We hypothesised that strict inactivity (bed rest) would lead to regional differences in fat deposition. Twenty-four male subjects underwent 60 d bed rest and remained inactive (n = 9), performed ...resistance exercise plus whole-body vibration (RVE; n = 7) or resistance exercise only (RE; n = 8). Fat mass was assessed via dual X-ray absorptiometry. In the inactive subjects, fat deposition differed between body regions (P = 0.0005) with android region visceral adipose tissue increasing the most (+29% at the end of bed rest), followed by remainder of the trunk (from chin to the iliac crest; +10%) and the arms and legs (both +7%). Insulin sensitivity reduced in the inactive subjects at the end of bed rest (P = 0.036). RE did not have a significant impact on regional fat mass changes (P ⩾ 0.055). In RVE, increases in visceral adipose tissue (-14%; P = 0.028 vs inactive subjects) and in the arms (arms -8%, P = 0.011 vs inactive) were not seen. We conclude that inactivity leads to a preferential increase in visceral adipose tissue.
Summary
The addition of whole-body vibration to high-load resistive exercise may provide a better stimulus for the reduction of bone loss during prolonged bed rest (spaceflight simulation) than ...high-load resistive exercise alone.
Introduction
Prior work suggests that the addition of whole-body vibration to high-load resistive exercise (RVE) may be more effective in preventing bone loss in spaceflight and its simulation (bed rest) than resistive exercise alone (RE), though this hypothesis has not been tested in humans.
Methods
Twenty-four male subjects as part of the 2nd Berlin Bed Rest Study performed RVE (
n
= 7), RE (
n
= 8) or no exercise (control,
n
= 9) during 60-day head-down tilt bed rest. Whole-body, spine and total hip dual X-ray absorptiometry (DXA) measurements as well as peripheral quantitative computed tomography measurements of the tibia were conducted during bed rest and up to 90 days afterwards.
Results
A better retention of bone mass in RVE than RE was seen at the tibial diaphysis and proximal femur (
p
≤ 0.024). Compared to control, RVE retained bone mass at the distal tibia and DXA leg sub-region (
p
≤ 0.020), but with no significant difference to RE (
p
≥ 0.10). RE impacted significantly (
p
= 0.038) on DXA leg sub-region bone mass only. Calf muscle size was impacted similarly by both RVE and RE. On lumbar spine DXA, whole-body DXA and calcium excretion measures, few differences between the groups were observed.
Conclusions
Whilst further countermeasure optimisation is required, the results provide evidence that (1) combining whole-body vibration and high-load resistance exercise may be more efficient than high-load resistive exercise alone in preventing bone loss at some skeletal sites during and after prolonged bed rest and (2) the effects of exercise during bed rest impact upon bone recovery up to 3 months afterwards.
Context:
Strontium ranelate reduces vertebral and nonvertebral fracture risk in postmenopausal osteoporosis.
Objective:
The objective of this study was to determine the efficacy and safety of ...strontium ranelate in osteoporosis in men over 2 years (main analysis after 1 year).
Design:
This was an international, unbalanced (2:1), double-blind, randomized placebo-controlled trial (MALEO MALE Osteoporosis).
Setting:
This international study included 54 centers in 14 countries.
Participants:
Participants were 261 white men with primary osteoporosis.
Intervention:
Strontium ranelate at 2 g/d (n = 174) or placebo (n = 87) was administered.
Main Outcome Measures:
Lumbar spine (L2–L4), femoral neck, and total hip bone mineral density (BMD), biochemical bone markers, and safety were measured.
Results:
Baseline characteristics were similar in both groups in the whole population (age, 72.9 ± 6.0 years; lumbar spine BMD T-score, −2.7 ± 1.0; femoral neck BMD T-score, −2.3 ± 0.7). Men who received strontium ranelate over 2 years had greater increases in lumbar spine BMD than those who received placebo (relative change from baseline to end, 9.7% ± 7.5% vs 2.0% ± 5.5%; between-group difference estimate (SE), 7.7% (0.9%); 95% confidence interval, 5.9%–9.5%; P < .001). There were also significant between-group differences in relative changes in femoral neck BMD (P < .001) and total hip BMD (P < .001). At the end of treatment, mean levels of serum cross-linked telopeptides of type I collagen, a marker of bone resorption, were increased in both the strontium ranelate group (10.7% ± 58.0%; P = .022) and the placebo group (34.9% ± 65.8%; P < .001). The corresponding mean changes of bone alkaline phosphatase, a marker of bone formation, were 6.4% ± 28.5% (P = .005) and 1.9% ± 25.4% (P = .505), respectively. After 2 years, the blood strontium level (129 ± 66 μmol/L) was similar to that in trials of postmenopausal osteoporosis. Strontium ranelate was generally well tolerated.
Conclusions:
The effects of strontium ranelate on BMD in osteoporotic men were similar to those in postmenopausal osteoporotic women, supporting its use in the treatment of osteoporosis in men.
Abstract A potential side effect associated with bisphosphonates, a class of drugs used in the treatment of osteoporosis, Paget's disease and metastatic bone disease, is osteonecrosis of the jaw ...(ONJ). The incidence of ONJ in the general population is unknown; this rare condition also may occur in patients not receiving bisphosphonates. Case reports have discussed ONJ development in patients with multiple myeloma or metastatic breast cancer receiving bisphosphonates as palliation for bone metastases. These patients are also receiving chemotherapeutic agents that might impair the immune system and affect angiogenesis. The incidence or prevalence of ONJ in patients taking bisphosphonates for osteoporosis seems to be very rare. No causative relationship has been unequivocally demonstrated between ONJ and bisphosphonate therapy. A majority of ONJ occurs after tooth extraction. Furthermore, the underlying risk of developing ONJ may be increased in osteoporotic patients by comorbid diseases. Treatment for ONJ is generally conservative.
Summary
Long-term bone mineral density (BMD) gains, bone marker levels, and safety of 3 mg quarterly intravenous (IV) ibandronate were studied in this 3-year extension to the Dosing IntraVenous ...Administration (DIVA) trial. Quarterly IV ibandronate consistently increased lumbar spine bone mineral density measured with dual-energy X-ray absorptiometry (DXA-BMD) over 5 years (8.1%) and was well tolerated in women with postmenopausal osteoporosis.
Introduction
Treatment with IV ibandronate regimens, 2 mg bimonthly and 3 mg quarterly, has been studied for up to 5 years in a long-term extension (LTE) to the 2-year DIVA trial.
Methods
DIVA LTE is an open-label extension to a 2-year randomized, double-blind, double-dummy, noninferiority, phase III study (DIVA core). DIVA LTE involved postmenopausal women who had completed 2 years of DIVA core, comparing daily oral and IV ibandronate (≥75% adherence with IV ibandronate in year 2 of DIVA). Patients previously treated with 2 mg bimonthly or 3 mg quarterly IV ibandronate continued on the same regimen; patients who had received 2.5 mg daily oral ibandronate and placebo IV in DIVA core were switched to IV ibandronate.
Results
Pooled analysis of 497 intent-to-treat (ITT) patients receiving IV ibandronate from DIVA core baseline showed consistent increases over 5 years in lumbar spine DXA-BMD (8.4% 95% confidence interval (CI) = 7.5, 9.3 with 2 mg bimonthly and 8.1% 95% CI = 7.2, 8.9 with 3 mg quarterly). Three-year data relative to DIVA LTE baseline in the full ITT population (756 patients randomized or reallocated from DIVA, including those previously on daily treatment) showed maintenance of DXA-BMD gains from DIVA core with further gains in lumbar spine DXA-BMD. These benefits are supported by sustained reductions in markers of bone metabolism. No tolerability concerns or new safety signals were observed.
Conclusions
Treatment with IV ibandronate 2 mg bimonthly or 3 mg quarterly is effective and well tolerated for up to 5 years in women with postmenopausal osteoporosis.
Muscle atrophy and bone loss pose substantial problems for long-term space flight and in clinical immobilization. We therefore tested the efficacy of flywheel resistive exercise and pamidronate to ...counteract such losses.
Twenty five young healthy males underwent strict bed rest with −6° head-down tilt for 90 days. Subjects were randomized into an exercise group that practiced resistive exercise with a ‘flywheel’ (FW) device every 2–3 days, a pamidronate group (Pam) that received 60 mg pamidronate i.v. 14 days prior to bed rest and a control group (Ctrl) that received none of these countermeasures.
During the study, Ca
++ and protein intake were controlled. Peripheral quantitative computed tomography (pQCT) was used to assess bone mineral content (BMC) and muscle cross sectional area (mCSA) of calf and forearm. Measurements were taken twice during baseline data collection, after 28 and after 89 days bed rest, and after 14 days recovery. On the same days, urinary Pyridinoline excretion and serum levels of alkaline phosphatase, Ca
++ and PTH were measured. Pre-study exercise habits were assessed through the Freiburg questionnaire.
Losses in calf mCSA were significantly reduced in FW (Ctrl: −25.6% ± 2.5% Pam: −25.6% ± 3.7%, FW: −17.3% ± 2.7%), but not in the forearm mCSA (Ctrl: −6.4% ± 4.33%, Pam: −7.7% ± 4.1%, FW: −7.6% ± 3.3%). Both diaphyseal and epiphyseal BMC losses of the tibia were mitigated in Pam and FW as compared to Ctrl, although this was significant only at the diaphysis.
Inter-individual variability was significantly greater for changes in BMC than in mCSA, and correlation of BMC losses was poor among different locations of the tibia. A significant
positive correlation was found between change in tibia epiphyseal BMC and serum cortisol levels.
These findings suggest that both countermeasures are only partly effective to preserve BMC (FW and Pam) and mCSA (FW) of the lower leg during bed rest. The partial efficacy of flywheel exercise as well as the bones' response to unloading per se underlines the importance of mechanical stimuli. The huge variability of BMC changes, however, suggests that other factors affect changes in whole-bone strength following acute mechanical disuse.
Summary During and after prolonged bed rest, changes in bone metabolic markers occur within 3 days. Resistive vibration exercise during bed rest impedes bone loss and restricts increases in bone ...resorption markers whilst increasing bone formation. Introduction To investigate the effectiveness of a resistive vibration exercise (RVE) countermeasure during prolonged bed rest using serum markers of bone metabolism and whole-body dual X-ray absorptiometry (DXA) as endpoints. Methods Twenty healthy male subjects underwent 8 weeks of bed rest with 12 months follow-up. Ten subjects performed RVE. Blood drawings and DXA measures were conducted regularly during and after bed rest. Results Bone resorption increased in the CTRL group with a less severe increase in the RVE group (p = 0.0004). Bone formation markers increased in the RVE group but decreased marginally in the CTRL group (p < 0.0001). At the end of bed rest, the CTRL group showed significant loss in leg bone mass (−1.8(0.9)%, p = 0.042) whereas the RVE group did not (−0.7(0.8)%, p = 0.405) although the difference between the groups was not significant (p = 0.12). Conclusions The results suggest the countermeasure restricts increases in bone resorption, increased bone formation, and reduced bone loss during bed rest.
Summary
In an open-label extension study, BMD increased continuously with strontium ranelate over 10 years in osteoporotic women (
P
< 0.01). Vertebral and nonvertebral fracture incidence was lower ...between 5 and 10 years than in a matched placebo group over 5 years (
P
< 0.05). Strontium ranelate's antifracture efficacy appears to be maintained long term.
Introduction
Strontium ranelate has proven efficacy against vertebral and nonvertebral fractures, including hip, over 5 years in postmenopausal osteoporosis. We explored long-term efficacy and safety of strontium ranelate over 10 years.
Methods
Postmenopausal osteoporotic women participating in the double-blind, placebo-controlled phase 3 studies SOTI and TROPOS to 5 years were invited to enter a 5-year open-label extension, during which they received strontium ranelate 2 g/day (
n
= 237, 10-year population). Bone mineral density (BMD) and fracture incidence were recorded, and FRAX® scores were calculated. The effect of strontium ranelate on fracture incidence was evaluated by comparison with a FRAX®-matched placebo group identified in the TROPOS placebo arm.
Results
The patients in the 10-year population had baseline characteristics comparable to those of the total SOTI/TROPOS population. Over 10 years, lumbar BMD increased continuously and significantly (
P
< 0.01 versus previous year) with 34.5 ± 20.2% relative change from baseline to 10 years. The incidence of vertebral and nonvertebral fracture with strontium ranelate in the 10-year population in years 6 to 10 was comparable to the incidence between years 0 and 5, but was significantly lower than the incidence observed in the FRAX®-matched placebo group over 5 years (
P
< 0.05); relative risk reductions for vertebral and nonvertebral fractures were 35% and 38%, respectively. Strontium ranelate was safe and well tolerated over 10 years.
Conclusions
Long-term treatment with strontium ranelate is associated with sustained increases in BMD over 10 years, with a good safety profile. Our results also support the maintenance of antifracture efficacy over 10 years with strontium ranelate.
In this study we sought to determine whether a Titin peptide fragment can serve as a clinical biomarker for changes in muscle mass.
Mass spectrometry was used to identify Titin fragment in urine. An ...antibody against this Titin sequence was raised and used to develop a competitive ELISA assay for measurement in serum. Rat tissue extractions in the presence or absence of a series of proteases of interest were used to identify its enzymatic origin. A rat model of dexamethasone (DEX) induced muscle atrophy and a human 56-day bed rest study with and without vibration therapy were used to assess biological and clinical relevance.
A technically robust ELISA measuring the Titin fragment was developed against a Titin peptide fragment identified in human urine. The fragment was shown to be produced primarily by MMP-2 cleavage of Titin. In the rat muscle DEX induced atrophy model, Titin-MMP2 fragment was decreased in the beginning of DEX treatment, and then significantly increased later on during DEX administration. In the human bed rest study, the Titin-MMP2 fragment was initially decreased 11.9 (±3.7) % after 1day of bed rest, and then gradually increased ending up at a 16.4 (±4.6) % increase at day 47.
We developed a robust ELISA measuring a muscle derived MMP-2 generated Titin degradation fragment in rat and human serum. Importantly, the fragment can be measured in serum and that these levels are related to induction of skeletal muscle atrophy.
•A Titin fragment was identified in human urine.•The Titin fragment was shown to be produced primarily by MMP-2 cleavage.•Titin-MMP2 fragment had higher expression in rat extensor digitorum longus muscle.•Titin-MMP2 decreased initially and gradually increased in muscle atrophy studies.
Summary
Strontium ranelate appears to influence more than alendronate distal tibia bone microstructure as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), and ...biomechanically relevant parameters as assessed by micro-finite element analysis (μFEA), over 2 years, in postmenopausal osteoporotic women.
Introduction
Bone microstructure changes are a target in osteoporosis treatment to increase bone strength and reduce fracture risk.
Methods
Using HR-pQCT, we investigated the effects on distal tibia and radius microstructure of strontium ranelate (SrRan; 2 g/day) or alendronate (70 mg/week) for 2 years in postmenopausal osteoporotic women. This exploratory randomized, double-blind trial evaluated HR-pQCT and FEA parameters, areal bone mineral density (BMD), and bone turnover markers.
Results
In the intention-to-treat population (
n
= 83, age: 64 ± 8 years; lumbar T-score: −2.8 ± 0.8 DXA), distal tibia Cortical Thickness (CTh) and Density (DCort), and cancellous BV/TV increased by 6.3%, 1.4%, and 2.5%, respectively (all
P
< 0.005), with SrRan, but not with alendronate (0.9%, 0.4%, and 0.8%, NS) (
P
< 0.05 for all above between-group differences). Difference for CTh evaluated with a distance transformation method was close to significance (
P
= 0.06). The estimated failure load increased with SrRan (+2.1%,
P
< 0.005), not with alendronate (−0.6%, NS) (between-group difference,
P
< 0.01). Cortical stress was lower with SrRan (
P
< 0.05); both treatments decreased trabecular stress. At distal radius, there was no between-group difference other than DCort (
P
< 0.05). Bone turnover markers decreased with alendronate; bALP increased (+21%) and serum-CTX-I decreased (−1%) after 2 years of SrRan (between-group difference at each time point for both markers,
P
< 0.0001). Both treatments were well tolerated.
Conclusions
Within the constraints of HR-pQCT method, and while a possible artefactual contribution of strontium cannot be quantified, SrRan appeared to influence distal tibia bone microstructure and FEA-determined biomechanical parameters more than alendronate. However, the magnitude of the differences is unclear and requires confirmation with another method.
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