnover. Interestingly, gene expression results further showed that exendin-4 not only inhibited bone resorption by increasing the osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio, but also promoted bone formation by increasing the expression of OC, Col1, Runx2, and ALP, which exhibited dual regulatory effects on bone turnover as compared with previous antiosteoporotic agents. In conclusion, these findings demonstrated for the first time the antiosteoporotic effects of exendin-4 in old OVX rats and that it might be a potential candidate for treatment of aged postmenopausal osteoporosis.

BACKGROUND

Adults with osteogenesis imperfecta (OI) have a high risk of fracture. Currently, few treatment options are available, and bone anabolic therapies have not been tested in clinical trials for OI treatment.

METHODS

79 adults with OI were randomized to receive 20 μg recombinant human parathyroid hormone (teriparatide) or placebo for 18 months in a double-blind, placebo-controlled trial. The primary endpoint was the percent change in areal bone mineral density (aBMD) of the lumbar spine (LS), as determined by dual-energy X-ray absorptiometry. Secondary endpoints included percent change in bone remodeling markers and vertebral volumetric BMD (vBMD) by quantitative computed tomography, estimated vertebral strength by finite element analysis, and self-reported fractures.

RESULTS

Compared with the placebo group, the teriparatide group showed increased LS aBMD (6.1% ± 1.0% vs. 2.8% ± 1.0% change from baseline; P < 0.05) and total hip aBMD (2.6% ± 1.0% vs. -2.4% ± 1.0% change; P < 0.001). Vertebral vBMD and strength improved with teriparatide therapy (18% ± 6% and 15% ± 3% change, respectively), but declined with placebo (-5.0% ± 6% and -2.0% ± 3% change; P < 0.05 for both comparisons). Serum procollagen type 1 N-terminal propeptide (P1NP) and urine collagen N-telopeptide (NTx) levels increased with teriparatide therapy (135% ± 14% and 64% ± 10% change, respectively). Teriparatide-induced elevation of P1NP levels was less pronounced in severe forms of OI (type III/IV) compared with the milder form (type I). Type I OI patients exhibited robust BMD increases with teriparatide; however, there was no observed benefit for those with type III/IV OI. There was no difference in self-reported fractures between the 2 groups.

CONCLUSIONS

Adults with OI, particularly those with less severe disease (type I), displayed a teriparatide-induced anabolic response, as well as increased hip and spine aBMD, vertebral vBMD, and estimated vertebral strength. Trial registration. Clinicaltrials.gov NCT00131469. Funding. The Osteoporosis Imperfecta Foundation, Eli Lilly and Co., the National Center for Advancing Translational Science (NCATS) at the NIH (grant no. UL1RR024140), and the Baylor College of Medicine General Clinical Research Center (grant no. RR00188).

Bone turnover markers (BTMs) are widely used for the management of osteoporosis, and the premenopausal reference range is the target value for the treatment of postmenopausal osteoporosis with antiresorbing agents. Three serum BTMs (serum C-telopeptide of type I collagen [CTX], osteocalcin [OC], and N-terminal propeptide of type I procollagen [P1NP]), serum calcium, creatinine, phosphate, magnesium, and follicle-stimulating hormone (FSH) were measured in 638 healthy premenopausal women aged 20-50 years. In 83 women on the contraceptive pill (CP), the levels of the three BTMs adjusted for all confounding factors were 14-26% lower (P < 0.005) than in non-CP users. In 18 women considered perimenopausal for serum FSH levels >30 IU/mL despite having regular menses, BTM levels were significantly higher than in age-matched women. This group of subjects and the women on the CP were excluded from further analysis. The three BTMs significantly decreased with advancing age and were negatively and independently correlated with body mass index (P < 0.001) and serum phosphate. In conclusion, we confirm that CP use is associated with significantly lower BTM values. An increase in BTM concentrations can be observed in perimenopausal women, i.e., women with normal menses but FSH levels >30 IU/mL. BTMs decrease substantially with advancing age, and this appears to be associated with changes in body weight and serum phosphate. New normative ranges for serum OC, CTX, and P1NP were identified; and our findings in general impose a redefinition of the criteria for establishing the normal ranges for BTMs.

BACKGROUND

Premenopausal women with idiopathic osteoporosis (IOP) have abnormal cortical and trabecular bone microarchitecture.

OBJECTIVE

The purpose of this study was to test the hypotheses that teriparatide increases bone mineral density (BMD) and bone formation and improves trabecular microarchitecture and stiffness in women with IOP.

METHODS

This was an open-label pilot study.

METHODS

The setting was a tertiary care referral center.

METHODS

Participants were 21 premenopausal women with unexplained fragility fractures or low BMD.

METHODS

Teriparatide was administered at 20 μg daily for 18 to 24 months.

METHODS

The primary endpoint was within-subject percent change in lumbar spine BMD. Secondary endpoints included percent change in hip and forearm BMD, transiliac biopsy parameters (trabecular bone volume, microarchitecture, stiffness, and adipocytes), serum N-terminal propeptide of procollagen type 1 (P1NP), and C-telopeptide.

RESULTS

BMD increased at the spine (10.8 ± 8.3% [SD]), total hip (6.2 ± 5.6%), and femoral neck (7.6 ± 3.4%) (all P < .001). Serum P1NP doubled by 1 month, peaked at 6 months, and returned to baseline by 18 to 24 months. Transiliac biopsies demonstrated significant increases in cortical width and porosity and trabecular bone volume and number increased, mirrored by a 71% increase in trabecular bone stiffness (P < .02-.001). Adipocyte area, perimeter, and volume/marrow volume decreased, with no change in adipocyte number. Four women had no increase in BMD and a blunted, delayed increase in serum P1NP. Nonresponders had markedly lower baseline bone formation rate (0.002 ± 0.001 vs 0.011 ± 0.006 mm²/mm/y; P < .001) and higher serum IGF-1 (208 ± 54 vs 157± 44 ng/mL; P = .03).

CONCLUSIONS

Teriparatide was associated with increased spine and hip BMD and improved trabecular microarchitecture and stiffness at the iliac crest in the majority of women with IOP.

Transiliac bone biopsies, while widely considered to be the standard for the analysis of bone microstructure, are typically restricted to specialized centers. The benefit of Trabecular Bone Score (TBS) in addition to areal bone mineral density (aBMD) for fracture risk assessment has been documented in cross-sectional and prospective studies. The aim of this study was to test if TBS may be useful as a surrogate to histomorphometric trabecular parameters of transiliac bone biopsies. Transiliac bone biopsies from 80 female patients (median age 39.9 years-interquartile range, IQR 34.7; 44.3) and 43 male patients (median age 42.7 years-IQR 38.9; 49.0) with idiopathic osteoporosis and low traumatic fractures were included. Micro-computed tomography values of bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), structural model index (SMI) as well as serum bone turnover markers (BTMs) sclerostin, intact N-terminal type 1 procollagen propeptide (P1NP) and cross-linked C-telopeptide (CTX) were investigated. TBS values were higher in females (1.282 vs 1.169, p< 0.0001) with no differences in spine aBMD, whereas sclerostin levels (45.5 vs 33.4 pmol/L) and aBMD values at the total hip (0.989 vs 0.971 g/cm(2), p<0.001 for all) were higher in males. Multiple regression models including: gender, aBMD and BTMs revealed TBS as an independent, discriminative variable with adjusted multiple R(2) values of 69.1% for SMI, 79.5% for Tb.N, 68.4% for Tb.Sp, and 83.3% for BV/TV. In univariate regression models, BTMs showed statistically significant results, whereas in the multiple models only P1NP and CTX were significant for Tb.N. TBS is a practical, non-invasive, surrogate technique for the assessment of cancellous bone microarchitecture and should be implemented as an additional tool for the determination of trabecular bone properties.

During teriparatide (TPTD) treatment, high levels of bone formation are accompanied by an increase in bone resorption. The aim of this work was to test if coadministration of raloxifene (RAL) or alendronate (ALN) following 9 months of ongoing TPTD therapy would reopen the anabolic window, thereby exerting additional benefit on bone mineral density (BMD). Postmenopausal women (n = 125) with severe osteoporosis on TPTD treatment for 9 months were randomized into three open-label groups for a further 9 months: ALN (70 mg/week) in addition to TPTD; RAL (60 mg/d) in addition to TPTD; or no medication in addition to TPTD. Amino-terminal propeptide of type I procollagen (P1NP) and cross-linked C-telopeptide (CTX), and areal and volumetric BMD at the lumbar spine and hip were assessed. During the combination period, P1NP concentrations did not change on TPTD monotherapy (693% ± 371%, p < 0.0001) and decreased in the ALN (360% ± 153%, p < 0.0001) and RAL (482% ± 243%, p < 0.0001) combination groups; whereas CTX did not change on TPTD monotherapy (283% ± 215%, p < 0.0001), decreased to the starting level in the ALN combination group (17% ± 72%, p = 0.39), and remained elevated in the RAL combination group (179% ± 341%, p < 0.0001). The increase in lumbar spine BMD was 5% ± 6.3% in the ALN and 6% ± 5.2% in the RAL combination groups compared with 2.8% ± 9.3% in the TPTD monotherapy group (p = 0.085 and p = 0.033, respectively). The increase of trabecular lumbar spine BMD for both the ALN and RAL combination groups was superior to TPTD monotherapy. Total hip BMD changes were 4% ± 5.3% for the ALN combination group and 1.4% ± 5.1% for the TPTD monotherapy (p = 0.032), and 1.4% ± 3.4% (p = 0.02) for the RAL combination group. With the exception of no differences in the trabecular compartment of femoral neck, volumetric BMD changes in the ALN combination group for all other comparisons were significantly superior to the two other groups. Our data suggest that ALN when added to TPTD 9 months after initiation of TPTD monotherapy results in a more robust increase in BMD, probably due to a reopening of the anabolic window. The clinical relevance of the BMD increase is unknown.

BACKGROUND

Anorexia nervosa (AN), a prevalent psychiatric disorder predominantly affecting women, is characterized by self-induced starvation and low body weight. Increased clinical fractures are common, and most women have low bone mineral density (BMD). Previously investigated treatments have led to no or modest increases in BMD in AN.

OBJECTIVE

Our objective was to investigate the effect of teriparatide (TPT; human PTH[1-34]), an anabolic agent, on low bone mass in women with AN.

METHODS

This randomized, placebo-controlled trial at a clinical research center included 21 women with AN: 10 (mean age ± SEM, 47 ± 2.7 years) treated with TPT and 11 (47.1 ± 2.3 years) treated with placebo.

METHODS

TPT (20 μg s.c.) or placebo was administered for 6 months.

METHODS

Our primary outcome measure was change in BMD of the spine and hip by dual-energy x-ray absorptiometry. Secondary outcome measures included changes in serum N-terminal propeptide of type 1 procollagen (P1NP), C-terminal collagen cross-links, sclerostin, and IGF-1 levels.

RESULTS

At 6 months, spine BMD increased significantly more with TPT (posteroanterior spine, 6.0% ± 1.4%; lateral spine, 10.5% ± 2.5%) compared with placebo (posteroanterior spine, 0.2% ± 0.7%, P < .01; lateral spine, -0.6% ± 1.0%; P < .01). The results remained significant after controlling for baseline body mass index, P1NP, and IGF-1. Changes in femoral neck (P = .4) and total hip (P = 0.8) BMD were comparable in both groups, as were changes in weight. Serum P1NP levels increased after 3 months of TPT treatment and remained at this higher level at 6 months, whereas P1NP levels were unchanged in the placebo group (P = .02). TPT was well-tolerated by all subjects.

CONCLUSIONS

This study demonstrates that TPT administration increases spine BMD substantially after only 6 months of therapy in women with AN.

Intravenous zoledronate 5 mg, administered annually, prevents fractures in people with osteoporosis, but the optimal dosing schedule is not known. Previously, we reported that a single dose of 5 mg zoledronate stably decreased bone turnover and increased bone mineral density (BMD) for 3 years in a randomized controlled trial in 50 postmenopausal women with osteopenia. We have now completed a 2-year double-blind extension of this trial, during which no additional treatment was administered. The primary endpoint was change in the bone turnover markers procollagen type-I N-terminal propeptide (P1NP) and β-C-terminal telopeptide of type I collagen (β-CTX); the secondary endpoint was change in BMD at lumbar spine, total hip and total body. Mean levels of the each of the bone turnover markers were lower in the zoledronate group throughout the study (P<0.0001 for each marker). After 5 years, mean (95% CI) levels of β-CTX and P1NP were 277 ng/L (150, 404) and 28 μg/L (16, 40) lower in the zoledronate group, corresponding to reductions of 48% and 45%, respectively. BMD was higher in the zoledronate group during the study (P<0.0001 for each site). After 5 years, BMD in the zoledronate group was higher by 4.2% (1.1, 7.2) at the lumbar spine, by 5.3% (2.7, 7.9) at the total hip, and by 2.7% (1.1, 4.2) at the total body. These findings suggest that the anti-resorptive effects of a single 5 mg dose of zoledronate persist for at least 5 years in postmenopausal women. Trials assessing the anti-fracture efficacy of dosing intervals of zoledronate of up to 5 years are justified.

OBJECTIVE

Crohn's disease (CD) is associated with altered bone metabolism. This study examined changes in bone formation and resorption after infliximab induction and associations between bone biomarkers, linear growth, and disease activity (Pediatric Crohn's Disease Activity Index [PCDAI]) after 54 weeks of infliximab therapy.

METHODS

One hundred twelve subjects ages 6-17 years with moderate to severe CD received infliximab induction (5 mg/kg/dose) at weeks 0, 2, and 6; week-10 responders were randomized to infliximab every 8 or every 12 weeks maintenance therapy. Serum bone-specific alkaline phosphatase (BSAP), N-terminal propeptide of type 1 collagen (P1NP), urine C-telopeptide of collagen cross-links (CTX-1), and deoxypyrodinoline (DPD) were collected at baseline and 10 weeks. PCDAI and height z-scores were assessed at baseline and at 10 and 54 weeks.

RESULTS

Models were adjusted for bone age, gender, height, and steroid use. Baseline BSAP and P1NP levels were negatively associated with PCDAI (both P = .01). BSAP and P1NP increased during induction (both P < .001) and were associated with 54-week increases in height z-score (P < .05 and P < .001, respectively). Improvements in P1NP were associated with 54-week decreases in PCDAI (P = .01). CTX-1 and DPD also increased during induction (P < .001 and P = .01, respectively) but were not associated with changes in PCDAI. Changes in CTX-1 were associated with improvements in height z-score (P < .002).

CONCLUSIONS

Infliximab therapy is associated with dramatic increases in BSAP and P1NP, consistent with inhibition of tumor necrosis factor-alpha effects on osteoblasts. The increases in CTX-1 and DPD likely reflect coupling of bone formation and resorption and increases in linear growth.

Van Buchem disease (VBD) is a rare bone sclerosing dysplasia caused by the lack of a regulatory element of the SOST gene, which encodes for sclerostin, an osteocyte-derived negative regulator of bone formation. We studied the demographic, clinical, biochemical, and densitometric features of 15 patients with VBD (12 adults and 3 children) and 28 related carriers of the gene mutation. The most common clinical findings in patients were facial palsy (100%) and various degrees of hearing impairment (93%); raised intracranial pressure had been documented in 20%. The clinical course of the disease appeared to stabilize in adulthood, with the majority of patients reporting no progression of symptoms or development of complications with time. Carriers of the disease had none of the clinical features or complications of the disease. Sclerostin could be detected in the serum in all but 1 VBD patients (mean 8.0 pg/mL; 95% confidence interval [CI], 4.9-11.0 pg/mL), and were lower than those of carriers (mean 28.7 pg/mL; 95% CI, 24.5-32.9 pg/mL; p < 0.001) and healthy controls (mean 40.0 pg/mL; 95% CI, 34.5-41.0 pg/mL; p < 0.). Serum procollagen type 1 amino-terminal propeptide (P1NP) levels were also significantly higher in adult patients (mean 96.0; 95% CI, 54.6-137.4 ng/mL versus mean 47.8; 95% CI, 39.4-56.2 ng/mL, p = 0.003 in carriers and mean 37.8; 95% CI, 34.5-41.0 ng/mL, p = 0.028 in healthy controls) and declined with age. Bone mineral density (BMD) was markedly increased in all patients (mean Z-score 8.7 ± 2.1 and 9.5 ± 1.9 at the femoral neck and spine, respectively); BMD of carriers was significantly lower than that of patients but varied widely (mean Z-scores 0.9 ± 1.0 and 1.3 ± 1.5 at the femoral neck and spine, respectively). Serum sclerostin levels were inversely correlated with serum P1NP levels (r = -0.39, p = 0.018) and BMD values (femoral neck r = -0.69, p < 0.001; lumbar spine r = -0.78, p < 0.001). Our results show that there is a gene-dose effect of the VBD deletion on circulating sclerostin and provide further in vivo evidence of the role of sclerostin in bone formation in humans. The small amounts of sclerostin produced by patients with VBD may explain their milder phenotype compared to that of patients with sclerosteosis, in whom serum sclerostin is undetectable.

OBJECTIVE

To evaluate serum levels of osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1PN) and beta-CrossLaps (beta-CTx) in obese subjects and their relationship with glucose metabolism parameters.

METHODS

Sixty-four obese patients classified according to their glucose tolerance.

METHODS

Case-control study.

METHODS

A 75-g oral glucose tolerance test was performed with determinations of glucose and insulin between 0 and 120 min. Serum concentrations of OC, P1PN and beta-CTx were quantified in baseline samples.

RESULTS

Patients with type 2 diabetes (T2D, n = 24) exhibited OC serum levels (2·6 ± 1·0 nm) significantly lower than those found in subjects with normal glucose tolerance (NGT, n = 20, 3·9 ± 1·5 nm, P < 0·01). We found no significant differences in P1NP and beta-CTX levels among patients with NGT, prediabetes and T2D. Multiple regression analysis showed that serum OC concentration, but not P1NP or beta-CTx levels, was independently related to 2-h plasma glucose.

CONCLUSIONS

Obese patients with T2D showed significantly reduced levels of OC in comparison with patients with lower degrees of glucose tolerance derangement. Our results also suggest that OC was the only bone marker independently related to the degree of glucose metabolism derangement in these patients.

BACKGROUND

Sarcopenia and osteopenia/osteoporosis show a high prevalence in old age and incur a high risk for falls, fractures, and further functional decline. Physical performance and bone metabolism in patients suffering from the so-called osteosarcopenia-the combination of sarcopenia and osteopenia-are currently still unknown.

OBJECTIVE

This study investigates physical performance and bone metabolism in osteosarcopenic, prefrail, community-dwelling older adults.

METHODS

68 prefrail adults between 65 and 94 years were assigned to four groups according to mean DXA results: osteosarcopenic [low T-score and low appendicular lean mass (aLM)], sarcopenic (low aLM), osteopenic (low T-score), and controls. Multiple linear regression analysis, adjusted for age, gender, physical activity, and 25-OH-vitamin D3 serum level, was used to identify the influence of being osteosarcopenic, sarcopenic, or osteopenic on physical performance (hand grip, chair rise test, sit-to-stand power, gait speed, SPPB) and serum markers for increased bone turnover [osteocalcin, β-crosslaps and procollagen type 1 amino-terminal propeptide (P1NP)].

RESULTS

Only osteosarcopenic participants showed significantly reduced hand grip strength, increased chair rising time, and STS power time as well as significantly increased bone turnover markers.

CONCLUSIONS

Due to low physical performance and high bone turnover, older adults with osteosarcopenia have to be regarded as the most at-risk population for fractures and further functional decline.

CONCLUSIONS

Up-to-date osteoporosis and post-fracture management of older persons should aim at both, bone and muscle.

BACKGROUND

Our objective was to compare the bone and renal effects among HIV-infected patients randomized to abacavir or tenofovir-based combination anti-retroviral therapy.

METHODS

In an open-label randomized trial, HIV-infected patients were randomized to switch from zidovudine/lamivudine (AZT/3TC) to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC). We measured bone mass density (BMD) and bone turnover biomarkers (osteocalcin, osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), alkaline phosphatase, type I collagen cross-linked C-telopeptide (CTx), and osteoprotegerin). We assessed renal function by estimated creatinine clearance, plasma cystatin C, and urinary levels of creatinine, albumin, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL). The changes from baseline in BMD and renal and bone biomarkers were compared across study arms.

RESULTS

Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. BMD was measured in 33, 26, and 27 patients at baseline, week 24, and week 48, respectively. In TDF/FTC-treated patients we observed significant reductions from baseline in hip and lumbar spine BMD at week 24 (-1.8% and -2.5%) and week 48 (-2.1% and -2.1%), whereas BMD was stable in patients in the ABC/3TC arm. The changes from baseline in BMD were significantly different between study arms. All bone turnover biomarkers except osteoprotegerin increased in the TDF/FTC arm compared with the ABC/3TC arm, but early changes did not predict subsequent loss of BMD. Renal function parameters were similar between study arms although a small increase in NGAL was detected among TDF-treated patients.

CONCLUSIONS

Switching to TDF/FTC-based therapy led to decreases in BMD and increases in bone turnover markers compared with ABC/3TC-based treatment. No major difference in renal function was observed.

BACKGROUND

Clinicaltrials.gov NCT00647244.

We investigated the association between undercarboxylated osteocalcin (ucOC) and lower-limb muscle strength in women over the age of 70years. The study also aims to confirm the association between bone turnover markers and heel ultrasound measures. A post-hoc analysis using data collected as part of a randomized placebo-controlled trial of vitamin D supplementation. An immunoassay was used to quantify total OC (tOC), with hydroxyapatite pre-treatment for ucOC. We determined associations of absolute and relative (ucOC/tOC; ucOC%) measures of ucOC with lower-limb muscle strength, heel ultrasound measures of speed of sound (SOS) and broadband ultrasound attenuation (BUA), bone turnover markers (BTMs; P1NP and CTx) and the acute phase protein alpha-1-antichymotrypsin (α-ACT). ucOC%, but not absolute ucOC concentration, was positively associated with hip flexor, hip abductor and quadriceps muscle strength (all p<0.05). ucOC% was negatively associated with α-ACT (β-coefficient=-0.24, p=0.02). tOC was positively associated with both P1NP and CTx (p<0.001). For each per unit increase in tOC (μg/L) there was a corresponding lower BUA, SOS and SI (β-coefficient = -0.28; -0.23 and -0.23, respectively; all p<0.04). In conclusion, ucOC% is positively associated with muscle strength and negatively associated with α-ACT. These data support a role for ucOC in musculoskeletal interactions in humans. Whilst tOC is associated with bone health, ucOC% and ucOC may also be linked to falls and fracture risk by influencing muscle function.

Obese children, particularly those who have fractured, have reduced body size-adjusted total body and regional bone mass. We performed an observational cross-sectional cohort study to determine the relationship between adipokines (leptin and adiponectin), bone-derived cytokines and bone turnover in children which may explain this observation. Participants aged 5-16 years were recruited into obese (BMI SDS 3.3±0.6) and lean (BMI SDS 0.2±1.0) groups and further subdivided into groups by fracture history. Free leptin (leptin/leptin soluble receptor) and adiponectin; RANK-ligand (RANKL), osteoprotegerin (OPG); Dickkopf-1 (DKK1); and the bone turnover markers procollagen type I amino propeptide (P1NP) and carboxy-terminal telopeptide of type I collagen (CTx). Total body and truncal fat mass were measured by DXA.

RESULTS

Free leptin (p>0.0001) and adiponectin (p=0.0002) were higher and lower in obese children respectively. OPG was lower in obese children (p=0.01), being inversely related to free leptin (p=0.009), total body and truncal fat mass (both p=0.01). RANKL was inversely related to free leptin in children with prior fracture (p=0.03). CTx was higher in obese children (p=0.003). Free leptin was positively associated with both CTx (p=0.03) and P1NP (p=0.02). DKK1 was inversely related to adiponectin (p=0.02).

CONCLUSIONS

Bone formation relative to resorption was reduced in obese children; this difference was accentuated in those with prior fracture. Adipokines may regulate these changes. Osteoprotegerin may play a fundamental role in the failure of obese children to accrue bone mass appropriately.

Obesity is associated with greater areal BMD (aBMD) and is considered protective against hip and vertebral fracture. Despite this, there is a higher prevalence of lower leg and proximal humerus fracture in obesity. We aimed to determine if there are site-specific differences in BMD, bone structure, or bone strength between obese and normal-weight adults. We studied 100 individually-matched pairs of normal (body mass index [BMI] 18.5 to 24.9 kg/m2) and obese (BMI >30 kg/m2) men and women, aged 25 to 40 years or 55 to 75 years. We assessed aBMD at the whole body (WB), hip (TH), and lumbar spine (LS) with dual-energy X-ray absorptiometry (DXA), LS trabecular volumetric BMD (Tb.vBMD) by quantitative computed tomography (QCT), and vBMD and microarchitecture and strength at the distal radius and tibia with high-resolution peripheral QCT (HR-pQCT) and micro-finite element analysis. Serum type 1 procollagen N-terminal peptide (P1NP) and collagen type 1 C-telopeptide (CTX) were measured by automated electrochemiluminescent immunoassay (ECLIA). Obese adults had greater WB, LS, and TH aBMD than normal adults. The effect of obesity on LS and WB aBMD was greater in older than younger adults (p < 0.01). Obese adults had greater vBMD than normal adults at the tibia (p < 0.001 both ages) and radius (p < 0.001 older group), thicker cortices, higher cortical BMD and tissue mineral density, lower cortical porosity, higher trabecular BMD, and higher trabecular number than normal adults. There was no difference in bone size between obese and normal adults. Obese adults had greater estimated failure load at the radius (p < 0.05) and tibia (p < 0.01). Differences in HR-pQCT measurements between obese and normal adults were seen more consistently in the older than the younger group. Bone turnover markers were lower in obese than in normal adults. Greater BMD in obesity is not an artifact of DXA measurement. Obese adults have higher BMD, thicker and denser cortices, and higher trabecular number than normal adults. Greater differences between obese and normal adults in the older group suggest that obesity may protect against age-related bone loss and may increase peak bone mass.

BACKGROUND

There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)2D] on bone health including turnover.

OBJECTIVE

The objective of the study was to determine the influence of 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.

METHODS

Men aged 40-79 years were recruited from population registers in 8 European centers. Subjects completed questionnaires that included questions concerning lifestyle and were invited to attend for quantitative ultrasound (QUS) of the heel, assessment of height and weight, and a fasting blood sample from which 1,25(OH)2D, 25(OH)D, and PTH were measured. 1,25(OH)2D was measured using liquid chromatography tandem mass spectrometry. Bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β-cTX) were also measured. Dual-energy x-ray absorptiometry (DXA) of the hip and lumbar spine was performed in 2 centers.

METHODS

QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.

RESULTS

A total of 2783 men, mean age 60.0 years (SD 11.0) were included in the analysis. After adjustment for age and center, 1,25(OH)2D was positively associated with 25(OH)D but not with PTH. 25(OH)D was negatively associated with PTH. After adjustment for age, center, height, weight, lifestyle factors, and season, 1,25(OH)2D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)2D was not correlated with P1NP. 25(OH)D was positively associated with the QUS and DXA parameters but not related to either bone turnover marker. Subjects with both high 1,25(OH)2D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.

CONCLUSIONS

Serum 1,25(OH)2D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health.

BACKGROUND

In mice, undercarboxylated osteocalcin (ucOC) modulates insulin secretion and sensitivity and increases testosterone (T) secretion from Leydig cells, but human data are lacking. We hypothesized that ucOC is associated with diabetes risk and modulates sex hormone concentrations in older men, distinct from other bone turnover markers.

METHODS

PARTICIPANTS were community-dwelling men aged 70 to 89 years resident in Perth, Western Australia.

METHODS

Serum total osteocalcin (TOC), N-terminal propeptide of type I collagen (P1NP), and collagen type I C-terminal cross-linked telopeptide (CTX) were measured by immunoassay, and ucOC by hydroxyapatite binding. Plasma total T, DHT, and estradiol (E2) were assayed by mass spectrometry.

RESULTS

Excluding men with osteoporosis or conditions affecting sex hormones or on bisphosphonates, glucocorticoids, or warfarin, 2966 men were included. In multivariate analyses, higher ucOC was associated with reduced diabetes risk (odds ratio [OR] per 1 SD increase = 0.55, P < .001). Similar results were seen for TOC (OR = 0.60, P < .001), P1NP (OR = 0.64, P < .001), and CTX (OR = 0.60, P < .001) but not ucOC/TOC. When all 4 markers were included in the fully adjusted model, higher ucOC (OR = 0.56, P < .001) and CTX (OR = 0.76, P = .008) remained associated with reduced diabetes risk. E2 was inversely associated with ucOC (coefficient -0.04, P = .031), TOC (-0.05, P = .001) and CTX (-0.04, P = .016); and positively with ucOC/TOC (0.05, P = .002). DHT was inversely associated with ucOC/TOC (-0.04, P = .040). T was not associated with bone turnover.

CONCLUSIONS

Higher bone remodeling rates are associated with reduced diabetes risk in older men. Higher ucOC is both a marker of bone remodeling and an independent predictor of reduced diabetes risk. E2 is inversely associated with bone turnover markers. We found no evidence ucOC modulates circulating T in older men.

Administration of blosozumab, a humanized monoclonal antibody that binds sclerostin, increases bone formation and bone mineral density (BMD) in postmenopausal women with low BMD. To evaluate the effect of discontinuing blosozumab, we studied women enrolled in a 1-year randomized, placebo-controlled phase 2 trial for an additional year after they completed treatment. Of the 120 women initially enrolled in the study, 106 women completed treatment and continued into follow-up; 88 women completed 1 year of follow-up. At the beginning of follow-up, groups remained balanced for age, race, and body mass index, but lumbar spine and total hip BMD were increased in prior blosozumab groups, reflecting an anabolic treatment effect. At the end of follow-up, 1 year after discontinuing treatment, lumbar spine BMD remained significantly greater than placebo in women initially treated with blosozumab 270 mg every 2 weeks (Q2W) and blosozumab 180 mg Q2W (6.9% and 3.6% above baseline, respectively). Total hip BMD also declined after discontinuation of treatment but at 1 year after treatment remained significantly greater than placebo in women initially treated with blosozumab 270 mg Q2W and blosozumab 180 mg Q2W (3.9% and 2.6% above baseline, respectively). During follow-up, median serum P1NP was not consistently different between the prior blosozumab groups and placebo. A similar pattern was apparent for median serum C-terminal telopeptide of type 1 collagen (CTx) levels, with more variability. Mean serum total sclerostin concentration increased with blosozumab, indicating target engagement, and declined to baseline after discontinuation. There were no adverse events considered related to prior treatment with blosozumab. Anti-drug antibodies generally declined in patients who had detectable levels during prior treatment. These findings support the continued study of blosozumab as an anabolic therapy for treatment of osteoporosis.

BACKGROUND

Strenuous exercise increases bone resorption but not formation. The effect of improved training status is unknown.

OBJECTIVE

Our objective was to examine the metabolic response of bone to strenuous running in recreationally active (RA) and endurance-trained (ET) men.

METHODS

Eleven RA, 10 ET, and 10 control (CON) subjects completed one 8-d trial. On d 4, RA and ET completed an exhaustive treadmill run. Blood was obtained at baseline (BASE), during exercise, during 2 h of recovery, and on four follow-up (FU) days (FU1-FU4). CON rested throughout, providing blood samples at BASE and on FU1-FU4. Markers of bone resorption [C-terminal telopeptide region of collagen type 1 (beta-CTX)] and bone formation [N-terminal propeptides of procollagen type 1 (P1NP) and bone alkaline phosphatase (ALP)], osteoprotegerin (OPG), PTH, albumin-adjusted calcium (ACa), and phosphate (PO4) were measured.

RESULTS

There were no significant differences between ET and RA and no changes in CON for any variable. Exercise increased beta-CTX at FU1-FU4 (P<0.001) but had no effect on P1NP or bone ALP. OPG was increased after 20 min of exercise (P<0.001) and remained elevated at FU1 (P<0.001). PTH, ACa, and PO4 were increased throughout exercise (P<0.01). ACa and PO4 remained elevated in the 2 h after exercise (P<0.001), whereas PTH was lower than BASE from 1-2 h after exercise (P<0.001).

CONCLUSIONS

After acute, exhaustive running, bone resorption but not formation was increased for 4 d in RA and ET men. The increased bone resorption might be related to the increase in PTH, whereas increased OPG might be a compensatory response to increased bone resorption. Training status did not significantly affect the metabolic response of bone to exhaustive running.