Prolonged bone health benefits for breast cancer patients following adjuvant bisphosphonate therapy: the BoHFAB study.

Adjuvant bisphosphonates are often recommended in postmenopausal women with early breast cancer at intermediate-to-high risk of disease recurrence, but the magnitude and duration of their effects on bone mineral density (BMD) and bone turnover markers (BTMs) are not well described. We evaluated the impact of adjuvant zoledronate on areal BMD and BTMs in a sub-group of patients who had completed the large 5-yr randomized Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial. About 224 women (recurrence free) who had completed the AZURE trial within the previous 3 mo were recruited from 20 UK AZURE trial sites. One hundred twenty had previously been randomized to zoledronate (19 doses of 4 mg over 5 yr) and 104 to the control arm. BMD and BTMs were assessed at sub-study entry, 6 (BTMs only), 12, 24, and 60 mo following the completion of AZURE. As expected, mean BMD, T-scores, and Z-scores at sub-study entry were higher in the zoledronate vs the control arm. At the lumbar spine, the mean (SD) standardized BMD (sBMD) was 1123 (201) and 985 (182) mg/cm2 in the zoledronate and control arms, respectively (P < .0001). The baseline differences in sBMD persisted at all assessed skeletal sites and throughout the 5-yr follow-up period. In patients completing zoledronate treatment, BTMs were significantly lower than those in the control arm (α- and ß-urinary C-telopeptide of type-I collagen, both P < .00001; serum intact pro-collagen I N-propeptide, P < .00001 and serum tartrate-resistant acid phosphatase 5b, P = .0001). Some offset of bone turnover inhibition occurred in the 12 mo following the completion of zoledronate treatment. Thereafter, during the 60 mo of follow-up, all BTMs remained suppressed in the zoledronate arm relative to the control arm. In conclusion, in addition to the known anti-cancer benefits of adjuvant zoledronate, there are likely to be positive, lasting benefits in BMD and bone turnover.

MRI-based anatomical characterisation of lower-limb muscles in older women.

The ability of muscles to produce force depends, among others, on their anatomical features and it is altered by ageing-associated weakening. However, a clear characterisation of these features, highly relevant for older individuals, is still lacking. This study hence aimed at characterising muscle volume, length, and physiological cross-sectional area (PCSA) and their variability, between body sides and between individuals, in a group of post-menopausal women. Lower-limb magnetic resonance images were acquired from eleven participants (69 (7) y. o., 66.9 (7.7) kg, 159 (3) cm). Twenty-three muscles were manually segmented from the images and muscle volume, length and PCSA were calculated from this dataset. Personalised maximal isometric force was then calculated using the latter information. The percentage difference between the muscles of the two lower limbs was up to 89% and 22% for volume and length, respectively, and up to 84% for PCSA, with no recognisable pattern associated with limb dominance. Between-subject coefficients of variation reached 36% and 13% for muscle volume and length, respectively. Generally, muscle parameters were similar to previous literature, but volumes were smaller than those from in-vivo young adults and slightly higher than ex-vivo ones. Maximal isometric force was found to be on average smaller than those obtained from estimates based on linear scaling of ex-vivo-based literature values. In conclusion, this study quantified for the first time anatomical asymmetry of lower-limb muscles in older women, suggesting that symmetry should not be assumed in this population. Furthermore, we showed that a scaling approach, widely used in musculoskeletal modelling, leads to an overestimation of the maximal isometric force for most muscles. This heavily questions the validity of this approach for older populations. As a solution, the unique dataset of muscle segmentation made available with this paper could support the development of alternative population-based scaling approaches, together with that of automatic tools for muscle segmentation.

Characterising variability and regional correlations of microstructure and mechanical competence of human tibial trabecular bone: An in-vivo HR-pQCT study.

OBJECTIVE: Quantifying spatial distribution of trabecular bone mechanical competence and microstructure is important for early diagnosis of skeletal disorders and potential risk of fracture. The objective of this study was to determine a spatial distribution of trabecular mechanical and morphological properties in human distal tibia and examine the contribution of regional variability of trabecular microarchitecture to mechanical competence. METHODS: A total of 340 representative volume elements at five anatomic regions of trabecular bone - anterior, posterior, lateral, medial and centre - from ten white European-origin postmenopausal women were studied. Region-specific trabecular parameters such as trabecular volume fraction, trabecular thickness, trabecular number, trabecular surface area, trabecular separation, plate-like structure fraction and finite element analysis of trabecular stiffness were determined based on in-vivo high resolution peripheral quantitative computed tomographic (HR-pQCT) images of distal tibiae from ten postmenopausal women. Mean values were compared using analysis of variance. The correlations between morphological parameters and stiffness were calculated. RESULTS: Significant regional variation in trabecular microarchitecture of the human distal tibia was observed (p < 0.05), with up to 106% differences between lowest (central and anterior) and highest (medial and posterior) regions. Higher proportion of plate-like trabecular morphology (63% and 53%) was found in medial and posterior regions in the distal tibia. Stiffness estimated from finite element models also differed significantly (p < 0.05), with stiffness being 4.5 times higher in the highest (medial) than lowest (central) regions. The bone volume fraction was the strongest correlate of stiffness in all regions. CONCLUSION: A novel finding of this study is the fact that significant regional variation of stiffness derived from two-phased FEA model with individual trabecula representation correlated highly to regional morphology obtained from in-vivo HR-pQCT images at the distal tibia. The correlations between regional morphological parameters and mechanical competence of trabecular bone were consistent at all regions studied, with regional BV/TV showing the highest correlation. The method developed for regional analysis of trabecular mechanical competence may offer a better insight into the relationship between mechanical behaviour and microstructure of bone. The findings provide evidence needed to further justify a larger-cohort feasibility study for early detection of bone degenerative diseases: examining regional variations in mechanical competence and trabecular specifications may allow better understanding of fracture risks in addition to others contributing factors.

Effect of Teriparatide Treatment on Circulating Periostin and Its Relationship to Regulators of Bone Formation and BMD in Postmenopausal Women With Osteoporosis.

Context: Treatment of postmenopausal osteoporosis with teriparatide parathyroid hormone amino terminal 1-34 increases bone formation and improves bone microarchitecture. A possible modulator of action is periostin. In vitro experiments have shown that periostin might regulate osteoblast differentiation and bone formation through Wnt signaling. The effect of teriparatide on periostin is not currently known. Objectives: To determine the effect of teriparatide treatment on circulating levels of periostin and other regulators of bone formation and investigate how changes in periostin relate to changes in bone turnover markers, regulators of bone formation, and bone mineral density (BMD). Participants and Design: Twenty women with osteoporosis; a 2-year open-label single-arm study. Intervention: Teriparatide 20 µg was administered by subcutaneous injection daily for 104 weeks. Periostin, sclerostin, and Dickkopf-related protein 1, procollagen type I N-terminal propeptide (PINP), and C-telopeptide of type I collagen were measured in fasting serum collected at baseline (two visits) and then at weeks 1, 2, 4, 12, 26, 52, 78, and 104. BMD was measured at the lumbar spine, total hip, and femoral neck using dual energy x-ray absorptiometry. Results: Periostin levels increased by 6.6% [95% confidence interval (CI), -0.4 to 13.5] after 26 weeks of teriparatide treatment and significantly by 12.5% (95% CI, 3.3 to 21.0; P < 0.01) after 52 weeks. The change in periostin correlated positively with the change in the lumbar spine BMD at week 52 (r = 0.567; 95% CI, 0.137 to 0.817; P < 0.05) and femoral neck BMD at week 104 (r = 0.682; 95% CI, 0.261 to 0.885; P < 0.01). Conclusions: Teriparatide therapy increases periostin secretion; it is unclear whether this increase mediates the effect of the drug on bone.

Validation of calcaneus trabecular microstructure measurements by HR-pQCT.

OBJECTIVE: Assessment of calcaneus microstructure using high-resolution peripheral quantitative computed tomography (HR-pQCT) might be used to improve fracture risk predictions or to assess responses to pharmacological and physical interventions. To develop a standard clinical protocol for the calcaneus, we validated calcaneus trabecular microstructure measured by HR-pQCT against 'gold-standard' micro-CT measurements. METHODS: Ten human cadaveric feet were scanned in situ using HR-pQCT (isotropic 82µm voxel size) at 100, 150 and 200ms integration times, and at 100ms integration time following removal of the calcaneus from the foot (ex vivo). Dissected portions of these bones were scanned using micro-computed tomography (micro-CT) at an isotropic 17.4µm voxel size. HR-pQCT images were rigidly registered to those obtained with micro-CT and divided into multiple 5mm sided cubes to evaluate and compare morphometric parameters between the modalities. Standard HR-pQCT measurements (derived bone volume fraction (BV/TVd); trabecular number, Tb.N; derived trabecular thickness, Tb.Thd; derived trabecular spacing, Tb.Spd) and corresponding micro-CT voxel-based measurements (BV/TV, Tb.N, Tb.Th, Tb.Sp) were compared. RESULTS: A total of 108 regions of interest were analysed across the 10 specimens. At all integration times HR-pQCT BV/TVd was strongly correlated with micro-CT BV/TV (r2=0.95-0.98, RMSE=1%), but BV/TVd was systematically lower than that measured by micro-CT (mean bias=5%). In contrast, HR-pQCT systematically overestimated Tb.N at all integration times; of the in situ scans, 200ms yielded the lowest mean bias and the strongest correlation with micro-CT (r2=0.61, RMSE=0.15mm-1). Regional analysis revealed greater accuracy for Tb.N in the superior regions of the calcaneus at all integration times in situ (mean bias=0.44-0.85mm-1; r2=0.70-0.88, p<0.001 versus mean bias=0.63-1.46mm-1; r2≤0.08, p≥0.21 for inferior regions). Tb.Spd was underestimated by HR-pQCT compared to micro-CT, but showed similar trends with integration time and the region evaluated as Tb.N. HR-pQCT Tb.Thd was also underestimated and moderately correlated (r2=0.53-0.59) with micro-CT Tb.Th, independently from the integration time. Stronger correlations, smaller biases and error were found in the scans of the calcaneus ex vivo compared to in situ. CONCLUSION: Calcaneus trabecular BV/TVd and trabecular microstructure, particularly in the superior region of the calcaneus, can be assessed by HR-pQCT. The highest integration time examined, 200ms, compared best with micro-CT. Weaker correlations for microstructure at inferior regions, and also with lower integration times, might limit the use of the proposed protocol, which warrants further investigation in vivo.

Effect of age and gender on serum periostin: Relationship to cortical measures, bone turnover and hormones.

Periostin is an extracellular matrix protein, and in bone is expressed most highly in the periosteum. It increases bone formation through osteoblast differentiation, cell adhesion, Wnt signalling and collagen cross-linking. We hypothesised that serum periostin would be high at times of life when cortical modeling is active, in early adulthood and in older age, and that it would correlate with cortical bone measures, bone turnover and hormones that regulate cortical modeling. We conducted a cross-sectional observational study of 166 healthy men and women at three skeletal stages; the end of longitudinal growth (16-18years), peak bone mass (30-32years) and older age (over 70years). We measured serum periostin with a new ELISA optimised for human serum and plasma which recognises all known splice variants (Biomedica). We measured the distal radius and distal tibia with HR-pQCT, and measured serum PINP, CTX, sclerostin, PTH, IGF-1, estradiol and testosterone. Periostin was higher at age 16-18 than age 30-32 (1253 vs 842pmol/l, p<0.001), but not different between age 30-32 and over age 70. Periostin was inversely correlated with tibia cortical thickness and density (R -0.229, -0.233, both p=0.003). It was positively correlated with PINP (R 0.529, p<0.001), CTX (R 0.427, p<0.001) and IGF-1 (R 0.440, p<0.001). When assessed within each age group these correlations were only significant at age 16-18, except for PINP which was also significant over age 70. We conclude that periostin may have a role in IGF-1 driven cortical modeling and consolidation in young adults, but it may not be an important mediator in older adults.

Bone density, microstructure and strength in obese and normal weight men and women in younger and older adulthood.

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.

Precision of high-resolution peripheral quantitative computed tomography measurement variables: influence of gender, examination site, and age.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is increasingly being used in the research setting to assess the effects of osteoporosis treatments and disease on trabecular and cortical bone compartments. Further in-depth study of HR-pQCT measurement variables is essential to ensure study strength and statistical confidence when designing large multicenter studies. Duplicate HR-pQCT examinations of the distal radius and tibia were performed in 180 healthy men and women ages 16-18, 30-32, and >70 years. HR-pQCT images were processed using standard and extended cortical bone analysis techniques. Biomechanical properties of bone were assessed using finite element analysis. Percent root mean square coefficient of variation (RMSCV) was calculated for each measurement variable. Age, site, and gender influences on measurement variability were investigated using variance ratio tests. Smaller precision errors were observed for densitometric (0.2-5.5%) than for microstructural (1.2-7.0%), extended cortical bone (3.4-20.3%), and biomechanical (0.3-9.9%) measures at both the radius and tibia. Tibial measurements (RMSCVs = 0.2-7.4%) tended to be more precise than radial measurements (RMSCVs = 0.7-20.3%). Variability was influenced by age, site, and gender (all p < 0.05). HR-pQCT measurements for the tibia were more precise than those for the radius, and this may be explained by the larger bone volumes examined and the reduced likelihood of movement artifact. The greater measurement variability observed for older volunteers may be due to the loss of bone density and microstructural integrity with age.

Analysis of body composition in individuals with high bone mass reveals a marked increase in fat mass in women but not men.

CONTEXT: High bone mass (HBM), detected in 0.2% of dual-energy x-ray absorptiometry (DXA) scans, is characterized by raised body mass index, the basis for which is unclear. OBJECTIVE: To investigate why body mass index is elevated in individuals with HBM, we characterized body composition and examined whether differences could be explained by bone phenotypes, eg, bone mass and/or bone turnover. DESIGN, SETTING, AND PARTICIPANTS: We conducted a case-control study of 153 cases with unexplained HBM recruited from 4 UK centers by screening 219 088 DXA scans. A total of 138 first-degree relatives (of whom 51 had HBM) and 39 spouses were also recruited. Unaffected individuals served as controls. MAIN OUTCOME MEASURES: We measured fat mass, by DXA, and bone turnover markers. RESULTS: Among women, fat mass was inversely related to age in controls (P = .01), but not in HBM cases (P = .96) in whom mean fat mass was 8.9 [95% CI 4.7, 13.0] kg higher compared with controls (fully adjusted mean difference, P < .001). Increased fat mass in male HBM cases was less marked (gender interaction P = .03). Compared with controls, lean mass was also increased in female HBM cases (by 3.3 [1.2, 5.4] kg; P < .002); however, lean mass increases were less marked than fat mass increases, resulting in 4.5% lower percentage lean mass in HBM cases (P < .001). Osteocalcin was also lower in female HBM cases compared with controls (by 2.8 [0.1, 5.5] µg/L; P = .04). Differences in fat mass were fully attenuated after hip bone mineral density (BMD) adjustment (P = .52) but unchanged after adjustment for bone turnover (P < .001), whereas the greater hip BMD in female HBM cases was minimally attenuated by fat mass adjustment (P < .001). CONCLUSIONS: HBM is characterized by a marked increase in fat mass in females, statistically explained by their greater BMD, but not by markers of bone turnover.

Cortical consolidation of the radius and tibia in young men and women.

CONTEXT: Bone size, geometry, density, and microarchitecture are important determinants of bone strength. By understanding how these properties change during skeletal development, we can better understand bone fragility. OBJECTIVES: The aim of the study was to compare the geometry, microarchitecture, and strength of the radius and tibia in men and women at the end of adolescence and in young adulthood and to relate these properties to biochemical bone turnover markers and bone regulatory hormones. DESIGN: We conducted a cross-sectional study of 116 healthy men and women ages 16-18 (n = 56) and 30-32 (n = 60) yr. OUTCOME MEASURES: We used high-resolution peripheral quantitative computed tomography to measure bone size, geometry, and microarchitecture at the distal radius and tibia and micro-finite element modeling to estimate bone strength. We measured bone turnover markers (ß C-terminal telopeptide of type I collagen and amino-terminal propeptide of type I procollagen) and hormones known to affect bone metabolism (estradiol, testosterone, IGF-I, and PTH). RESULTS: Bone strength was greater in men than in women, and at the radius it was greater in men ages 30-32 yr than ages 16-18 yr. The gender difference was due to greater cortical perimeter, trabecular area, and trabecular density in men. The age difference was due to greater cortical thickness and cortical tissue mineral density and lower cortical porosity. IGF-I was related to two of these five key properties at the radius (cortical perimeter and cortical thickness). None of the hormones were predictors of density or structure at the tibia. CONCLUSIONS: Cortical modeling of long bones continues beyond the end of adolescence. IGF-I may be a determinant of this process at the radius.

Performance of quantitative ultrasound measurements of bone for monitoring raloxifene therapy.

Raloxifene increases bone mineral density (BMD) and decreases vertebral fracture risk; the effects on quantitative ultrasound (QUS) variables, however, have been less well studied. We aimed to further evaluate the effectiveness of QUS for monitoring raloxifene treatment and withdrawal effects. Osteopenic, postmenopausal women (age=50-80 yr, n=125), who completed a 96-wk study (phase A) evaluating treatment compliance or monitoring, were invited to participate in a 96-wk raloxifene withdrawal study (phase B). Those originally receiving treatment were then randomized to continue on raloxifene (60 mg/d)+calcium (500 mg/d) (n=23) or to discontinue raloxifene and take placebo+calcium (500 mg/d) (n=23). Previously untreated women remained untreated (n=12). Yearly QUS and BMD measurements were performed. At the end of phase A, lumbar spine BMD (p=0.005), amplitude-dependent speed of sound (Ad-SoS) (p=0.006) and average SoS (p=0.040) decreased in untreated women but remained stable in treated women. Significant changes in Ad-SoS and ultrasonic bone profiler index had occurred in treated women by the end of phase B (p<0.01). All variables, except bone transmission time, were higher for those receiving any raloxifene treatment (p<0.05). Until further knowledge has been acquired, QUS measurement variables should only be used in conjunction with BMD when assessing changes in bone because of raloxifene therapy.

Effect of temperature on the longitudinal variability of quantitative ultrasound variables.

It is unclear whether longitudinal change in phantom measurements bears any relation to the long-term in vivo instrument performance of quantitative ultrasound devices. Longitudinal quantitative ultrasound phantom data were obtained by measuring the manufacturer-provided phantom at ambient temperature and two different sets of Leeds phantoms at either ambient temperature or following a phantom temperature-control protocol. Measurements were performed using the Achilles Plus bone densitometer. Changes in longitudinal phantom data were compared to in vivo quantitative ultrasound data obtained from seven healthy, young volunteers. A cosinor model with linear trend and Hotelling's T2-test were used to quantify seasonal rhythms and long-term drift in quantitative ultrasound variables. Temperature effects and marked seasonal rhythms on quantitative ultrasound phantom measurements were evident but were far less apparent in vivo. Longitudinal precision of quantitative ultrasound variables was poorer for the manufacturer-provided phantom than for phantoms that were subjected to a temperature-control protocol or for healthy volunteers. This study has shown that longitudinal precision and longitudinal change differs between in vivo and phantom data. Longitudinal quantitative ultrasound measurements for monitoring change in skeletal status cannot, as yet, be properly controlled.