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.

DIAGNOSIS OF ENDOCRINE DISEASE: Bone turnover markers: are they clinically useful?

Bone turnover markers (BTMs) are useful in clinical practice as they are inexpensive, and they have proven useful for treatment monitoring and identification of poor adherence. BTMs cannot be used in individual patients for identifying accelerated bone loss or an increase in fracture risk or in deciding on the optimal therapy. They are useful for monitoring both anti-resorptive and anabolic treatment. Response can be defined as a result that exceeds an absolute target, or by a change greater than the least significant change; if such a response is not present, then poor compliance or secondary osteoporosis are likely causes. A baseline BTM measurement is not always made; in that case, a value of BTM on anti-resorptive treatment that is low or low normal or above the reference interval for anabolic therapy may be taken to indicate a satisfactory response. We provide an approach to using these bone turnover markers in clinical practice by describing algorithms for anti-resorptive and anabolic therapy and describing the changes we observe in the clinical practice setting.

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.

Determination of Free 25(OH)D Concentrations and Their Relationships to Total 25(OH)D in Multiple Clinical Populations.

Context: The optimal measure of vitamin D status is unknown. Objective: To directly measure circulating free 25-hydroxyvitamin D [25(OH)D] concentrations and relationships to total 25(OH)D in a clinically diverse sample of humans. Design: Cross-sectional analysis. Setting: Seven academic sites. Patients: A total of 1661 adults: healthy (n = 279), prediabetic (n = 479), outpatients (n = 714), cirrhotic (n = 90), pregnant (n = 20), nursing home resident (n = 79). Interventions: Merge research data on circulating free 25(OH)D (directly-measured immunoassay), total 25(OH)D (liquid chromatography/tandem mass spectrometry), D-binding protein [DBP; by radial (polyclonal) immunodiffusion assay], albumin, creatinine, intact parathyroid hormone, and DBP haplotype. Main outcome measures: Distribution of free 25(OH)D (ANOVA with Bonferroni correction for post hoc comparisons) and relationships between free and total 25(OH)D (mixed-effects modeling incorporating clinical condition, DBP haplotype with sex, race, estimated glomerular filtration rate (eGFR), body mass index (BMI), and other covariates). Results: Free 25(OH)D was 4.7 ± 1.8 pg/mL (mean ± SD) in healthy persons and 4.3 ± 1.9 pg/mL in outpatients, with levels of 0.5 to 8.1 pg/mL and 0.9 to 8.1 pg/mL encompassing 95% of healthy persons and outpatients, respectively. Free 25(OH)D was higher in patients with cirrhosis (7.1 ± 3.0 pg/mL; P < 0.0033) and nursing home residents (7.9 ± 2.1 pg/mL; P < 0.0033) than in other groups and differed between whites and blacks (P < 0.0033) and between DBP haplotypes (P < 0.0001). Mixed-effects modeling of relationships between free and total 25(OH)D identified clinical conditions (patients with cirrhosis > nursing home residents > patients with prediabetes > outpatients > pregnant women) and BMI (lesser effect) as covariates affecting relationships but not eGFR, sex, race, or DBP haplotype. Conclusions: Total 25(OH)D, health condition, race, and DBP haplotype affected free 25(OH)D, but only health conditions and BMI affected relationships between total and free 25(OH)D. Clinical importance of free 25(OH)D needs to be established in studies assessing outcomes.

Free 25-hydroxyvitamin D is low in obesity, but there are no adverse associations with bone health.

BACKGROUND: The mechanism and clinical significance of low circulating 25-hydroxyvitamin D [25(OH)D] in obese people are unknown. Low total 25(OH)D may be due to low vitamin D-binding proteins (DBPs) or faster metabolic clearance. However, obese people have a higher bone mineral density (BMD), which suggests that low 25(OH)D may not be associated with adverse consequences for bone. OBJECTIVE: We sought to determine whether 1) vitamin D metabolism and 2) its association with bone health differ by body weight. DESIGN: We conducted a cross-sectional observational study of 223 normal-weight, overweight, and obese men and women aged 25-75 y in South Yorkshire, United Kingdom, in the fall and spring. A subgroup of 106 subjects was also assessed in the winter. We used novel techniques, including an immunoassay for free 25(OH)D, a stable isotope for the 25(OH)D3 half-life, and high-resolution quantitative tomography, to make a detailed assessment of vitamin D physiology and bone health. RESULTS: Serum total 25(OH)D was lower in obese and overweight subjects than in normal-weight subjects in the fall and spring (geometric means: 45.0 and 40.8 compared with 58.6 nmol/L, respectively; P < 0.001) but not in the winter. Serum 25(OH)D was inversely correlated with body mass index (BMI) in the fall and spring and in the winter. Free 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D] were lower in obese subjects. DBP, the DBP genotype, and the 25(OH)D3 half-life did not differ between BMI groups. Bone turnover was lower, and bone density was higher, in obese people. CONCLUSIONS: Total and free 25(OH)D and 1,25(OH)2D are lower at higher BMI, which cannot be explained by lower DBP or the shorter half-life of 25(OH)D3 We speculate that low 25(OH)D in obesity is due to a greater pool of distribution. Lower 25(OH)D may not reflect at-risk skeletal health in obese people, and BMI should be considered when interpreting serum 25(OH)D as a marker of vitamin D status.

Absence of marked seasonal change in bone turnover: a longitudinal and multicenter cross-sectional study.

UNLABELLED: The effect of season on bone turnover is controversial. No information is available on seasonality of new serum markers of bone resorption. In this study, we have been unable to confirm findings of a marked wintertime increase in bone formation and resorption within the general population. Seasonality was assessed by cosinor analysis. INTRODUCTION: We investigated the effect of season on seven markers of bone turnover in a longitudinal study (six men and six premenopausal women; age, 24-44 years) and a separate large population-based multicenter European study (n = 2780 women, Osteoporosis and Ultrasound Study [OPUS]). MATERIALS AND METHODS: Measurements included serum Crosslaps, procollagen type I N-terminal propeptide (PINP), osteocalcin (OC), and the N-telopeptide fragment of type I collagen in urine (NTX). Seasonality was assessed by cosinor analysis with Hotelling's T2 test. RESULTS: Serum 25(OH) vitamin D showed a marked seasonal rhythm. There was no significant seasonal component for any marker of bone turnover in the longitudinal analysis (cosinor analysis, p > 0.05). The percentage of within subject variance accounted for by any seasonal trend was very small for all markers (less than 2.5%). Less than 1% of the between-person variance was accounted for by seasonality in the cross-sectional analysis for all markers (n = 2780). There was a small but statistically significant summertime increase in OC and PINP in the healthy postmenopausal population after exclusions based on disease or medication use (remaining n = 1226, amplitudes 5.6% and 5.4%, respectively, p < 0.001). CONCLUSIONS: We have been unable to confirm findings of a marked wintertime increase in bone formation and resorption within the general population. The absence of marked seasonality was irrespective of age, menopausal status, reported supplemental Vitamin D intake, age or geographical location. The small but statistically significant summertime increase in bone formation in this and other studies is unlikely to confound clinical interpretation of these measurements.

Use of DXA-based finite element analysis of the proximal femur in a longitudinal study of hip fracture.

Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is used for clinical assessment of fracture risk; however, measurements that incorporate bone strength could improve predictive ability. The aim of this study was to determine whether bone strength derived from finite element (FE) analysis was associated with hip fracture risk in a longitudinal study. We studied 728 women (mean age 82 years), 182 with subsequent hip fracture. FE models were generated from baseline DXA scans of the hip to determine femoral bone strength and load-to-strength ratio (LSR). The baseline LSR was significantly higher in fracture cases (median 1.1) compared with controls (0.7, p < 0.0001). Femoral strength and BMD were also significantly lower in cases (median 1820 N, 0.557 g/cm(2)) compared with controls (2614 N, 0.618 g/cm(2) ) both p < 0.0001. Fracture risk increased per standard deviation decrease in femoral strength (odds ratio [OR] = 2.2, 95% confidence interval [CI] 1.8-2.8); femoral neck (FN) BMD (OR = 2.1, 95% CI 1.7-2.6); total hip BMD (OR = 1.8, 95% CI 1.5-2.1); and per SD increase in LSR (OR = 1.8, 95% CI 1.5-2.1). After adjusting for FN BMD, the odds ratio for femoral strength (OR = 1.7, 95% CI 1.2-2.4) and LSR (OR = 1.4, 95% CI 1.1-1.7) remained significantly greater than 1. The area under the curve (AUC) for LSR combined with FN BMD (AUC 0.69, 95% CI 0.64-0.73) was significantly greater than FN BMD alone (AUC 0.66, 95% CI 0.62-0.71, p = 0.004). Strength and LSR remained significant when adjusted for prevalent fragility fracture, VFA, and FRAX score. In conclusion, the DXA-based FE model was able to discriminate incident hip fracture cases from controls in this longitudinal study independently from FN BMD, prior fracture, VFA, and FRAX score. Such an approach may provide a useful tool for better assessment of bone strength to identify patients at high risk of hip fracture who may benefit from treatment to reduce fracture risk.