Minodronic acid ameliorates vertebral bone strength by increasing bone mineral density in 9-month treatment of ovariectomized cynomolgus monkeys

The effect of treatment for 9 months with minodronic acid, a nitrogen-containing bisphosphonate, on vertebral mechanical strength was examined in ovariectomized (OVX) cynomolgus monkeys. Forty skeletally mature female monkeys were randomized into four OVX groups and one sham group (n = 8) based on lumbar bone mineral density (BMD). OVX animals were treated orally with 15 and 150 μg/kg QD of minodronic acid or 500 μg/kg QD alendronate as a reference drug. Measurements of bone turnover markers and lumbar BMD were conducted at 0, 4 and 8 months. Measurements of bone mechanical strength and minodronic acid concentration in vertebral bodies were also performed. OVX resulted in a decrease in lumbar BMD and an increase in bone turnover markers at 4 and 8 months, compared to the sham group, and the ultimate load on the lumbar vertebra was decreased in OVX animals. Minodronic acid and alendronate prevented the OVX-induced increase in bone turnover markers and decrease in lumbar BMD. Minodronic acid at 150 μg/kg increased the ultimate load on lumbar vertebra compared to untreated OVX animals. Regression analysis revealed that the ultimate load was correlated with lumbar BMD and bone mineral content (BMC), and most strongly with the increase in lumbar BMD and BMC over 8 months. In a separate analysis within the sham-OVX controls and minodronic acid and alendronate treatment groups, the ultimate loads were also correlated with BMD and BMC. The load-BMD (BMC) correlation in the minodronic acid group showed a trend for a shift to a higher load from the basal relationship in the sham-OVX controls. These results indicate that treatment with minodronic acid for 9 months increases vertebral mechanical strength in OVX monkeys, mainly by increasing BMD and BMC.     

Associations between hypothalamic–pituitary–adrenal axis function and peak bone mass at 20 years of age in a birth cohort

In older adults, high-normal circulating cortisol levels are associated with lower bone mass, but relationships between hypothalamic–pituitary–adrenal axis function and peak bone mass in young adults have not been examined. We studied 411 male and 390 female participants in the Western Australia Pregnancy Cohort (Raine) Study. At 18 years of age, participants underwent a Trier Social Stress Test (TSST) with measurement of plasma and salivary cortisol at baseline and at multiple time points after stress. Cortisol responses were classified as anticipatory responder (significant fall in cortisol during the test), reactive responder (significant increase) or non-responder. At 20 years, total body bone mineral content (BMC) and density (BMD) were measured by DXA. In males, after adjustment for weight, height (for BMC and bone area only), alcohol and smoking, there was a significant inverse relationship between both plasma and salivary cortisol measured at baseline in the TSST and each of BMC and BMD, such that each additional 10% of salivary cortisol was associated with reductions of 6.9 g (95% CI − 11.7, − 2.2) in BMC, and 1.8 mg/cm² (95% CI − 3.3, − 0.4) in BMD. Males classified as anticipatory responders in the TSST had 3.2% lower BMC (adjusted mean ± SE: 3131 ± 28 vs. 3233 ± 18 g, P = 0.006) and 2.5% lower BMD (1108 ± 9 vs. 1136 ± 6 mg/cm², P = 0.022) than reactive responders. In females, there were no significant relationships between baseline cortisol or TSST responses and BMC or BMD in covariate-adjusted analyses. We conclude that in young males (but not females), higher circulating cortisol at the baseline of the stress test and an anticipatory responder pattern on the TSST are associated with lower total body bone mass.     

Dual-energy X-ray absorptiometry of human metatarsals: Precision,least significant change and association to ex vivo fracture force

BackgroundFractures are common in foot bones, but clinicians lack adequate indices of bone strength.ObjectivesWe used dual-energy X-ray absorptiometry (DXA) to measure bone mineral density (BMD) and content (BMC) of excised human metatarsals, determined intra- and inter-rater measurement precision, and assessed associations between BMD/BMC and ex vivo bone fracture strength.MethodsTwo raters each made two measurements of whole-bone and sub-regional BMD and BMC in both second and third metatarsals from 10 cadavers. Variance components analysis was used to assess variability attributable to repeat measurements, raters, sub-regions, bones, sides, and cadavers. Root-mean-square standard deviation (RMS-SD) and least-significant change (LSC) were used to assess rater precision and ultimate forces during 3-point bending were tested for correlations with BMD and BMC.ResultsVariation due to repeat measurements and rater was low (<1% combined) for BMD and BMC. RMS-SD for whole metatarsal BMD of both metatarsals ranged from 0.004 to 0.010 g/cm² and 0.062 to 0.086 g for BMC. Whole metatarsal and sub-region BMD and BMC were strongly correlated to ex vivo fracture force (r² = 0.67–0.93).ConclusionsDXA measurements of BMD and BMC have high intra- and inter-rater precision and are strongly correlated to ex vivo bone strength.     

Effects of 16-month treatment with the cathepsin K inhibitor ONO-5334 on bone markers,mineral density,strength and histomorphometry in ovariectomized cynomolgus monkeys

We examined the effects of ONO-5334, a cathepsin K inhibitor, on bone markers, BMD, strength and histomorphometry in ovariectomized (OVX) cynomolgus monkeys. ONO-5334 (1.2, 6 and 30 mg/kg/day, p.o.), alendronate (0.05 mg/kg/2 weeks, i.v.), or vehicle was administered to OVX monkeys (all groups N = 20) for 16 months. A concurrent Sham group (N = 20) was also treated with vehicle for 16 months. OVX significantly increased bone resorption and formation markers and decreased BMD in lumbar vertebra, femoral neck, proximal tibia and distal radius. Alendronate suppressed these parameters to a level similar to that in the Sham-operated monkeys. ONO-5334 at doses 6 and 30 mg/kg decreased bone resorption markers to a level roughly half of that in the Sham group, while keeping bone formation markers level above that in the Sham monkeys. Changes in DXA BMD confirmed that ONO-5334 at doses 6 and 30 mg/kg increased BMD to a level greater than that in the Sham group in all examined sites. In the proximal tibia, in vivo pQCT analysis showed that ONO-5334 at doses 6 and 30 mg/kg suppressed trabecular BMD loss to the sham level. However, ONO-5334 increased cortical BMD, cortical area and cortical thickness to a level greater than that in the Sham group, suggesting that ONO-5334 improves both cortical BMD and cortical geometry. Histomorphometric analysis revealed that ONO-5334 suppressed bone formation rate (BFR) at osteonal site in the midshaft femur but did not influence OVX-induced increase in BFR at either the periosteal or endocortical surfaces. Unlike alendronate, ONO-5334 increased osteoclasts surface (Oc.S/BS) and serum tartrate-resistant acid phosphatise 5b (TRAP5b) activity, highlighting the difference in the mode of action between these two drugs. Our results suggest that ONO-5334 has therapeutic potential not only in vertebral bones, but also in non-vertebral bones.     

Improvements in hip trabecular,subcortical, and cortical density and mass in postmenopausal women with osteoporosis treated with denosumab

In the FREEDOM study, denosumab treatment (60 mg every 6 months) decreased bone resorption, increased bone mineral density (BMD), and reduced new vertebral, nonvertebral, and hip fractures over 36 months in postmenopausal women with osteoporosis. In a subset of these women, hip quantitative computed tomography (QCT) was performed at baseline and months 12, 24, and 36. These scans were analyzed using Medical Image Analysis Framework (MIAF) software, which allowed assessment of total hip integral, trabecular, subcortical, and cortical compartments; the cortical compartment was further divided into 2 areas of interest (outer and inner cortex). This substudy reports changes in BMD and bone mineral content (BMC) from baseline and compared placebo with denosumab over 36 months of treatment (placebo N = 26; denosumab N = 36). Denosumab treatment resulted in significant improvements in total hip integral volumetric BMD (vBMD) and BMC from baseline at each time point. At month 36, the mean percentage increase from baseline in total hip integral vBMD and BMC was 6.4% and 4.8%, respectively (both p < 0.0001). These gains were accounted for by significant increases in vBMD and BMC in the trabecular, subcortical, and cortical compartments. In the placebo group, total hip integral vBMD and BMC decreased at month 36 from baseline by − 1.5% and − 2.6%, respectively (both p < 0.05). The differences between denosumab and placebo were also significant at months 12, 24, and 36 for integral, trabecular, subcortical, and cortical vBMD and BMC (all p < 0.05 to < 0.0001). While the largest percentage differences occurred in trabecular vBMD and BMC, the largest absolute differences occurred in cortical vBMD and BMC. In summary, denosumab significantly improved both vBMD and BMC from baseline and placebo, assessed by QCT MIAF, in the integral, trabecular, subcortical, and cortical hip compartments, all of which are relevant to bone strength.     

Measurement of Bone Density Around the Oxford Medial Compartment Knee Replacement Using iDXA. A Precision Study

The goal of this study was to evaluate whether the Lunar iDXA densitometer can accurately measure the bone mineral density (BMD) around the tibial component of the Oxford unicompartment knee replacement (UKR). Both knees in 20 patients were measured 3 times in the supine position with repositioning between each scan. We chose 7 regions of interest to evaluate the bone density around the implant. Small but significant differences between the implant and nonimplanted knee were noticed with the nonimplanted knee having slightly higher BMD and bone mineral content (BMC) in areas 1–3 (p ≤ 0.001) and area 6 (p = 0.002). There was higher BMD in area 4 (p = 0.028). The precision for BMD in the 7 areas of interest in the implanted knee varied between 0.55% and 4.04% and BMC between 1.8% and 5.3%. There was no significant difference in the precision between the nonimplanted and implanted knees. Prospective serial measurements around the Oxford UKR using iDXA will be able to assess specific areas of stress shielding and potential implant stability, which is likely to help predict the survival of the implant.     

Sclerostin antibody and interval treadmill training effects in a rodent model of glucocorticoid-induced osteopenia

Glucocorticoids have a beneficial anti-inflammatory and immunosuppressive effect, but their use is associated with decreased bone formation, bone mass and bone quality, resulting in an elevated fracture risk. Exercise and sclerostin antibody (Scl-Ab) administration have both been shown to increase bone formation and bone mass, therefore the ability of these treatments to inhibit glucocorticoid-induced osteopenia alone or in combination were assessed in a rodent model. Adult (4 months-old) male Wistar rats were allocated to a control group (C) or one of 4 groups injected subcutaneously with methylprednisolone (5 mg/kg/day, 5 days/week). Methylprednisolone treated rats were injected subcutaneously 2 days/week with vehicle (M) or Scl-Ab-VI (M + S: 25 mg/kg/day) and were submitted or not to treadmill interval training exercise (1 h/day, 5 days/week) for 9 weeks (M + E, M + E + S). Methylprednisolone treatment increased % fat mass and % apoptotic osteocytes, reduced whole body and femoral bone mineral content (BMC), reduced femoral bone mineral density (BMD) and osteocyte lacunae occupancy. This effect was associated with lower trabecular bone volume (BV/TV) at the distal femur. Exercise increased BV/TV, osteocyte lacunae occupancy, while reducing fat mass, the bone resorption marker NTx, and osteocyte apoptosis. Exercise did not affect BMC or cortical microarchitectural parameters. Scl-Ab increased the bone formation marker osteocalcin and prevented the deleterious effects of M on bone mass, further increasing BMC, BMD and BV/TV to levels above the C group. Scl-Ab increased femoral cortical bone parameters at distal part and midshaft. Scl-Ab prevented the decrease in osteocyte lacunae occupancy and the increase in osteocyte apoptosis induced by M. The addition of exercise to Scl-Ab treatment did not result in additional improvements in bone mass or bone strength parameters. These data suggest that although our exercise regimen did prevent some of the bone deleterious effects of glucocorticoid treatment, particularly in trabecular bone volume and osteocyte apoptosis, Scl-Ab treatment resulted in marked improvements in bone mass across the skeleton and in osteocyte viability, resulting in decreased bone fragility.     

Associations among endocrine,inflammatory, and bone markers,body composition and weight loss induced bone loss

IntroductionWeight loss reduces co-morbidities of obesity, but decreases bone mass.PurposeOur aims were to 1) determine if adequate dairy intake attenuates weight loss-induced bone loss; 2) evaluate the associations of endocrine, inflammatory and bone markers, anthropometric and other parameters to bone mineral density and content (BMD, BMC) pre- and post-weight loss; and 3) model the contribution of these variables to post weight-loss BMD and BMC.MethodsOverweight/obese women (BMI: 28–37 kg/m²) were enrolled in an energy reduced (− 500 kcal/d; − 2092 kJ/d) diet with adequate dairy (AD: 3–4 servings/d; n = 25, 32.2 ± 8.8 years) or low dairy (LD: ≤ 1 serving/d; n = 26, 31.7 ± 8.4 years). BMD, BMC and body composition were measured by DXA. Bone markers (CTX, PYD, BAP, OC), endocrine (PTH, vitamin D, leptin, adiponectin, ghrelin, amylin, insulin, GLP-1, PAI-1, HOMA) and inflammatory markers (CRP, IL1-β, IL-6, IL-8, TNF-α, cortisol) were measured in serum or plasma. PA was assessed by accelerometry.ResultsFollowing weight loss, AD intake resulted in significantly greater (p = 0.004) lumbar spine BMD and serum osteocalcin (p = 0.004) concentration compared to LD. Pre- and post-body fat was negatively associated with hip and lumbar spine BMC (r = − 0.28, p = 0.04 to − 0.45, p = 0.001). Of note were the significant negative associations among bone markers and IL-1β, TNFα and CRP ranging from r = − 0.29 (p = 0.04) to r = − 0.34 (p = 0.01); magnitude of associations did not change with weight loss. Adiponectin was negatively related to change in osteocalcin. Factor analysis resulted in 8 pre- and post-weight loss factors. Pre-weight loss factors accounted for 13.7% of the total variance in pre-weight loss hip BMD; post-weight loss factors explained 19.6% of the total variance in post-weight loss hip BMD. None of the factors contributed to the variance in lumbar spine BMD.ConclusionAD during weight loss resulted in higher lumbar spine BMD and osteocalcin compared to LD. Significant negative associations were observed between bone and inflammatory markers suggesting that inflammation suppresses bone metabolism. Using factor analysis, 19.6% of total variance in post-weight loss hip BMD could be explained by endocrine, immune, and anthropometric variables, but not lumbar spine BMD.     

Effects of milk salt supplementation on bone mineral gain in pubertal Chinese adolescents: A 2-year randomized,double-blind,controlled, dose–response trial

Background/objectiveAdequate calcium intakes may enhance bone mineral accumulation during childhood. Little is known about the optimal calcium intake in Chinese adolescents. We examined the effects of three levels of calcium intake on bone mineral accretion in adolescents.MethodsThis was a 2-year randomized, double-blind, controlled trial. The subjects were randomly assigned to receive 40 g of milk powder containing 300 mg of calcium and 200 IU of vitamin D (Low-Ca group), or same milk powder additionally fortified with 300 mg of calcium (Mid-Ca group) or 600 mg of calcium (High-Ca group) for 2 years. The subjects' bone mineral density (BMD) and bone mineral content (BMC) at the total body, lumbar spine and left hip were determined by dual-energy X-ray absorptiometry at baseline and after the second year of treatment. Of the 111 girls and 109 boys (aged 12–14 years) enrolled, 91 girls and 91 boys completed the trial.ResultsThe girls in the High-Ca group (1,110 mg/d) had 2.3%, 2.7% and 2.6% greater BMD accretion at the total hip, femoral neck and shaft (P < 0.05) but not at total body less head and spine than those in the Low-Ca group (655 mg/d). A significant effect of higher calcium intake was also observed for percentage change of size-adjusted BMC at femur neck (P = 0.047). Bonferroni tests indicated no significant differences in the percentage changes in BMD, BMC or size-adjusted BMC between the Mid- and Low-Ca groups and between the High- and Mid-Ca groups. Extra calcium had no observable additional effect in the boys (P > 0.05).ConclusionAn intake of 1000 mg/d or more might be helpful in maximizing bone mineral accretion in the hip for girls. But further large studies are required to identify its long-term effects and the optimal calcium intake for boys.     

Embryonic stem cell therapy improves bone quality in a model of impaired fracture healing in the mouse; tracked temporally using in vivo micro-CT

In the current study, we used an estrogen-deficient mouse model of osteoporosis to test the efficacy of a cell-generated bone tissue construct for bone augmentation of an impaired healing fracture. A reduction in new bone formation at the defect site was observed in ovariectomized fractures compared to the control group using repeated measures in vivo micro-computed tomography (μCT) imaging over 4 weeks. A significant increase in the bone mineral density (BMD), trabecular bone volume ratio, and trabecular number, thickness and connectivity were associated with fracture repair in the control group, whereas the fractured bones of the ovariectomized mice exhibited a loss in all of these parameters (p < 0.001). In a separate group, ovariectomized fractures were treated with murine embryonic stem (ES) cell-derived osteoblasts loaded in a three-dimensional collagen I gel and recovery of the bone at the defect site was observed. A significant increase in the trabecular bone volume ratio (p < 0.001) and trabecular number (p < 0.01) was observed by 4 weeks in the fractures treated with cell-loaded collagen matrix compared to those treated with collagen I alone. The stem cell-derived osteoblasts were identified at the fracture site at 4 weeks post-implantation through in situ hybridization histochemistry. Although this cell tracking method was effective, the formation of an ectopic cellular nodule adjacent to the knee joints of two mice suggested that alternative in vivo cell tracking methods should be employed in order to definitively assess migration of the implanted cells. To our knowledge, this study is the first of its kind to examine the efficacy of stem cell therapy for fracture repair in an osteoporosis-related fracture model in vivo. The findings presented provide novel insight into the use of stem cell therapies for bone injuries.     

HR-pQCT based FE analysis of the most distal radius section provides an improved prediction of Colles' fracture load in vitro

The remarkable performances of high-resolution peripheral quantitative computed tomography (HR-pQCT) make the distal radius a favorable site for early diagnosis of osteoporosis and improved Colles' fracture risk assessment. The goal of this study was to investigate if the HR-pQCT-based micro finite element (μFE) method applied on specific sections of the distal radius provides improved predictions of Colles' fracture load in vitro compared to bone mineral content (BMC), bone mineral density (BMD), or histomorphometric indices. HR-pQCT based BMC, BMD, histomorphometric parameters, and μFE models of 9-mm-thick bone sections were used to predict fracture load of 21 distal radii assessed in an experimental model of Colles' fracture reported in a previous study. The analysis was performed on two bone sections: a standard one recommended by the HR-pQCT manufacturer and a second one defined just proximal to the distal subchondral plate. For most of the investigated parameters, significant differences were found between the values of the two sections. Correlations with experimental fracture load and strength were higher in the most distal section, and the difference was statistically significant for μFE strength. Furthermore, the most distal section was computed to have significantly lower ultimate force and strength by 13% and 35%, respectively, than the standard section. BMC provided a better estimation of Colles' fracture load (R² = 0.942) than aBMD or any other histomorphometric indices. The best prediction was achieved with μFE analyses of the most distal slice (R² = 0.962), which provided quantitatively correct ultimate forces.     

Contribution of Serum Inflammatory Markers to Changes in Bone Mineral Content and Density in Postmenopausal Women: A 1-Year Investigation

Bone formation and resorption are influenced by inflammatory processes. We examined the relationships among inflammatory markers and bone mineral content (BMC) and density (BMD) and determined the contribution of inflammatory markers to 1-yr changes in BMC and BMD in healthy postmenopausal women. This analysis included 242 women at baseline from our parent Soy Isoflavones for Reducing Bone Loss project who were randomly assigned to 1 of 3 treatment groups: placebo, 80 mg/d soy isoflavones, or 120 mg/d soy isoflavones. BMD and BMC from the lumbar spine (LS), total proximal femur (hip), and whole body were measured by dual energy X-ray absorptiometry and the 4% distal tibia by peripheral quantitative computed tomography. Serum inflammatory markers (C-reactive protein, interleukin [IL]-1β, IL-6, tumor necrosis factor-alpha [TNF-α], and white blood cell count [WBC]) were measured at baseline, 6, and 12 mo. Because of attrition or missing values, data analysis at 12 mo includes only 235 women. Significant associations among IL-6, TNF-α, and WBC were observed with percent change in LS, hip, and whole body BMC and BMD. Multiple regression analysis indicated that in combination inflammatory markers accounted for 1.1–6.1% of the variance to the observed 12-mo changes in BMC and BMD. Our results suggest that modifying inflammatory markers, even in healthy postmenopausal women, may possibly reduce bone loss.     

Influence of the weight status on bone mineral content and bone mineral density in a group of Lebanese adolescent girls

AimThe aim of this study was to determine the influence of being overweight on whole-body (WB) bone mineral content (BMC) and bone mineral density (BMD) in a group of Lebanese adolescent girls.MethodsThis study included 32 overweight (BMI > 25 kg/m²) adolescent girls (15.3 ± 2.3 years old) and 24 maturation-matched (15.7 ± 1.7 years old) controls (BMI < 25 kg/m²). Bone mineral area (BMA), BMC, BMD at the WB and body composition (lean mass and fat mass) were assessed by dual-energy X-ray absorptiometry (DXA). Calculation of the ratio BMC/height and bone mineral apparent density (BMAD) were completed for the WB.ResultsExpressed as crude values, BMA, BMC and the ratio BMC/height were higher in overweight adolescent girls compared to controls. After adjusting for body weight, there were no differences in BMC or in the ratio BMC/height between the two groups. However, BMA was lower in overweight girls compared to controls. After adjusting for either lean mass or fat mass, there were no significant differences between the two groups regarding these variables: BMC, BMA, BMD, BMC/height and BMAD.ConclusionThis study suggests that the positive effect of overweight on BMC is due to body weight. In fact, the difference in BMC between the overweight and the control girls disappears after adjusting for body weight. In contrast, overweight girls have lower BMA compared to controls when values are adjusted to body weight.     

Calcium and vitamin D supplementation maintains parathyroid hormone and improves bone density during initial military training: A randomized,double-blind,placebo controlled trial

Calcium and vitamin D are essential nutrients for bone health. Periods of activity with repetitive mechanical loading, such as military training, may result in increases in parathyroid hormone (PTH), a key regulator of Ca metabolism, and may be linked to the development of stress fractures. Previous studies indicate that consumption of a Ca and vitamin D supplement may reduce stress fracture risk in female military personnel during initial military training, but circulating markers of Ca and bone metabolism and measures of bone density and strength have not been determined. This randomized, double-blind, placebo-controlled trial sought to determine the effects of providing supplemental Ca and vitamin D (Ca + Vit D, 2000 mg and 1000 IU/d, respectively), delivered as 2 snack bars per day throughout 9 weeks of Army initial military training (or basic combat training, BCT) on PTH, vitamin D status, and measures of bone density and strength in personnel undergoing BCT, as well as independent effects of BCT on bone parameters. A total of 156 men and 87 women enrolled in Army BCT (Fort Sill, OK; 34.7°N latitude) volunteered for this study. Anthropometric, biochemical, and dietary intake data were collected pre- and post-BCT. In addition, peripheral quantitative computed tomography was utilized to assess tibia bone density and strength in a subset of volunteers (n = 46). Consumption of supplemental Ca + Vit D increased circulating ionized Ca (group-by-time, P = 0.022), maintained PTH (group-by-time, P = 0.032), and increased the osteoprotegerin:RANKL ratio (group-by-time, P = 0.006). Consistent with the biochemical markers, Ca + Vit D improved vBMD (group-by-time, P = 0.024) at the 4% site and cortical BMC (group-by-time, P = 0.028) and thickness (group-by-time, P = 0.013) at the 14% site compared to placebo. These data demonstrate the benefit of supplemental Ca and vitamin D for maintaining bone health during periods of elevated bone turnover, such as initial military training.This trial was registered with ClincialTrials.gov, NCT01617109.     

Quantitative computed tomography (QCT) of the forearm using general purpose spiral whole-body CT scanners: Accuracy,precision and comparison with dual-energy X-ray absorptiometry (DXA)

BackgroundDual-energy X-ray absorptiometry (DXA) allows clinically relevant measurement of bone mineral density (BMD) at central and appendicular skeletal sites, but DXA has a limited ability to assess bone geometry and cannot distinguish between the cortical and trabecular bone compartments. Quantitative computed tomography (QCT) can supplement DXA by enabling geometric and compartmental bone assessments. Whole-body spiral CT scanners are widely available and require only seconds per scan, in contrast to peripheral QCT scanners, which have restricted availability, limited spatial resolution, and require several minutes of scanning time.This study evaluated the accuracy and precision of whole-body spiral CT scanners for quantitatively assessing the distal radius, a common site of non-vertebral osteoporosis-related fractures, and compared the CT-measured densitometric values with those obtained from dual-energy-X-ray absorptiometry.Subjects and methodsA total of 161 postmenopausal women with baseline lumbar spine BMD T-scores between ? 1.0 and ? 2.5 underwent left forearm QCT using whole-body spiral CT scanners twice, 1 month apart. QCT volumes of interest were defined and analyzed at 3 specific radial regions: the ultradistal region by using slices at 8, 9, and 10 mm proximal to the ulnar styloid tip; the distal region by a slice 20 mm proximal; and the middle region by a slice 40 mm proximal. BMD, bone mineral content (BMC), volume, and average cortical thickness and circumference were measured. We evaluated QCT accuracy and precision and also report correlations between QCT and DXA for BMD and BMC.ResultsOverall accuracy and precision errors for BMD, BMC and volume were consistent with known skeletal QCT technology precision and were generally less than 3%. BMD and BMC assessed by QCT and DXA were correlated (r = 0.55 to 0.80).DiscussionWhole-body spiral CT scanners allow densitometric evaluations of the distal radius with good accuracy and very good precision. This original and convenient method provides a tool to further investigate cortical and trabecular bone variables in the peripheral skeleton in osteoporotic patients. These assessments, coupled with evaluation of the effects on cortical and trabecular bone measured in response to therapies for osteoporosis, may advance our understanding of the contributors to non-vertebral fracture occurrence.     

Hedgehog signaling mediates woven bone formation and vascularization during stress fracture healing

Hedgehog (Hh) signaling is critical in developmental osteogenesis, and recent studies suggest it may also play a role in regulating osteogenic gene expression in the post-natal setting. However, there is a void of studies directly assessing the effect of Hh inhibition on post-natal osteogenesis. This study utilized a cyclic loading-induced ulnar stress fracture model to evaluate the hypothesis that Hh signaling contributes to osteogenesis and angiogenesis during stress fracture healing. Immediately prior to loading, adult rats were given GDC-0449 (Vismodegib — a selective Hh pathway inhibitor; 50 mg/kg orally twice daily), or vehicle. Hh signaling was upregulated in response to stress fracture at 3 days (Ptch1, Gli1 expression), and was markedly inhibited by GDC-0449 at 1 day and 3 days in the loaded and non-loaded ulnae. GDC-0449 did not affect Hh ligand expression (Shh, Ihh, Dhh) at 1 day, but decreased Shh expression by 37% at 3 days. GDC-0449 decreased woven bone volume (− 37%) and mineral density (− 17%) at 7 days. Dynamic histomorphometry revealed that the 7 day callus was composed predominantly of woven bone in both groups. The observed reduction in woven bone occurred concomitantly with decreased expression of Alpl and Ibsp, but was not associated with differences in early cellular proliferation (as determined by callus PCNA staining at 3 days), osteoblastic differentiation (Osx expression at 1 day and 3 days), chondrogenic gene expression (Acan, Sox9, and Col2α1 expression at 1 day and 3 days), or bone resorption metrics (callus TRAP staining at 3 days, Rankl and Opg expression at 1 day and 3 days). To evaluate angiogenesis, vWF immunohistochemistry showed that GDC-0449 reduced fracture callus blood vessel density by 55% at 3 days, which was associated with increased Hif1α gene expression (+ 30%). Dynamic histomorphometric analysis demonstrated that GDC-0449 also inhibited lamellar bone formation. Lamellar bone analysis of the loaded limb (directly adjacent to the woven bone callus) showed that GDC-0449 significantly decreased mineral apposition rate (MAR) and bone formation rate (BFR/BS) (− 17% and − 20%, respectively). Lamellar BFR/BS in the non-loaded ulna was also significantly decreased (− 37%), indicating that Hh signaling was required for normal bone modeling. In conclusion, Hh signaling plays an important role in post-natal osteogenesis in the setting of stress fracture healing, mediating its effects directly through regulation of bone formation and angiogenesis.     

Bone mineral density changes following discontinuation of ronacaleret treatment: Off-treatment extension of a randomized,dose-finding phase II trial

ContextParathyroidectomy in patients with hyperparathyroidism can produce subsequent increases in bone mineral density (BMD). Ronacaleret, a selective calcium-sensing receptor antagonist that stimulates endogenous parathyroid hormone release, induced mild hyperparathyroidism.ObjectiveThe aim of this study is to evaluate whether BMD changes after cessation of ronacaleret treatment.DesignObservational, off-treatment, extension of a randomized, placebo-controlled, dose-ranging phase II trial.SettingFifteen academic centers in seven countries.PatientsPostmenopausal women with low BMD; 171 out of 569 women in the parent study were enrolled in the extension study.InterventionsSubjects were treated with ronacaleret 100 mg (n = 16), 200 mg (n = 38), 300 mg (n = 35), or 400 mg (n = 32) once daily, alendronate 70 mg (n = 17) once weekly, or matching placebo (n = 33) for 10–12 months; BMD was measured after discontinuation of ronacaleret or alendronate treatment.Main outcome measureMean percent change in lumbar spine areal BMD by dual-energy X-ray absorptiometry at 6–12 months after discontinuing ronacaleret or alendronate compared with the 10- to 12-month BMD measurement of the parent study.ResultsAt the lumbar spine, all doses of ronacaleret resulted in gains in BMD while on treatment. These increases in BMD were maintained or increased after discontinuation of ronacaleret. All doses of ronacaleret caused bone loss at the total hip while on active treatment. However, there was an attenuation of this loss in the off-treatment extension study.ConclusionThe gain in BMD at the lumbar spine was maintained post-treatment and the loss of BMD at the total hip was attenuated. We hypothesize that there may have been some bone remineralization after cessation of ronacaleret.     

Active Comparator Trial of Teriparatide vs Alendronate for Treating Glucocorticoid-Induced Osteoporosis: Results From the Hispanic and Non-Hispanic Cohorts

Glucocorticoid use is a leading cause of secondary osteoporosis. This post hoc analysis compared teriparatide vs alendronate on bone mineral density (BMD) in Hispanic and non-Hispanic patients with glucocorticoid-induced osteoporosis. The 18-mo results from all patients (N = 428) in a double-blind trial of teriparatide (20 μg/d) and alendronate (10 mg/d) who had taken glucocorticoids for ≥3 mo were reported (Saag et al. N Engl J Med 2007). The present study analyzed results from the Hispanic (n = 61) and non-Hispanic (n = 367) cohorts. The BMD was measured by dual-energy X-ray absorptiometry (DXA). In the Hispanic cohort at 18 mo, there were significantly greater increases from baseline in the teriparatide vs alendronate group in lumbar spine BMD (9.8% ± 1.7% vs 4.2% ± 1.4%; p < 0.001; mean ± SE) and total hip BMD (5.9% ± 1.6% vs 1.3% ± 1.3%, p < 0.001), with no significant difference between groups at the femoral neck (4.3% ± 2.2% vs 2.0% ± 1.8%, p = 0.228). Within each treatment group, the BMD responses were not significantly different in the Hispanic vs non-Hispanic cohort. The number of patients reporting ≥1 adverse event was not significantly different between treatments in either cohort, with more patients reporting nausea in the teriparatide group. In summary, teriparatide was more efficacious than alendronate in increasing BMD in Hispanic and non-Hispanic patients with glucocorticoid-induced osteoporosis. Both treatments were generally well tolerated.     

Cost-Minimization Study Comparing Annual Infusion of Zoledronic Acid or Weekly Oral Alendronate in Women With Low Bone Mineral Density

Cost-minimization study to assess the annual direct costs of 2 antiresorptive strategies in postmenopausal women with low bone mineral densities (BMDs). Patients were randomly assigned to receive 70 mg of oral weekly alendronate or a 1-time 5 mg of intravenous zoledronic acid. All medical and nonmedical direct costs were recorded for 1 yr. Student's t-test or the Chi-squared test was used. A total of 101 postmenopausal women were enrolled with a mean age of 58.3 ± 7.6 yr and a postmenopausal period of 13.5 ± 8.3 yr. A total of 50 patients completed 1 yr of alendronate and 51 patients received zoledronic acid. At baseline, no differences were seen between the 2 groups in anthropometric measures, comorbidities, and bone mineral density. The costs for medical attention for low bone mass were $81,532 (US Dollars) for the alendronate group and $69,251 for the zoledronic acid group; the cost per patient was $1631 in the alendronate group vs $1358 in the zoledronic acid group (p < 0.0001). Therefore, zoledronic acid treatment provided an annual savings of 15% of the direct costs compared with oral alendronate treatment. Moreover, there was a significant increase in lumbar spine T-scores in the zoledronic acid group when compared with the alendronate group. Annual zoledronic acid infusion as an antiresorptive treatment in women with low BMD provides significant monetary savings when compared with weekly alendronate therapy for 1 yr. Zoledronic acid infusion is also linked to higher increase in BMD and compliance.     

Use of selective serotonin reuptake inhibitors and bone mass in adolescents: An NHANES study

ContextSelective serotonin reuptake inhibitors (SSRIs) are commonly prescribed medications to treat depression and anxiety. SSRIs exert their effects by inhibiting the serotonin transporter and modulating extracellular serotonin levels, a neurotransmitter that has been shown to affect bone metabolism in animals. Studies in adults suggest a negative association between SSRI use and bone mineral density (BMD), greater rates of bone loss with SSRI use and increased risk of fractures. However, the results on bone mass have been inconsistent. Furthermore, there is a dearth of studies examining an association between SSRI use and bone mass in the pediatric and adolescent age group.ObjectiveTo investigate associations between SSRI use and bone mass in adolescents.DesignCross-sectional analysis of data from the 2005–2010 National Health and Nutrition Examination Study (NHANES).Participants4303 NHANES participants aged 12–20 years. The mean age was 15.65 ± 2.42 years.Main outcomesTotal femur, femoral neck and lumbar spine bone mineral content (BMC) and BMD assessed via dual-energy X-ray absorptiometry (DXA).Results62 out of 4303 subjects used SSRIs. SSRI use was an independent predictor of bone mass after adjusting for age, gender, height and weight Z score, socioeconomic status, physical activity, serum cotinine level and race/ethnicity. After multivariable adjustment, total femur BMC was 8.8% lower among SSRI users versus non-users (mean difference 2.98 g, SE ± 0.105 g, p = 0.0006), while total femur BMD was 6.1% lower (mean difference 0.06 g/cm², SE ± 0.002 g/cm², p = 0.016). Femoral neck BMC and BMD and lumbar spine BMC were similarly negatively associated with SSRI use. Compared to nonusers, lumbar spine BMC was 7% lower among SSRI users (mean difference 0.97 g, SE ± 0.048 g, p = 0.02) and BMD was 3.2% lower (mean difference 0.03 g/cm², SE ± 0.015 g/cm², p = 0.09). Sub-analysis of those individuals treated for more than 6 months yield similar results. Finally, the association of SSRIs with bone mass persisted after excluding individuals with Body Mass Index (BMI) less than 5th percentile thus accounting for the possible confounding effect of anorexia nervosa, which can be treated with SSRIs.ConclusionIn this NHANES study, adolescents treated with SSRIs had lower DXA measurements of the total femur and lumbar spine compared to SSRI non-users. These findings support the need for future prospective studies to examine the effects of SSRI use on bone mass in adolescents.