High-impact exercise stimulated localised adaptation of microarchitecture across distal tibia in postmenopausal women.

We provided evidence that a 6-month regular hopping exercise intervention can increase trabecular number and possibly trabecular volume fraction of the distal tibia. Our novel localised analysis demonstrated region-specific changes, predominantly in the anterior region, in postmenopausal women. INTRODUCTION: The localisation of bone remodelling and microarchitectural adaptation to exercise loading has not been demonstrated previously in vivo in humans. The aim of this study is to assess the feasibility of using 3D image registration and high-resolution peripheral quantitative computed tomography (HR-pQCT) to investigate the effect of high-impact exercise on human trabecular bone variables and remodelling rate across the distal tibia. METHODS: Ten postmenopausal women were recruited for 6-month unilateral hopping exercises, with HR-pQCT scans taken of both exercise leg (EL) and control leg (CL) for each participant before and after the intervention. A 3D image registration was used to ensure measurements were taken at the same region. Short-term reproducibility tests were conducted prior to the assessment using identical setup. The results were assessed comparing CL and EL, and interaction (time × leg) using a two-way repeated measures analysis of variance (RM-ANOVA). RESULTS: Across the whole tibia, we observed significant increases in trabecular number (Tb.N) (+ 4.4%) and trabecular bone formation rate (tBFR) (3.3%), and a non-significant increase in trabecular bone volume fraction (BV/TV) (+ 1%) in the EL. Regional resorption was higher in the CL than the EL, with this difference being statistically significant at the lateral tibia. In the EL, tBFR was significantly higher in the anterior region than the medial but a trabecular bone resorption rate (tBRR) showed no significant regional variation. Conversely in the CL, both tBFR and tBRR were significantly higher in the anterior and lateral than the medial region. CONCLUSION: We demonstrated that it was possible to detect exercise-related bone adaptation with 3D registration of HR-pQCT scan data. Regular hopping exercise increased Tb.N and possibly BV/TV across the whole distal tibia. A novel finding of the study was that tBFR and tBRR responses to loading were localised: changes were achieved by formation rate exceeding resorption rate in the exercise leg, both globally and at the anterior region where turnover was greatest. TRIAL REGISTRATION: clinicaltrials.gov : NCT03225703.

Quantitative computed tomography discriminates between postmenopausal women with low spine bone mineral density with vertebral fractures and those with low spine bone mineral density only: the SHATTER study.

Lumbar spine volumetric bone mineral density (BMD) measured using quantitative computed tomography (QCT) can discriminate between postmenopausal women with low areal BMD with and without vertebral fractures. QCT provides a 3D measure of BMD, excludes the vertebral posterior elements and accounts for bone size. This knowledge could contribute to effective treatment targeting of patients with low BMD. INTRODUCTION: We evaluated the ability of lumbar spine bone mineral apparent density (BMAD), trabecular bone score (TBS) and volumetric bone mineral density (vBMD) to discriminate between postmenopausal women with low areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) with and without vertebral fractures. The discriminatory ability of lumbar spine aBMD was compared with that of BMAD, TBS and vBMD. METHODS: We studied three groups of postmenopausal women, i.e. group 1, aBMD T-score < - 1.0 and ≥ 1 vertebral fracture (n = 39); group 2, aBMD T-score < - 1.0 and no vertebral fracture, age- and aBMD-matched to group 1 (n = 34); group 3, aBMD score > - 1 and no vertebral fracture, age-matched to group 1 (n = 37). Lumbar spine aBMD was measured by DXA. BMAD was calculated using the DXA scan results. TBS was derived following DXA scan image reanalysis. Lumbar spine vBMD was assessed by quantitative computed tomography and Mindways Pro software. Differences in variables between groups 1, 2 and 3 were examined using general linear univariate modelling approaches. Area under the receiver operating characteristic (ROC) curve was calculated for BMAD, TBS and vBMD to determine the ability of lumbar spine measurement variables to discriminate between group 1 and group 2. A comparison of ROCs was performed. RESULTS: Lumbar spine BMAD and TBS measurement variables were similar for groups 1 and 2. However, vBMD was significantly lower in group 1 and could discriminate between those women with low aBMD with (group 1) and without vertebral fractures (group 2). CONCLUSIONS: We conclude that lumbar spine vBMD may discriminate well between postmenopausal women with low aBMD with and without vertebral fractures as it provides a 3D measure of bone mineral density, excludes the posterior elements of the vertebrae and takes into account bone size. A unique feature of the SHATTER study is that groups 1 and 2 were matched for aBMD, thus our study findings are independent of aBMD. Furthermore, we observed that neither BMAD nor TBS could distinguish between women with low aBMD with and without vertebral fractures. The knowledge gained from the SHATTER study will influence clinical and therapeutic decision-making, thereby optimising the care of patients with and without vertebral and other fragility fractures.

Clinical utility of bone turnover markers in monitoring the withdrawal of treatment with oral bisphosphonates in postmenopausal osteoporosis.

Bone markers may be useful to monitor response to treatment withdrawal in osteoporosis. We used two criteria for investigating the change in BTMs after withdrawal of bisphosphonate treatment. A larger increase in BTMs was associated with greater bone loss. Bone markers may be useful in monitoring of patients taking a pause from treatment. INTRODUCTION: Measurement of bone turnover markers (BTMs) may be useful to monitor offset of treatment with bisphosphonates (BP) in osteoporosis. We assessed the effect of withdrawal of BP treatment by comparing the changes in BTMs and total hip (TH) bone density (BMD). METHODS: We studied postmenopausal osteoporotic women who had completed a randomised study of three oral BPs. After 2 years of treatment, participants with BMD T-score > - 2.5 and in whom it was considered clinically appropriate to discontinue treatment, were invited to participate in a further 2-year observational study. Biochemical response was assessed using BTMs (CTX and PINP) with offset being defined by two criteria: (1) an increase greater than the least significant change (LSC) and (2) an increase above the reference mean value. RESULTS: Fifty women completed the study. At 48 weeks after stopping BPs, CTX was greater than the LSC for 66% of women and PINP 72%; CTX was above the reference mean for 64% of women and PINP 42%. The decrease in THBMD was greater for women with the largest increase in BTM compared to those with continued suppression (mean difference for CTX was - 2.98%, 95%CI - 4.75 to - 1.22, P < 0.001, PINP - 2.25%, 95% CI - 4.46 to - 0.032, P = 0.046). CONCLUSION: The measurement of BTM after withdrawal of BPs is potentially useful to evaluate patients that are taking a pause from treatment. An increase in BTMs more than the LSC and/or reference mean reflects loss of treatment effect and identifies patients that are likely to have a decrease in BMD. Such changes could provide an indication for reintroduction of treatment.

Teriparatide treatment exerts differential effects on the central and peripheral skeleton: results from the MOAT study.

The central and peripheral skeleton was characterised using imaging techniques during 104 weeks of teriparatide treatment. Teriparatide exerts differential effects on the central and the peripheral skeleton. Overall, we did not observe a change in total body bone mineral. Our conclusions are constrained by the study limitations. INTRODUCTION: Teriparatide stimulates bone formation and resorption and therefore can cause bone gain and loss. We simultaneously characterised the central and peripheral skeleton using imaging techniques to better understand the mechanism of action of teriparatide. METHODS: Postmenopausal, osteoporotic women (n = 20, 65.4 ± 5.5 years) were recruited into a 104-week study of teriparatide. Imaging techniques included DXA, quantitative computed tomography (QCT), and high-resolution peripheral quantitative computed tomography (HR-pQCT). RESULTS: Total lumbar spine areal bone mineral content (aBMC) (+ 11.2%), total lumbar spine areal bone mineral density (aBMD) (+ 8.1%), subregional thoracic spine aBMD (+ 7.5%), lumbar spine aBMC (+ 23.5%), lumbar spine aBMD (+ 11.9%), pelvis aBMC (+ 9.3%), and pelvis aBMD (+ 4.3%) increased. However, skull aBMC (- 5.0%), arms aBMC (- 5.1%), legs aBMC (- 2.9%), and legs aBMD (- 2.5%) decreased. Overall, we did not observe a change in total body bone mineral. Increases in L1-L3 volumetric BMD (vBMD) (+ 28.5%) occurred but there was no change in total proximal femur vBMD. Radius and tibia cortical vBMD (- 3.3 and - 3.4%) and tissue mineral density (- 3.2 and - 3.8%) decreased and there was an increase in porosity (+ 21.2 and + 10.3%). Tibia, but not radius, trabecular inhomogeneity (+ 3.2%), and failure load (+ 0.2%) increased, but cortical thickness (- 3.1%), area (- 2.9%), and pore volume (- 1.6%) decreased. CONCLUSIONS: Teriparatide exerts differential effects on the central and the peripheral skeleton. Central trabecular vBMD (L1-L3) is improved, but there is a concomitant decrease in peripheral cortical vBMD and an increase in porosity. Overall, we did not observe a change in total body bone mineral. We acknowledge that our conclusions may be speculative and are constrained by the technical limitations of the imaging techniques used, the lack of a control group, and the small sample size studied.

Effects of discontinuing oral bisphosphonate treatments for postmenopausal osteoporosis on bone turnover markers and bone density.

The antiresorptive potency varies between different bisphosphonates. We investigated the effect of stopping oral bisphosphonate treatment for postmenopausal osteoporosis (ibandronate, alendronate, risedronate) on BTMs and BMD. After stopping treatment, all three groups showed an increase in BTMs and a decrease in hip BMD; however, none returned to pre-treatment baseline values. INTRODUCTION: Bisphosphonates (BPs) continue to suppress bone turnover markers (BTMs) after treatment has stopped, leading to the suggestion that a pause in treatment could be considered for low-risk patients. Indirect comparisons suggest that after cessation of treatment, the effects on bone may differ between drugs. We investigated the effects of stopping oral BP treatments for postmenopausal osteoporosis on BTMs and bone mineral density (BMD). METHODS: We studied postmenopausal osteoporotic women who had previously taken part in a 2-year randomised study of three oral BPs (ibandronate, alendronate, or risedronate). At the end of the study, women with hip BMD T-score > - 2.5 and considered clinically appropriate to discontinue treatment were invited to participate in a further 2-year observational study. Biochemical response was assessed using BTMs, and BMD was measured by dual-energy X-ray absorptiometry. RESULTS: All BTMs increased after treatment withdrawal but remained below the pre-treatment baseline with less suppression of BTMs for the risedronate group compared to alendronate and ibandronate up to 48 weeks. There was no difference between the BP groups 96 weeks after stopping treatment. The change in BMD during the 96 weeks after stopping treatment was - 1.6% (95% CI - 1.9 to - 1.2, P < 0.001) for the total hip and - 0.6% (95% CI - 1.1 to - 0.2, P = 0.17) at the lumbar spine with no difference between the three BP groups (P = 0.85 and P = 0.48, respectively). CONCLUSION: For all treatment groups, there was an increase in BTMs and a decrease in hip BMD after stopping BPs for 2 years; however, none returned to pre-treatment baseline values.

The impact of glucocorticoid therapy on trabecular bone score in older women.

UNLABELLED: We propose that trabecular bone score could be a useful tool for the study of glucocorticoid-associated bone effects. Trabecular bone score alone and lumbar spine bone mineral density (BMD) used in combination with trabecular bone score, but not lumbar spine BMD alone was able to discriminate between glucocorticoid-treated and glucocorticoid-naïve women. INTRODUCTION: Glucocorticoids result in rapid bone loss and an increase in fracture risk that cannot be fully explained by changes in BMD. Trabecular bone score (TBS) correlates with three-dimensional bone micro-architectural parameters and can be derived from grey-level variations within dual energy X-ray absorptiometry (DXA) scans. We propose that TBS could be a useful tool for the study of glucocorticoid-associated bone effects. METHODS: We assessed the ability of lumbar spine BMD (LS-BMD), TBS, and LS-BMD with TBS (LS-BMD + TBS) to discriminate between healthy women and (i) glucocorticoid-treated women, and (ii) glucocorticoid-naïve women with recent fractures. Older women (n = 484, ages 55-79 years) who had (i) taken prednisolone ≥5 mg/day for >3 months (n = 64), (ii) sustained a recent fracture of the distal forearm (n = 46), proximal humerus (n = 37), vertebra (n = 30) or proximal femur (n = 28), or (iii) were healthy population-based women (n = 279) were recruited. LS-BMD was measured by DXA and TBS values were derived. RESULTS: Compared to healthy, population-based women, women with recent fractures had lower LS-BMD (-0.34 to -1.38) and TBS (-0.38 to -1.04) Z-scores. Glucocorticoid-treated women had lower TBS Z-scores than glucocorticoid-naïve women (-0.80 versus 0) but their LS-BMD Z-scores did not differ (-0.13 versus 0). TBS alone (area under the receiver operating characteristic curve (AUC) = 0.721) and LS-BMD + TBS (AUC = 0.721), but not LS-BMD alone (AUC = 0.572) was able to discriminate between glucocorticoid-treated and glucocorticoid-naïve women. CONCLUSIONS: TBS provides additional information regarding glucocorticoid-associated alterations in bone quality. We conclude that TBS may be a useful tool for the further study of glucocorticoid-induced osteoporosis.

Comparison of the effects of three oral bisphosphonate therapies on the peripheral skeleton in postmenopausal osteoporosis: the TRIO study.

UNLABELLED: We compared the effects of oral alendronate, ibandronate and risedronate on the central and peripheral skeleton over 2 years. We report differences in effect on the central skeleton but not on the peripheral skeleton. Greater effects were observed for ibandronate (and alendronate) than risedronate at the spine but not the hip. INTRODUCTION: Generally, comparative clinical trials of bisphosphonates have examined changes in bone within central skeletal regions. We have examined the effects of bisphosphonate treatment on the peripheral skeleton. METHODS: We conducted a 2-year, open-label, parallel randomised control trial of three orally administered bisphosphonates, at their licensed dose, to examine and compare their effects on the peripheral skeleton using multiple modes of measurement. We studied 172 postmenopausal women (53-84 years) who had either a bone mineral density (BMD) T-score of ≤ -2.5 at the spine and/or total hip or < -1.0 at either site plus a previous low trauma fracture. Participants were randomised to receive either (i) ibandronate 150 mg/month, (ii) alendronate 70 mg/week or (iii) risedronate 35 mg/week, plus calcium (1,200 mg/day) and vitamin D (800 IU/day), for 2 years. Premenopausal women (33-40 years, n = 226) were studied to monitor device stability. RESULTS: We measured central BMD of the lumbar spine, total hip, total body and forearm using dual-energy X-ray absorptiometry. We measured calcaneus BMD (using dual-energy X-ray absorptiometry plus laser), radius and tibia BMD (using peripheral quantitative computed tomography), finger BMD (using radiographic absorptiometry), and phalangeal and calcaneal ultrasound variables (using quantitative ultrasound). Mixed effects regression models were used to evaluate effects of time and treatment allocation on BMD change. By 2 years, there were significant increases (p < 0.05) in central BMD sites (lumbar spine, total hip). In the peripheral skeleton, only significant changes in calcaneus BMD, 33 % total radius BMD and quantitative ultrasound (QUS)-2 broadband ultrasound attenuation (BUA) were evident for women receiving oral bisphosphonates. CONCLUSIONS: The increases in lumbar spine and total body BMD were greater with ibandronate and alendronate than with risedronate. Treatment effects on peripheral measurements did not differ between the three bisphosphonates.

Adherence to raloxifene therapy: assessment methods and relationship with efficacy.

UNLABELLED: Response to therapy depends on patient compliance but accurate assessment is difficult and adequate levels of adherence are uncertain. Adherence to raloxifene treatment may be assessed more accurately by electronic monitoring than by counting returned tablets. The level of adherence is positively associated with the degree of bone response. INTRODUCTION: Adherence to study medication is usually estimated by counting returned tablets. This method relies on subjects' honesty and may be inaccurate. We aimed to assess adherence more accurately, and examine its effect on measures of bone response, by using electronic monitoring. METHODS: Osteopenic women, ages 50 to 80, were prescribed daily raloxifene for 2 years. Electronic bottle caps (Medication Event Monitoring System (MEMS), Aardex) recorded the date and time on opening. Returned tablets were also counted. We measured bone mineral density (BMD) in duplicate at the spine and hip at baseline and 2 years. We also measured urinary N-terminal cross-linked telopeptide of type I collagen (NTX) at baseline, 1 and 2 years. We calculated the percentage changes in BMD and NTX from mean baseline to mean follow up measurements. Percentage adherence was assessed by both methods for 71 subjects that completed the study. RESULTS: The two methods correlated significantly (p <0.001, Spearman's rho = 0.73) but the tablet count showed a higher median adherence than the MEMS caps (95.7 vs. 85.0%, p <0.001), with greater divergence at lower adherence levels. MEMS adherence in 65 subjects with complete data correlated with NTX response (p <0.01, rho = -0.33) but with BMD response only at the femoral neck. However, adherence in the lowest quartile was associated with poorer BMD response at all sites (p <0.05). CONCLUSION: Tablet counts may give similar results overall but conceal substantial individual non-adherence. Monitoring caps may assess adherence more accurately than tablet counts and would be the preferred method in clinical trials. The degree of adherence is associated with both bone turnover and BMD responses to anti-resorptive therapy.

A European multicenter comparison of quantitative ultrasound measurement variables: the OPUS study.

UNLABELLED: Quantitative ultrasound (QUS) measurement variables vary between European countries in a different way to hip bone mineral density. Standardization of data can be achieved through statistical approaches to reduce any between-center differences in QUS measurement variables. However, further validation of this method is required before it can be widely applied. INTRODUCTION: European between-center differences in hip bone mineral density (BMD) have been shown to exist; however, little is known about the geographical heterogeneity of QUS measurement variables. We aimed to examine the differences in QUS variables between three different European countries. METHODS: Five calcaneal and phalangeal QUS devices in Sheffield, Aberdeen (UK), Kiel and Berlin (Germany), and three devices in Paris (France) were used to measure QUS variables in younger (n = 463, 20-39 years old) and older (n = 2,399, 55-79 years old) women participating in the European multicenter Osteoporosis and Ultrasound (OPUS) study. Broadband ultrasound attenuation, speed of sound, stiffness index, amplitude-dependent speed of sound, bone transmission time, and ultrasonic bone profiler index data were collected. Between-center differences were examined using ANOVA followed by post hoc Fisher's least significant difference tests, and ANCOVA with linear contrasts. p < 0.05 indicated statistical significance. RESULTS: Between-center differences in nonstandardized QUS measurement variables existed for younger (p = 0.0023 to p < 0.0001) and older women (p < 0.001). Anthropometric characteristics exerted a significant influence on nonstandardized data (p = 0.045 to p < 0.001). However, following statistical standardization, based on height and weight or based on measurements made in young people, geographical heterogeneity in QUS measurement variables was no longer apparent. CONCLUSIONS: QUS measurement variables vary between European countries in a different way to those for hip BMD. Standardization of data can be achieved through statistical approaches to reduce any between-center differences in QUS measurement variables. However, further validation of this method is required before it can be widely applied.

International variation in proximal femur bone mineral density.

UNLABELLED: We observed higher proximal femur bone mineral density (BMD) in European women compared to average values derived from US Caucasian women in the National Health and Nutrition Examination Survey (NHANES) study. Across European centres, Parisian women had lower proximal femur BMD compared to women from Kiel or Sheffield. INTRODUCTION: Proximal femur BMD of US adults (NHANES III) may not accurately reflect that of European women. We examined the heterogeneity of BMD across European and US Caucasian women and across different European populations. METHODS: Proximal femur BMD was measured in women ages 20-39 years (n=258) and 55-79 years (n=1,426) from three European centres. Cross-calibrated BMD for total hip, femoral neck, trochanter and intertrochanter were examined. International variation in BMD was assessed by comparing means and SDs in the European data with those from the US NHANES III study. European populations were stratified into 5-year age bands to establish individual centre reference intervals. Between-centre differences were assessed using ANOVA and post hoc Fisher's least significant difference tests. RESULTS: European women had higher BMD than US women: The differences were 7.1% to 14.2% (p<0.001) and 0% to 3.9% (p<0.05) in the older and younger women, respectively. Standard deviations for BMD at the different sites were comparable to those for US women. Among older, but not younger European women, proximal femur BMD was significantly lower in French women (Paris) than in women from Germany (Kiel) or the UK (Sheffield) (difference=5.0% to 9.6%, p<0.05). CONCLUSIONS: International variation in hip BMD does exist, with international and between-centre differences being less evident at the femoral neck.

The effect of bisphosphosphonates on bone turnover and bone balance in postmenopausal women with osteoporosis: The T-score bone marker approach in the TRIO study.

Postmenopausal osteoporosis is characterised by increased bone turnover and an imbalance between bone resorption and formation. Bisphosphonate treatment reduces bone turnover but their effect on bone balance is yet to be fully investigated. Using the T-score approach our aims were to: i) investigate the effects of oral nitrogen-containing bisphosphonates on bone balance and turnover in postmenopausal women with osteoporosis and ii) determine the relationship of the change in bone balance and turnover with the change in BMD at the lumbar spine and total hip. Women were recruited, mean age 67 years, and randomised to receive: ibandronate (n = 55, 150 mg/month), alendronate (n = 54, 70 mg/week) or risedronate (n = 56, 35 mg/week). They also received calcium and vitamin D daily. A fasting serum sample was collected at baseline and weeks 1, 2, 4, 12, 13, 48 and 96. The control group were 226 healthy premenopausal women receiving no treatments. PINP and CTX were measured using the iSYSIDS analyser and BMD (in g/cm2) of the lumbar spine and total hip were measured by DXA (Hologic Inc). PINP and CTX values were log10-transformed and normalised. T-scores were calculated using the mean and standard deviation from the premenopausal group. Bone turnover and bone balance were calculated from the T-scores. Mean levels (95% CI) of balance and turnover are shown in the table. The change in turnover at weeks 4, 12 and 48 was inversely correlated with the change in lumbar spine and total hip BMD at weeks 48 and 96, (p < .01 to p < .001). The change in balance at week 4 positively correlated with the change in total hip BMD at weeks 48, (p < .01). Bisphosphonates resulted in an initial positive balance and a reduction in turnover. Some of these changes were associated with increases in BMD. Bone turnover is a better predictor of BMD than bone balance.

The effect of cessation of raloxifene treatment on bone turnover in postmenopausal women.

There is evidence to suggest accelerated bone loss following estrogen cessation. The effect of cessation of raloxifene therapy on bone turnover is unknown. Our aim was to determine the effect of cessation of raloxifene treatment on bone turnover and bone mineral density (BMD) in postmenopausal, osteopenic women. Women aged 50 to 80 years received raloxifene for 96 weeks and were then randomized to continue raloxifene (group 1, n=20) or placebo (group 2, n=20) for a further 96 weeks. A third group (group 3, n=14) received no treatment. Bone turnover markers and bone density (BMD) were measured throughout the study. Raloxifene treatment for 96 weeks resulted in a decrease in bone turnover (PINP by 31%) and an increase in spine BMD (by 2%) but no change in hip BMD for groups 1 and 2. Continuation of raloxifene (group 1) maintained these changes. Following cessation of raloxifene (group 2), bone markers returned to baseline levels (by 120 weeks). Hip BMD was decreased by 2% at 192 weeks compared to baseline. Bone markers in the controls (group 3) remained at the upper limit of the reference range throughout, with decreases in BMD of 2.3% (spine) and 2.8% (hip). Bone loss following cessation of raloxifene therapy at 96 weeks was greater than in the control group, suggesting accelerated bone loss. The beneficial effect on bone turnover of 96 weeks of raloxifene was lost 6 months after cessation of treatment.