Tibia Cortical Thickness Research Articles

The varus alignment and morphologic alterations of proximal tibia affect the onset of medial knee osteoarthritis in rural Japanese women: Case control study from the longitudinal evaluation of Matsudai Knee Osteoarthritis Survey.

Relationship malalignment of the knee and the onset of knee OA are unclear. Moreover, it has not been clarified whether malalignment of the knee affects the morphological change of the proximal tibia. The purpose of current study was to investigate whether varus knee alignment and morphological change of the proximal medial tibia influence the onset of medial knee OA and to clarify the relationship between them. The subjects comprised 736 knees from 390 women that went under both the first survey in 1979 and the fourth survey in 2000 in the Matsudai district in Niigata Prefecture in Japan. None of the subjects demonstrated radiographic knee OA at the first survey. OA was graded according to the Kellgren-Lawrence classification and the subjects were divided according to the OA grades in the forth survey into the 3 groups (non-OA, early OA, and advanced OA). Age, BMI, Femorotibial angle (FTA), the tibial plateau angle and medial tibial cortical bone thickness (MTCBT) were measured. We performed multivariate logistic regression analysis using the stepwise method to identified the risk factors regarding onset of knee OA and calculated the odds ratio (OR) and 95% confidence intervals (95% CI). Advanced OA had a significantly higher OR compared to non-OA in 1979 with the tibial plateau angle (OR: 1.15) and MTCBT (OR: 2.11). And also advanced OA had a significantly higher OR compared to early-OA in 1979 with the tibial plateau angle (OR: 1.17) and MTCBT (OR: 1.62). In the advanced OA, varus alignment of the proximal tibia had already existed before the onset of knee OA. In addition, we thought that varus alignment due to the proximal tibia had influenced the morphologic alterations of proximal medial tibia.

Role of endocortical contouring methods on precision of HR-pQCT-derived cortical micro-architecture in postmenopausal women and young adults

Precision errors of cortical bone micro-architecture from high-resolution peripheral quantitative computed tomography (pQCT) ranged from 1 to 16% and did not differ between automatic or manually modified endocortical contour methods in postmenopausal women or young adults. In postmenopausal women, manually modified contours led to generally higher cortical bone properties when compared to the automated method. First, the objective of the study was to define in vivo precision errors (coefficient of variation root mean square (CV%RMS)) and least significant change (LSC) for cortical bone micro-architecture using two endocortical contouring methods: automatic (AUTO) and manually modified (MOD) in two groups (postmenopausal women and young adults) from high-resolution pQCT (HR-pQCT) scans. Second, it was to compare precision errors and bone outcomes obtained with both methods within and between groups. Using HR-pQCT, we scanned twice the distal radius and tibia of 34 postmenopausal women (mean age ± SD 74 ± 7years) and 30 young adults (27 ± 9years). Cortical micro-architecture was determined using AUTO and MOD contour methods. CV%RMS and LSC were calculated. Repeated measures and multivariate ANOVA were used to compare mean CV% and bone outcomes between the methods within and between the groups. Significance was accepted at P < 0.05. CV%RMS ranged from 0.9 to 16.3%. Within-group precision did not differ between evaluation methods. Compared to young adults, postmenopausal women had better precision for radial cortical porosity (precision difference 9.3%) and pore volume (7.5%) with MOD. Young adults had better precision for cortical thickness (0.8%, MOD) and tibial cortical density (0.2%, AUTO). In postmenopausal women, MOD resulted in 0.2-54% higher values for most cortical outcomes, as well as 6-8% lower radial and tibial cortical BMD and 2% lower tibial cortical thickness. Results suggest that AUTO and MOD endocortical contour methods provide comparable repeatability. In postmenopausal women, manual modification of endocortical contours led to generally higher cortical bone properties when compared to the automated method, while no between-method differences were observed in young adults.

Sensorial, structural and functional response of rats subjected to hind limb immobilization.

This study analyzed the sensorial, structural and functional response of rats subjected to paw immobilization. Animal pelvis, hip, knee and ankle were immobilized using waterproof tape during two weeks for assessment of sensorial response to thermal (hot plate test) and mechanical stimuli (Von Frey test), motor system structure (histology and radiography) and muscle function (soleus contractility). Disuse animals became more responsive to thermal stimuli (49%), although less responsive to mechanical challenge (58%). Disuse animals showed local injuries such as reduction in muscle fiber diameter (16.7% in gastrocnemius, 5.7% in soleus), contractile activity (55% of the control maximal tonic contraction) and tibia cortical thickness (9.3%), besides increased nitrite:protein ratio, suggestive of protein degradation. Disuse also evoked systemic adaptations that include increase in serum lactate dehydrogenase (36.1%) and alkaline phosphatase (400%), but reduction in calcium (8.4%) and total serum protein (5.5%), especially albumin (34.2%). Two weeks of functional paw disuse leads to local and systemic harmful adaptive changes in sensorial and structural systems. This study brings new insights into nervous and motor system mechanism associated with therapeutic limb immobilization in muscle and skeletal pathological conditions.

Lean mass and fat mass have differing associations with bone microarchitecture assessed by high resolution peripheral quantitative computed tomography in men and women from the Hertfordshire Cohort Study

Understanding the effects of muscle and fat on bone is increasingly important in the optimisation of bone health. We explored relationships between bone microarchitecture and body composition in older men and women from the Hertfordshire Cohort Study. 175 men and 167 women aged 72–81years were studied. High resolution peripheral quantitative computed tomography (HRpQCT) images (voxel size 82μm) were acquired from the non-dominant distal radius and tibia with a Scanco XtremeCT scanner. Standard morphological analysis was performed for assessment of macrostructure, densitometry, cortical porosity and trabecular microarchitecture. Body composition was assessed using dual energy X-ray absorptiometry (DXA) (Lunar Prodigy Advanced). Lean mass index (LMI) was calculated as lean mass divided by height squared and fat mass index (FMI) as fat mass divided by height squared. The mean (standard deviation) age in men and women was 76 (3) years. In univariate analyses, tibial cortical area (p<0.01), cortical thickness (p<0.05) and trabecular number (p<0.01) were positively associated with LMI and FMI in both men and women. After mutual adjustment, relationships between cortical area and thickness were only maintained with LMI [tibial cortical area, β (95% confidence interval (CI)): men 6.99 (3.97,10.01), women 3.59 (1.81,5.38)] whereas trabecular number and density were associated with FMI. Interactions by sex were found, including for the relationships of LMI with cortical area and FMI with trabecular area in both the radius and tibia (p<0.05). In conclusion, LMI and FMI appeared to show independent relationships with bone microarchitecture. Further studies are required to confirm the direction of causality and explore the mechanisms underlying these tissue-specific associations.

Effect of dietary available phosphorus and phytase on production performance of old laying hens and tibia bone quality

Background: Old laying hens are more prone to dietary calcium (Ca) and phosphorus (P) deficiencies as they absorb Ca and P less efficiently than younger hens. OBJECTIVES: In a 2×2 factorial design, the influence of diets with two levels of available phosphorus (AP) and phytase enzyme on the laying performance, egg quality and tibia bone characteristics of laying hens at their late 2nd production phase was studied. METHODS: The experiment used four treatments of 20 Hy-Line W36 hens of 140 weeks old. Treatments 1 and 2 received a 3.5 g kg-1 AP diet while Treatments 3 and 4 received a 2.5 g kg-1 AP diet for 12 weeks. Treatments 2 and 4 received 250 FTU kg-1 phytase in their diet. Laying performance, egg weight, shell weight and shell thickness were measured. On the last day of the experiment, all birds were weighed and blood samples were collected for serum Ca and P measurements. Ten birds from each treatment were sacrificed and both tibiae were excised, defatted, weighed and ashed for Ca and P contents, cortical thickness and bone breaking strength measurements. RESULTS: Hens fed with 2.5 g kg-1 AP diet without enzyme had the lowest body weight gain, serum P, tibia cortical thickness and tibia breaking strength among the treatments (p<0.05). Phytase enhanced body weight gain, egg shell thickness, serum P, tibia weight/body weight and tibia ash/body weight ratios, tibia cortical thickness and breaking strength, particularly in birds receiving 2.5 g kg-1 AP diet (p<0.05). CONCLUSIONS: Phytase may improve bone quality and strength of hens in the late 2nd laying period.

Moderate weight loss in obese and overweight men preserves bone quality

Weight loss (WL) negatively affects bone mineral density (BMD) in older populations and has specifically been shown in women. In this prospective controlled trial, we examined variables of bone quality and endocrine changes after intentional WL in men. Thirty-eight overweight and obese [mean ± SD body mass index (in kg/m²): 31.9 ± 4.4; age: 58 ± 6 y] men were recruited to either WL through caloric restriction or weight maintenance (WM) for 6 mo. There was a -7.9 ± 4.4% and +0.2 ± 1.6% change in body weight in the WL and WM groups, respectively. There was a greater increase in femoral neck and total body BMD and bone mineral content (BMC) in the WM group than in the WL group (P-interaction effect < 0.05). In contrast, there was a trend for the tibia cortical thickness and area to decrease more in the WM group than in the WL group (P ≤ 0.08). There was a decrease in the periosteal circumference in both groups over time (P < 0.01) and no statistically significant changes in trabecular bone. Circulating total, free, and bioavailable estradiol decreased in the WL group compared with the WM group, and changes were different between groups (P < 0.05). Serum total and bioavailable testosterone increased in both groups (P < 0.01). Serum 25-hydroxyvitamin D increased to a similar extent in both groups (P < 0.05). Moderate WL in overweight and obese men did not decrease BMD at any anatomical site or alter cortical and trabecular bone and geometry. Also, despite increased BMD at some sites when maintaining excess body weight, cortical bone showed a trend in the opposite direction.

Effects of in ovo injection of bovine lactoferrin before incubation in layer breeder eggs on tibia measurements and performance of laying hens

There is increasing concern about welfare of laying hens in cages, and one aspect of this topic relates to bone fragility. Therefore, bone anabolic components such as bovine lactoferrin (bLF) may be an effective strategy to maintain the integrity and health of bones. A total of 1080 eggs were divided into four groups with three replicates, each comprising 270 eggs; (1) control group was injected with 100 μl of normal saline per egg; (2, 3 and 4) groups including 22.5 (low), 45 (medium) and 67.5 µg (high) of bLF in 100 µl of normal saline per egg. Eggs were incubated and after hatching, chicks were reared to 28 weeks of age. Tibia measurements were obtained at hatch and at 28 weeks of age. Tibia weight at hatch, was not influenced by in ovo injection of bLF in comparison with the control. Eggs injected with the high concentration of bLF (67.5 µg of bLF per egg) showed significant strengthening in laying-hen tibias at 28 weeks of age, as measured by ultimate force and bending stress, compared with the control. Egg weights from hens treated with this concentration of bLF were also significantly greater than the control. Our data suggest that tibia cortical thickness is a suitable variable for evaluating bone status reflecting bone integrity and strength. The present study also shows that bLF (67.5 µg of bLF per egg) injected into layer breeder eggs before incubation can be used to improve bone strength and egg weight of laying hens at 28 weeks of age, while having no detrimental effect on embryo hatchability.

Tibial cortical thickness: A dependable tool for assessing osteoporosis in the absence of dual energy X-ray absorptiopmetry.

Background and Objective:Bone mineral density measurements with absorptiometry dual-energy X-ray absorptiometry (DXA) is the gold standard for diagnosing low bone mass and risk for fragility fractures. DXA is not available at every center, and physicians require an alternative method of diagnosis before referring patients. We conducted this study to assess and compare total cortical thickness (TCT) and its relation to the T score by DXA and its correlation-ship in the diagnosis of osteoporosis.Patients and Methods:Total cortical thickness was carried out in 50 Saudi Arabian females ≥ 45 years with DXA scans and 25 patients with age of ≤ 35 years whose radiographs of the upper tibia were available for analysis. Postero-medial cortical thickness of the tibia was measured 13 cm from the joint line and an average was calculated. The average T score of the spine and the hip was taken. A comparison was made between age, T score, and the TCT. Inter cortical distance (ICD) was measured and compared in both groups. Data were analyzed for predictive value for diagnosis of osteopenia and osteoporosis.Results:There was a significant association between the T score and the TCT and age. As the age advanced the T score and TCT was very low (<0.05, 95% confidence interval [CI] <0.2). Forty patients were osteopenic and 10 osteoporotic. The T score in the former was − 1.33 ± 0.71 and the later was − 3.22 ± 0.56 (P < 0.0001 95% CI: <−1.67) and the TCT was 0.655 ± 0.06 versus 0.51 ± 0.05 (P < 0.0001 95% CI: <−0.17). In women ≤35 years the average TCT was 0.804 ± 0.155 cm and IMD was 3.34 ± 0.45 cm.Conclusions:We conclude that if TCT is less than the threshold value of ≤ 0.5 cm, patients should be referred for further investigations with DXA. We believe that further studies are needed to confirm our findings and in areas where DXA is not available, based on the TCT measurement anti-osteoporotic therapy could be initiated when other risk factors for osteoporosis is present.

Nasal salmon calcitonin blunts bone microstructure alterations in healthy postmenopausal women

In healthy postmenopausal women, nasal salmon calcitonin blunted distal radius and tibia bone microstructure degradation. Nasal salmon calcitonin (NSC) has been reported to lower vertebral fracture risk by 33%, but to modestly increase spine areal bone mineral density (aBMD) by 1.5%. Thus, NSC may also influence bone microstructure, another known determinant of bone strength. In a randomized, double-blind, placebo-controlled trial, we investigated the effects of 200 IU/day NSC on distal radius and tibia bone microstructure (by high-resolution 3-dimensional peripheral quantitative computerized tomography), aBMD (by dual-energy X-ray absorptiometry), and serum bone turnover markers in healthy postmenopausal women. Mean age was 57.6 ± 0.8 (±SEM) and 57.4 ± 0.7 in NSC (n = 45) and placebo groups (n = 45), respectively. Mean femoral neck T-score was in the osteopenic range; prevalent vertebral fracture was 4% in each group. There was no observed between-group difference in the primary outcome distal radius BV/TV (-2.8 ± 0.6% vs. -4.3 ± 1.0%, NS). By 2 years, the decrease in distal radius total density vs. baseline was 4.4 ± 0.7% in controls and 2.1 ± 0.6% in NSC-receiving patients (p < 0.05). Distal radius and tibia cortical thickness decreased by 3.7 ± 1.0 and 2.4 ± 0.5% in placebo (p < 0.05 vs. baseline for both), respectively, but not in the NSC group. Distal radius total density and cortical thickness changes were lower in NSC group than in placebo (p < 0.05 for both) in the subgroup with baseline C-terminal telopeptides (CTX) above the median. By 6 and 12 months, serum CTX decreased by 17.3 ± 6.2 and 19.1 ± 6.6% (both p < 0.05 vs. baseline), respectively, in NSC, but remained stable in controls (NS vs. baseline). There was no difference in aBMD. NSC was well tolerated, with less arthralgia than the placebo group (14 vs. 26, p < 0.05). Nasal salmon calcitonin blunted the degradation of distal radius and tibia bone microstructure in healthy postmenopausal women.

THU0397 Increased Bone Mass and Bone Strength by Sclerostin Antibody (Scl-Ab) is Maintained by a RANKL Inhibitor in OVX Rats with Established Osteopenia

BackgroundSome Scl-Ab-induced BMD gains gradually reversed after treatment discontinuation in rats.ObjectivesTo examine if follow-up treatment with a RANKL inhibitor, OPG-Fc, would maintain Scl-Ab-induced bone mass gains in OVX rats.MethodsSix-month-old OVX...

Adaptations in tibial cortical thickness and total volumetric bone density in postmenopausal South Asian women with small bone size

There is some evidence that South Asian women may have an increased risk of osteoporosis compared with Caucasian women, although whether South Asians are at increased risk of fracture is not clear. It is unknown whether older South Asian women differ from Caucasian women in bone geometry. This is the first study, to the authors' knowledge, to use peripheral Quantitative Computed Tomography (pQCT) to measure radial and tibial bone geometry in postmenopausal South Asian women. In comparison to Caucasian women, Asian women had smaller bone size at the 4% (−18% p<0.001) and 66% radius (−15% p=0.04) as well as increased total density at the 4% (+13% p=0.01) radius. For the tibia, they had a smaller bone size at the 4% (−16% p=0.005) and 14% (−38% p=0.002) sites. Also, Asians had increased cortical thickness (−17% p=0.04) at the 38% tibia, (in proportion to bone size (−30% p=0.003)). Furthermore, at the 4% and 14% tibia there were increased total densities (+12% to +29% p<0.01) and at the 14% tibia there was increased cortical density (+5% p=0.005) in Asians. These differences at the 14% and 38% (but not 4%) remained statistically significant after adjustment for Body Mass Index (BMI). These adaptations are similar to those seen previously in Chinese women. Asian women had reduced strength at the radius and tibia, evidenced by the 20–40% reduction in both polar Strength Strain Index (SSIp) and fracture load (under bending). Overall, the smaller bone size in South Asians is likely to be detrimental to bone strength, despite some adaptations in tibial cortical thickness and tibial and radial density which may partially compensate for this.

Evaluation of bone mineral density and morphology using pQCT in children after spinal cord injury

Objective: To evaluate the effects of spinal cord injury (SCI) on bone density and morphology in children using peripheral quantitative computer tomography (pQCT).Design: Retrospective cohort study of 19 paediatric patients with SCI (9 paraplegics and 10 tetraplegics).Results: There was significant reduction in tibial metaphysial volumetric bone mineral density (vBMD), diaphysial cortical cross-sectional area (CSA), cortical thickness and polar strength–strain index. There was a significant loss of calf muscle CSA. Those who were able to stand had greater trabecular vBMD, tibial cortical thickness and tibial muscle CSA Z-scores. Lower limb fractures did not occur if tibial trabecular vBMD was greater than 100 mg/cm3. Tibial geometry following SCI was more circular compared to controls.Conclusions: pQCT provides a valuable insight into the regional changes in bone and muscle development in children following SCI. Residual muscle function with the ability to weight bear provides a significant benefit to bone development.

Reduced gravitational loading does not account for the skeletal effect of botulinum toxin-induced muscle inhibition suggesting a direct effect of muscle on bone

Intramuscular injection of botulinum toxin (botox) into rodent hindlimbs has developed as a useful model for exploring muscle–bone interactions. Botox-induced muscle inhibition rapidly induces muscle atrophy and subsequent bone loss, with the latter hypothesized to result from reduced muscular loading of the skeleton. However, botox-induced muscle inhibition also reduces gravitational loading (as evident by reduced ground reaction forces during gait) which may account for its negative skeletal effects. The aim of this study was to investigate the skeletal effect of botox-induced muscle inhibition in cage control and tail suspended mice, with tail suspension being used to control for the reduced gravitational loading associated with botox. Female C57BL/6J mice were injected unilaterally with botox and contralaterally with vehicle, and subsequently exposed to tail suspension or normal cage activities for 6weeks. Botox-induced muscle inhibition combined with tail suspension had the largest detrimental effect on the skeleton, causing the least gains in midshaft tibial bone mass, cortical area and cortical thickness, greatest gains in midshaft tibial medullary area, and lowest proximal tibial trabecular bone volume fraction. These data indicate botox-induced muscle inhibition has skeletal effects over and above any effect it has in altering gravitational loading, suggesting that muscle has a direct effect on bone. This effect may be relevant in the development of strategies targeting musculoskeletal health.

Skeletal Effects of the Tyrosine Kinase Inhibitors Imatinib, Dasatinib, and Bosutinib in Young Rats

Abstract 4429 Background:In patients with chronic myeloid leukemia (CML) tyrosine kinase inhibitors (TKIs) such as imatinib (IMA), dasatinib (DASA), and bosutinib (BOSU) are used to selectively inhibit the oncogenic BCR-ABL tyrosine kinase. However, these TKIs also exhibit off-target effects on other kinases (e.g. PDGFR, c-FMS) involved in the regulation of bone metabolism. In adult patients with CML, disturbances in bone structure and metabolism are observed during IMA therapy, while in pediatric patients longitudinal growth retardation represents a major concern. Here, we compared the skeletal effects of chronically administered IMA, DASA, and BOSU in young, growing rats. Methods:From age 4 weeks to age 14 weeks, groups (n=10 each) of male Wistar rats were chronically exposed via the drinking water to concentrations representing i) standard dose and ii) two-fold dose of the standard dose of IMA (i: 1 mM and ii: 2 mM), DASA (i: 50 μM and ii: 100 μM), or BOSU (i: 50 μM and ii: 100 μM). Additional groups received the high doses of the TKIs tested in an intermittent fashion over 3 consecutive days per week. Controls were left untreated. Three to four rats of each group were sacrificed after 2 weeks (prepubertal), 4 weeks (pubertal), or 10 weeks (postpubertal) of exposure, respectively. Biochemical bone markers were analyzed in serum. Bone length of femora and tibiae was determined with calipers. Trabecular (trab) and cortical (cort) bone mineral density (BMD) and cortical thickness were assessed by pQCT. Bone strength of femora was measured by a 3-point bending test. Results:Continuous exposure to IMA and DASA led to dose dependent reductions in femoral and tibial length. No such effect was observed under BOSU exposure. Intermitted exposure of all 3 TKIs tested reduced effects on femoral and tibial length. IMA and DASA lowered femoral and tibial trab BMD in prepubertal rats. At pubertal age, rats receiving high dose IMA showed reduced femoral and tibial trab BMD compared to controls, while no such effect was observed for DASA and BOSU. Postpubertally, femoral and tibial trab BMD did not differ from controls in all groups. Moreover, TKI exposure did not affect femoral or tibial cortical BMD and cortical thickness at any dose and age tested. The bone resorption marker tartrate resistant acidic phosphatase (TRACP) was reduced in rats receiving continuously high dose of IMA at all time points tested, and also in postpubertal rats receiving 50 μM and 100 μM of BOSU. The bone formation marker osteocalcin was reduced in all groups and at all time points under IMA exposure, whereas no such effect was observed for DASA and BOSU. Femoral mechanical properties did not differ from controls pre- and pubertally for all 3 TKIs tested. However, high dose IMA reduced femoral breaking strength in postpubertal rats (Fig.1). DASA or BOSU did not cause changes in biomechanical bone strength. Conclusion:The juvenile rat model is an appropriate model to examine side effects of long-term exposure of TKIs on growing bones. Compared with IMA and DASA, BOSU seems to exert a less negative effect on the bone parameters tested. Given the limited pediatric experience with TKI, regular monitoring of skeletal side effects under long-term TKI treatment is warranted. Moreover, skeletal status and fracture rates should be systematically analyzed in patients under IMA treatment. Acknowledgment:Supported by grant DFG SU122-3/1 to MS, DFG HO 1875/10-1 to LCH, and FWF I 734 to RGE. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Alterations of bone microstructure and strength in end-stage renal failure

End-stage renal disease (ESRD) patients have a high risk of fractures. We evaluated bone microstructure and finite-element analysis-estimated strength and stiffness in patients with ESRD by high-resolution peripheral computed tomography. We observed an alteration of cortical and trabecular bone microstructure and of bone strength and stiffness in ESRD patients. Fragility fractures are common in ESRD patients on dialysis. Alterations of bone microstructure contribute to skeletal fragility, independently of areal bone mineral density. We compared microstructure and finite-element analysis estimates of strength and stiffness by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 33 ESRD patients on dialysis (17 females and 16 males; mean age, 47.0 ± 12.6 years) and 33 age-matched healthy controls. Dialyzed women had lower radius and tibia cortical density with higher radius cortical porosity and lower tibia cortical thickness, compared to controls. Radius trabecular number was lower with higher heterogeneity of the trabecular network. Male patients displayed only a lower radius cortical density. Radius and tibia cortical thickness correlated negatively with bone-specific alkaline phosphatase (BALP). Microstructure did not correlate with parathyroid hormone (PTH) levels. Cortical porosity correlated positively with "Kidney Disease: Improving Global Outcomes" working group PTH level categories (r = 0.36, p < 0.04). BMI correlated positively with trabecular number (r = 0.4, p < 0.02) and negatively with trabecular spacing (r = -0.37, p < 0.03) and trabecular network heterogeneity (r = -0.4, p < 0.02). Biomechanics positively correlated with BMI and negatively with BALP. Cortical and trabecular bone microstructure and calculated bone strength are altered in ESRD patients, predominantly in women. Bone microstructure and biomechanical assessment by HR-pQCT may be of major clinical relevance in the evaluation of bone fragility in ESRD patients.

P02-19 Auxology, GH-IGF-I status and response to rhGH in 3-M syndrome

and has prompted research into alternative approaches to GH treatment. NNC0195–0092 is a hGH derivative conjugated with an albumin binding moiety. The in vivo pharmacodynamic and pharmacokinetic properties of NNC195–0092 have been studied in hypophysectomised rats, mini-pigs and cynomolgus monkeys. NNC0195–0092 induced a dose-dependent increase in body weight of hypophysectomised rats and increase in plasma IGF-I levels in rats, mini-pigs, and cynomolgus monkeys. Multiple once weekly dosing of hypophysectomised rats with NNC195–0092 induced a step-wise increase in body weight with an initial linear growth the first 3–4 days in each dosing interval. During the 28 days study period with 4 once weekly doses of NNC195–0092, body weight was increased by 52% compared to a vehicle control group. The IGF-I levels increased after each dose and returned to the same trough level in each dosing interval. Significant increases in body lean mass, tibia bone mineral content, and tibia cortical thickness were observed together with a decrease in body fat mass compared to a vehicle control group. Pharmacokinetics in all three species has indicated a 1. order absorption from the subcutaneous tissue after a s.c. injection and a non-linear elimination. Apparent terminal half-lives of 5–6 hours in rats, 10–12 hours in mini-pigs, and 17–20 hours in monkeys have been observed. The bioavailability was estimated to 39% in rats, 36 % in mini-pigs, and 69 % in monkeys. In conclusion, once weekly s.c. administration of NNC0195– 0092 exhibit pharmacokinetic and pharmacodynamic properties indicating that NNC195–0092 is a potential once weekly growth hormone candidate.

Enhanced trabecular bone resorption and microstructural bone changes in rats after removal of the cecum

The cecum, the proximal part of the large intestine, has the highest rate of calcium absorption compared with other intestinal segments. Previously, we showed that rats with the cecum surgically removed (cecectomized rats) had severe negative calcium balance, low bone mineral density (BMD), and a compensatory increase in colonic calcium absorption. Herein, we used the computer-assisted bone histomorphometric technique and microcomputed tomography (μCT) to analyze bone microstructural defects in cecectomized rats at 1 and 3 mo postsurgery compared with age-matched sham-operated control rats. Relatively low BMD as determined by dual energy X-ray absorptiometry was observed in the femora, tibiae, and lumbar vertebrae of the 3-mo cecectomized rats. μCT analysis revealed decreases in the tibial cortical thickness, periosteal and endosteal perimeters, and moment of inertia in cecectomized rats. The histomorphometric results further showed that trabecular bone volume and number were markedly decreased, whereas trabecular separation was increased in the proximal tibial metaphysis of cecectomized rats, thus leading to a decrease in trabecular volumetric BMD. Since osteoclast surface and eroded surface were increased after cecectomy, such bone loss in cecectomized rats appeared to result from an enhanced bone resorption. Moreover, decreases in bone formation rate and osteoblast surface indicated a suppression of osteoblast-mediated bone formation. In conclusion, cecectomy induced widespread osteopenia in rats presumably by enhancing the osteoclast-mediated bone resorption and suppressing bone formation. The present results underline the important role of cecum in the body calcium homeostasis.

Comparison of Cortical Bone Measurements Between pQCT and HR-pQCT

The primary purpose of this study was to determine the accuracy of tibial cortical thickness measurements derived from peripheral quantitative computed tomography (pQCT) with analysis based on the circular ring model, using high-resolution peripheral quantitative computed tomography (HR-pQCT) (isotopic voxel size of 82μm) as a gold standard. The secondary objective was to evaluate whether the accuracy of the pQCT-based estimates of cortical thickness (CTh), cortical area (CoA), cortical density (CDen), and total area (TotA) improve with alterations of voxel size from the standard 0.5–0.2mm. Fifteen dry tibia specimens were immersed in saline in a sealed cylinder and scanned 22.5mm from the distal tibia plateau using pQCT and HR-pQCT. pQCT yielded higher values for CTh and CDen and lower values for CoA. The differences between imaging techniques increased as the average CTh increased. No systematic bias was observed for CDen, CoA, and TotA. Similar differences were found between pQCT with voxel size 0.2mm and HR-pQCT. Significant correlations were observed for CTh (R=0.97, p≤0.0001), CDen (R=0.99, p≤0.0001), CoA (R=0.98, p≤0.0001), and TotA (R=1.0, p≤0.0001) when pQCT- and HR-pQCT-derived values were compared irrespective of which voxel size was used. Measurement variability between the imaging techniques was evident. Future studies aimed at examining cortical structure with pQCT should note that there are differences between the 2 techniques.

X-ray Knee as a Screening Tool for Osteoporosis

Cortical thickness (Cor-Th) of tibia varies considerably on X-ray knees. It was hypothesized that Cor-Th can be used for preliminary prediction of BMD. Ninety nine patients underwent a digital X-ray left knee fixed flexion PA view with an external calibration scale attached to X-ray plate and BMD by DXA using GE lunar machine (Madison, Wisconsin.). Cor-Th was measured at 5 selected levels (A,B,C,D, and E) ranging from 5–7cm below the tibial plateau on its medial aspect. T-scores were recorded for BMD at AP spine, left forearm and left femur. Cor-Th of tibia at each level significantly correlated with each site of BMD measurement namely AP spine, left femur and left forearm. This correlation varied in the range from 0.241 to 0.426. For AP spine, it was maximum at level C (r=0.347, p<0.001) whereas for left femur and forearm sites, it was maximum at level B (r=0.426 &r=0.373 respectively, p<0.001). The correlation of Cor-Th with BMD varied with age. Above 56 years of age, Cor-Th at each level significantly correlated to BMD at each site. Medial tibial cortical thickness, 6cm (level C) below tibial plateau can be used as preliminary predictor of patients who need a DXA scan.

Alcohol-induced Bone Loss and Quality during Adolescence is Improved by Green Tea Polyphenols

Our previous studies have shown significant osteo-protective effects of green tea polyphenols (GTP, green tea extract) in various bone loss models. To test the hypothesis that green tea supplementation would protect against binge alcohol-induced deterioration of bone quality in adolescent drinkers, we used a similar approach with green tea supplementation in drinking water. Using a six week, 2 × 3 factorial design of treatment × dose in male Sprague Dawley (SD) adolescent rats, bone parameters [femoral and lumbar vertebrae-4 (LV-4) area (BMA), bone mineral content (BMC), bone mineral density (BMD)], bone turnover biomarkers [serum osteocalcein (OC) and tartrateresistant acid phosphatase-5b (TRAP-5b)] and blood chemistry were measured. The blood chemistry results showed that alcohol administration significantly decreased albumin, glucose, alkaline phosphatase, and amylase levels; increased globulin, phosphorus, creatine kinase, cholesterol, and potassium levels; and had no effect on protein, calcium, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, sodium, and chloride. GTP supplementation significantly suppressed alkaline phosphatase levels and had no impact on other blood chemistry parameters. Alcohol administration lowered BMA, BMC, and BMD of the femur and LV-4, as well as serum TRAP-5b, but had no impact on serum OC. Supplementation of GTP into the drinking water increased BMD for the femur and BMC for the LV-4. GTP had no effect on scanned BMA or serum OC concentration. There was an interaction between the alcohol administration and GTP dosage in serum TRAP-5b and several parameters of bone strength, which reduced the negative effect on alcohol-induced bone modeling. In summary, our results show that a 6-week binge alcohol administration lowered bone mineral content, density, and strength in femura, reduced proximal tibial trabecular bone volume and lumbar vertebrae, and decreased cortical thickness at the tibial middiaphysis. Supplementation of GTP into the drinking water increased femoral bone mineral density and tibial cortical thickness at the mid-diaphysis. Importantly, GTP supplementation into drinking water improved overall bone quality in young binge-alcohol treated male rats through suppressing bone turnover rate.