Trabecular Bone Mineral Content Research Articles

Androgens, But Not Mechanical Loading, Attenuate Bone Loss And High-turnover Osteopenia In Orchiectomized Rats

Supraphysiologic testosterone (T) administration attenuates high turnover osteopenia in orchiectomized (ORX) rats; however, this treatment results in undesirable increases in prostate mass. Trenbolone enanthate (TREN) is a highly anabolic synthetic T analogue which purportedly induces less prostate enlargement than T. PURPOSE: Determine if TREN prevents bone loss and prostate enlargement in middle-aged ORX rats and compare the bone protective effects of TREN to that induced by mechanical overload. METHODS: Ten month old male Brown Norway/F344 rats (n = 10/group) were randomized into Sham surgery, ORX, ORX+weighted ladder climbing (EX), ORX+T (7.0mg/week), and ORX+TREN (1.0mg/week) groups. All animals freely ambulated, while the EX group also completed progressively overloaded 1m ladder climbs (5 climbs × 3 days/week). Animals were sacrificed 42 days following surgery, blood was acquired to measure bone formation (osteocalcin) and resorption (Trap5b), prostates were removed and weighed, and the femurs were prepped for pQCT to determine bone characteristics at the femoral metaphysis. Differences were evaluated by ANOVA. RESULTS: ORX and ORX+EX resulted in a 71% reduction in prostate mass compared to SHAMs (p<0.05). ORX+TREN treatment reduced prostate mass by 20% compared with SHAMs, while ORX+T treatment nearly doubled prostate mass (p<0.05). ORX increased serum osteocalcin by 34% and Trap5b by 13%, and reduced trabecular bone mineral content (tBMC) and bone mineral density (tBMD), and cortical (c)BMD compared with SHAMs (p<0.05). ORX+EX prevented the ORX-induced change in osteocalcin (p<0.05), but did not prevent the increase in Trap5b or ORX-induced bone loss. Conversely, ORX+TREN and ORX+T treatments induced a similar 40% and 51% reduction in osteocalcin and a 37-43% reduction in Trap5b compared with ORX (p<0.05), while maintaining tBMC, tBMD, and cBMD at the level of SHAMs, demonstrating a prevention of ORX-induced high-turnover osteopenia. CONCLUSION: In the absence of endogenous androgens, mechanical overload fails to prevent bone loss. As such, TREN appears to be a suitable agent for further pre-clinical trials intended to prevent hypogonadism-induced bone loss based on its ability to prevent bone loss and beneficially reduce prostate mass. Supported by a VA Merit Award (SEB).

Protective effect of Citrus sinensis and Citrus aurantifolia against osteoporosis and their phytochemical constituents

The efficacy of Citrus aurantifolia L. cv. Swingle and Citrus sinensis L. cv. Liucheng against osteoporosis was evaluated in an ovariectomized rat model. Administration ofCitrus extracts increased trabecular bone mineral content and bone mineral density of tibia, improved the levels of phosphorus and calcium. The results demonstrated that Citrusextracts reduced bone loss in ovariectomized rats. These findings have prompted the authors to investigate the phytochemical constituents of those plants, collected in Saudi Arabia, for the first time. Eighteen compounds were obtained from both plants and classified into, eight coumarins (1 - 8), eight flavonoids (9 - 16) and two sterols analogues (17 and 18). Leaves and peels of C. aurantifolia afforded eleven components, while those of C. sinensis afforded fourteen compounds. Structures of the isolated compounds were deduced by UV, NMR and MS spectra, and comparison with related structures, in whichisobergapten (6), marmesin (7), myricetin (11), 4',5,7-trihydroxy-3,6-dimethoxy flavone (12), and quercetin-3-O-robinobioside (14), were reported to first time from Citrus species,Coumarins, flavonoids and sterols from C. aurantifolia and C. sinensis could be responsible for their antiosteoporotic activity and the action mechanism of these constituents needs to be further studied. Therefore, Citrus extracts have the potential to develop a clinically useful antiosteoporotic agent. Key words: Citrus sinensis, Citrus aurantifolia, osteoporosis, bone mineral density, coumarins, flavonoids, sterols.

Effects of long-term vitamin K 1 (phylloquinone) or vitamin K 2 (menaquinone-4) supplementation on body composition and serum parameters in rats

Vitamin K is a cofactor for γ-glutamyl carboxylase, which is an essential enzyme for the γ-carboxylation of vitamin K-dependent proteins such as osteocalcin and matrix Gla protein. Although it has been suggested that vitamin K plays an important role in the improvement of bone metabolism, the relationship between dietary vitamin K intake and bone metabolism has not been thoroughly investigated. Moreover, vitamin K is thought to have other actions beyond influencing the γ-carboxylation status. In the present study, we examined the effects of the long-term addition of phylloquinone (PK) or menaquinone-4 (MK-4) to a control diet on bone mineral density, bone strength, body composition, and serum parameters in rats. A total of 23 female Sprague–Dawley strain rats (6 weeks old) were divided into three groups: basic control diet group, PK diet (PK: 600 mg/kg diet) group, and MK diet (MK-4: 600 mg/kg diet) group. Three months after starting the experimental diet, the addition of PK to the basic control diet significantly increased the bone mineral density (BMD) of the femur ( p < 0.05). In the MK group, there was no significant difference in the BMD of the femur. However, two types of bone strength parameter: the minimum cross-sectional moment of inertia and the polar moment of inertia, were significantly higher in the MK group than in the control ( p < 0.05, respectively). Furthermore, the femoral bone parameters (the width, dry weight and ash weight, and cortical, cancellous, trabecular, and total bone mineral contents) in the MK group were increased significantly compared with the control. Interestingly, the addition of PK or MK-4 significantly decreased the total fat accumulation ( p < 0.01 and p < 0.05, respectively), and serum triglycerides were reduced by 48% in the PK group and 29% in the MK group compared with the control. There were no significant differences in the levels of serum calcium, phosphorus, alkaline phosphatase, growth hormone, insulin-like growth hormone-1, insulin-like growth hormone binding protein-3, and cross-linked N-teleopeptide of type I collagen among the three groups. This is the first study to demonstrate the effect of the long-term addition of PK or MK-4 to the control diet on body composition and serum parameters in an in vivo system using rats. Further studies on the mechanism of vitamin K supplementation in the regulation of bone metabolism would provide valuable data on the prevention of lifestyle-related disorders, including osteoporosis.

Skeletal recovery after weaning does not require PTHrP

Mice lose 20% to 25% of trabecular bone mineral content (BMC) during lactation and restore it after weaning through unknown mechanisms. We found that tibial Pthrp mRNA expression was upregulated fivefold by 7 days after weaning versus end of lactation in wild-type (WT) mice. To determine whether parathyroid hormone–related protein (PTHrP) stimulates bone formation after weaning, we studied a conditional knockout in which PTHrP is deleted from preosteoblasts and osteoblasts by collagen I promoter–driven Cre (CreColI). These mice are osteopenic as adults but have normal serum calcium, calcitriol, and parathyroid hormone (PTH). Pairs of Pthrpflox/flox;CreColI (null) and WT;CreColI (WT) females were mated and studied through pregnancy, lactation, and 3 weeks of postweaning recovery. By end of lactation, both genotypes lost lumbar spine BMC: WT declined by 20.6% ± 3.3%, and null decreased by 22.5% ± 3.5% (p < .0001 versus baseline; p = NS between genotypes). During postweaning recovery, both restored BMC to baseline: WT to –3.6% ± 3.7% and null to 0.3% ± 3.7% (p = NS versus baseline or between genotypes). Similar loss and full recovery of BMC were seen at the whole body and hind limb. Histomorphometry confirmed that nulls had lower bone mass at baseline and that this was equal to the value achieved after weaning. Osteocalcin, propeptide of type 1 collagen (P1NP), and deoxypyridinoline increased equally during recovery in WT and null mice; PTH decreased and calcitriol increased equally; serum calcium was unchanged. Urine calcium increased during recovery but remained no different between genotypes. Although osteoblast-derived PTHrP is required to maintain adult bone mass and Pthrp mRNA upregulates in bone after weaning, it is not required for recovery of bone mass after lactation. The factors that stimulate postweaning bone formation remain unknown. © 2011 American Society for Bone and Mineral Research.

Age-Related Differences of Bone Mass, Geometry, and Strength in Treatment-Naïve Postmenopausal Women. A Tibia pQCT Study

Most studies addressing the effects of aging on bone strength have focused mainly on (areal) bone mineral densities and bone mineral content (BMC) and less on bone geometry. We assessed age-related differences of bone mass (grams of bone mineral), geometry, and derived strength in 219 treatment-naïve postmenopausal women using peripheral quantitative computed tomography of the load-bearing tibia. Subjects were separated in 3 age groups: A = 48–59 yr (N = 80), B = 60–69 yr (N = 84), C = 70–80 yr (N = 55). Three slices were obtained for each individual, at the 4% (trabecular), 14% (subcortical and cortical), and 38% (cortical bone) of tibia length sites. Trabecular, subcortical, and cortical BMC (mg per 1-mm slice), volumetric bone mineral densities (mg/cm 3), bone cross-sectional areas (mm 2), periosteal (PERI_C, mm) and endosteal circumference (ENDO_C, mm), mean cortical thickness (CRT_THK, mm), and Stress Strain Indexes (SSIs, mm 3) were studied. Trabecular and cortical BMC and volumetric densities were significantly lower in the elder subjects (group C) compared with younger subjects (groups A and B), p < 0.0005. Cortical area and CRT_THK were significantly lower in group C (vs A and B, p < 0.0005), whereas total cross-sectional area was higher in group C compared with A and B. ENDO_C was significantly higher in older subjects (group C vs A and B, p < 0.0005), whereas PERI_C did not differ significantly between the age groups. SSIs were significantly lower in older subjects at the 14% site (group C vs A, p < 0.0005 and C vs B, p < 0.005), and at the 38% site (group C vs group A, p < 0.01). Our results indicate that age-induced differences on bone strength entail significant alterations not only of bone mass, but also of bone geometry.

Areal and volumetric bone mineral density and geometry at two levels of protein intake during caloric restriction: A randomized, controlled trial

Weight reduction induces bone loss by several factors, and the effect of higher protein (HP) intake during caloric restriction on bone mineral density (BMD) is not known. Previous study designs examining the longer-term effects of HP diets have not controlled for total calcium intake between groups and have not examined the relationship between bone and endocrine changes. In this randomized, controlled study, we examined how BMD (areal and volumetric), turnover markers, and hormones [insulin-like growth factor 1 (IGF-1), IGF-binding protein 3 (IGFBP-3), 25-hydroxyvitamin D, parathyroid hormone (PTH), and estradiol] respond to caloric restriction during a 1-year trial using two levels of protein intake. Forty-seven postmenopausal women (58.0 ± 4.4 years; body mass index of 32.1 ± 4.6 kg/m(2) ) completed the 1-year weight-loss trial and were on a higher (HP, 24%, n = 26) or normal protein (NP, 18%, n = 21) and fat intake (28%) with controlled calcium intake of 1.2 g/d. After 1 year, subjects lost 7.0% ± 4.5% of body weight, and protein intake was 86 and 60 g/d in the HP and NP groups, respectively. HP compared with NP diet attenuated loss of BMD at the ultradistal radius, lumbar spine, and total hip and trabecular volumetric BMD and bone mineral content of the tibia. This is consistent with the higher final values of IGF-1 and IGFBP-3 and lower bone-resorption marker (deoxypyridinoline) in the HP group than in the NP group (p < .05). These data show that a higher dietary protein during weight reduction increases serum IGF-1 and attenuates total and trabecular bone loss at certain sites in postmenopausal women.

Comparison of pQCT-Based Measures of Radial Bone Geometry and Apparent Trabecular Bone Structure Using Manufacturer and In-House-Developed Algorithms

Peripheral quantitative computed tomography (pQCT) provides noninvasive densitometric and morphometric measures of total, trabecular, and cortical bone compartments. Skeletal changes over time can be determined by repeated measurements. Image thickness of 2.5 mm is thought to be advantageous with respect to test-retest reliability through interrogation of a significant tissue volume. However, the error associated with slight shifts in image location is unknown. The primary purpose of this study was to determine the effects of positional variability around the 4% site on radial bone measures. The secondary objective was to compare different software algorithms for estimating the same bone characteristics. Eight left cadaveric forearms (aged 65–88 yr) were imaged at 0.5-mm intervals around the 4% site of the radial bone using pQCT (10 slices; in-plane resolution: 0.2 × 0.2 mm; thickness: 2.5 mm; Stratec XCT2000L. We used the manufacturer’s software (Stratec v6.0B) to determine the total bone mineral density (BD_tot), total bone mineral content (BMC_tot), total bone area (Area_tot), trabecular bone mineral density (BD_trab), trabecular bone mineral content (BMC_trab), and trabecular bone area (Area_trab) from each image. For comparison, in-house-developed software was also used to analyze Area_tot and Area_trab at the 4% site. The in-house software also produced measures of apparent trabecular structure, including number (App.Tb.N), thickness (App.Tb.Th), and spacing (App.Tb.Sp), quantified using 2 different stereological approaches: the parallel-plate method using trabecular perimeter lengths and mean intercept length analysis. The effect of slice position was assessed using a 1-way repeated-measures analysis of variance (ANOVA). Reliability of nonsignificant slice distances around the 4% site was determined using intraclass correlation coefficients (ICCs). One-way repeated-measures ANOVA was used to compare measures of similar bone characteristics at the 4% site. Bland-Altman plots were created to assess the level of agreement between pairs of algorithms quantifying comparable apparent trabecular structure. Area_tot and Area_trab differed significantly at greater than or equal to 1.0 mm proximal and greater than or equal to 0.5 mm distal to the 4% site. BMC_tot and BMC_trab differ significantly greater than or equal to 1.5 mm proximally (for both) and greater than or equal to 2.0 and 1.0 mm distally, respectively. BD_tot differed significantly at greater than or equal to 1 mm proximal and distal to the 4% site. BD_trab did not differ among the 10 slices. For images acquired at the 4% site, and 0.5 mm more proximally, reliability was excellent (ICC = 0.98 to 0.99). Although the in-house software yielded a higher value for Area_tot and Area_trab at the 4% site ( p < 0.05), no systematic bias was observed. The parallel-plate method yielded higher values for App.Tb.N and lower values for App.Tb.Th ( p < 0.05), with no systematic bias. App.Tb.Sp values were smaller using the parallel-plate method, and the difference in methods increased as App.Tb.Sp values increased. Statistically, tolerance for repositioning around the 4% site of the radial bone is least for measures of bone area and greatest for BD_trab. On repeated measures, a proximal shift of 0.5 mm will not influence the results.

Pregnant ewes exposed to multiple endocrine disrupting pollutants through sewage sludge-fertilized pasture show an anti-estrogenic effect in their trabecular bone

Pregnant ewes were maintained on pastures fertilized, twice yearly, with either sewage sludge (2.25 tonnes dry matter/ha; Treated; T) or inorganic fertilizer containing equivalent amounts of nitrogen (Control; C), to determine effects on maternal and fetal bone structures, density and mechanical properties of exposure to environmental concentrations of multiple endocrine disrupting compounds (EDCs) and heavy metal pollutants. The ewes were maintained on the respective pastures from the age of about 8 months until they were 4–6 years of age and they were slaughtered at 110 d gestation. Metaphyseal parts of adult ewe femurs exhibited a significantly reduced mean, total cross sectional area (CSA, − 4%; p < 0.05), lower trabecular bone mineral content (BMC, mg/mm; − 18%; p < 0.05), trabecular bone mineral density (BMD, mg/cm 3, − 8.0%; p < 0.05) and trabecular CSA, mm 2, − 11.1%; p < 0.05) in T compared with C animals. Femurs of T ewes were stronger than those of C ewes but this may reflect greater body weights. At the mid-diaphyseal part of the fetal bones, there was a reduction in endosteal circumference (− 6.7%, p < 0.05) and marrow cavity area (− 13.8%, p < 0.05) in the female T fetuses compared with female C fetuses. In the male fetuses the mid-diaphyseal part total bone mineral content was higher (+ 3.0%, p < 0.05) in T than in C animals. No treatment difference in biomechanical bending was detected in the fetuses. It is concluded that ewes grazing pasture fertilized with sewage sludge exhibited an anti-estrogenic effect on their trabecular bone in the form of reduced mineral content and density, despite increased body weight. It is suggested that human exposure to low levels of multiple EDCs may have implications for bone structure and human health.

Changes in bone structure of Corriedale sheep with inherited rickets: A peripheral quantitative computed tomography assessment

An inherited skeletal disease with gross and microscopic features of rickets has been diagnosed in Corriedale sheep in New Zealand. The aim of this study was to quantify the changes present in tibia from sheep with inherited rickets using peripheral quantitative computed tomography. In affected sheep, scans in the proximal tibia, where metaphysis becomes diaphysis, showed significantly greater trabecular bone mineral content (BMC) and bone mineral density (BMD). The sheep with inherited rickets had significantly greater BMC and bone area in the mid-diaphysis of the proximal tibia compared to control sheep. However, BMD in the mid-diaphysis was significantly less in affected sheep than in controls, due to the greater cortical area and lower voxel density values in affected sheep. From this it was concluded that the increased strain on under-mineralised bone in sheep with inherited rickets led to increased bone mass in an attempt to improve bone strength.

Effects on bone tissue in ewes ( Ovies aries) and their foetuses exposed to PCB 118 and PCB 153

The aim of the present study was to investigate whether low levels of mono-ortho PCB 118 and di-ortho PCB 153, affect bone composition and strength in ewes ( Dala breed) and their foetuses following exposure starting at conception and ending a week before expected delivery. In male foetuses, trabecular bone mineral content at the metaphysis was almost 30% lower in the PCB 118 (49 μg/kg body wt/day) group compared to the control group (corn oil) (ANCOVA, P < 0.05). In female foetuses of the PCB 153 (98 μg/kg body wt/day) group trabecular cross-sectional area at the metaphysis was 19% smaller than in the controls (ANCOVA, P<0.05). At the diaphysis a smaller marrow cavity area (up to 24% reduction) was observed in female and male foetuses exposed to PCB 153 compared with controls (ANCOVA, P < 0.05). There were also significant differences at the mid diaphyseal measure point between the PCB 153 and the control group females (ANCOVA, P < 0.05). Cortical and total bone mineral density, cortical thickness were significantly higher, endosteal circumference shorter and marrow cavity significantly smaller in the PCB 153 group (ANCOVA, P < 0.05). In conclusion there were gender dependent effects on bone tissue and cortical bone was more affected than trabecular bone.

Inhibitory Effects of Morinda officinalis Extract on Bone Loss in Ovariectomized Rats

The present study was undertaken to investigate the protective effects of ethanol extract from the root of Morinda Officinalis (RMO) on ovariectomy-induced bone loss. Administration of RMO extract increased trabecular bone mineral content and bone mineral density of tibia, improved the levels of phosphorus (P), calcium (Ca) and OPG, decreased the levels of DPD/Cr, TRAP, ACTH and corticosterone, but did not reverse the levels of ALP, TNF-α and IL-6 in serum of ovariectomized rats. These findings demonstrated that RMO extract reduced bone loss in ovariectomized rats, probably via the inhibition of bone resorption, but was not involved with bone formation. Anthraquinones and polysaccharides from Morinda officinals could be responsible for their antiosteoporotic activity, and the action mechanism of these constituents needs to be further studied. Therefore, RMO has the potential to develop a clinically useful antiosteoporotic agent.

Differential Osteogenic Effect of Phytase Supplementation to a Low Zinc Diet in Rats

Adding vitamin D to a low calcium diet is known to effect trabecular but not cortical bone. Although adding phytase (P) to a low zinc (Zn) diet improves overall bone strength by increasing the bioavailability of Zn and other micronutrients, it is unknown if this supplementation has a differential effect on cortical and trabecular bone.PurposeExamine the effect of P‐supplementation to a low Zn diet in cortical and trabecular bone in both, L‐4 vertebrae and tibiae of rats.MethodsMale Sprague‐Dawley rats were fed a diet containing either 5ppm Zn (ZnLo) (n=10), 5ppm Zn+1,500FTU/kg P (ZnLo+P) (n=10), or 30ppm Zn (ZnAd) (n=10) for 9 wks. In vivo peripheral quantitative computed tomography was used to scan right tibiae at 10% (trabecular parameters) and 50% (cortical parameters) of total. The L‐4 vertebrae were scanned at the 40, 50, and 60% of total length; an average of these represented the mid‐20% vertebral region. One way ANOVA determined group differences for cortical and trabecular bone mineral content (BMC), bone area (BA) and bone mineral density (BMD).ResultsCortical parameters at the L‐4 were significantly higher in rats fed ZnLo+P compared to ZnLo diets. There was no significant difference between groups in trabecular parameters.ConclusionIn contrast to the vitamin D:calcium relationship, P‐supplementation of a low Zn diet exhibited a positive effect on cortical BMD, BMC and BA at the L‐4 site, but had no effect on trabecular or tibial parameters.The study was funded by the U.S.Army MRMC

Targeted Transgenic Expression of an Osteoclastic Transmembrane Protein-tyrosine Phosphatase in Cells of Osteoclastic Lineage Increases Bone Resorption and Bone Loss in Male Young Adult Mice

This study evaluated whether transgenic expression of PTP-oc (osteoclastic transmembrane protein-tyrosine phosphatase) in cells of the osteoclast lineage would affect bone resorption and bone density in young adult mice. Transgenic mice were generated with a transgenic construct using a tartrate-resistant acid phosphatase exon 1C promoter to drive expression of rabbit PTP-oc in osteoclastic cells. pQCT evaluation of femurs of young adult male progeny of three lines showed that transgenic mice had reduced bone volume and area, cortical and trabecular bone mineral content, and density. Histomorphometric analyses at secondary spongiosa of the femur and at metaphysis of the L4 vertebra confirmed that male transgenic mice had decreased trabecular surface, reduced percentage of trabecular area, decreased trabecular number, increased trabecular separation, and increased osteoclast number per bone surface length. Consistent with an increase in bone resorption, the serum C-telopeptide level was 25% higher in transgenic mice than in wild-type littermates. However, the bone phenotype was not readily observed in female young adult transgenic mice. This could in part be due to potential interactions between estrogen and PTP-oc signaling, since the bone loss phenotype was seen in young adult ovariectomized transgenic mice by microcomputed tomography analysis. In vitro, the average pit area per resorption pit created by marrow-derived transgenic osteoclasts was approximately 50% greater than that created by wild-type osteoclasts. Transgenic osteoclasts showed a lower c-Src phosphotyrosine 527 level, greater c-Src kinase activity, and increased tyrosine phosphorylation of paxillin. In summary, this study provides compelling in vivo evidence that PTP-oc is a positive regulator of osteoclasts.

Tibial geometry in individuals with neurofibromatosis type 1 without anterolateral bowing of the lower leg using peripheral quantitative computed tomography

IntroductionLower leg bowing with tibial pseudarthrosis is associated with neurofibromatosis type 1 (NF1). The objective of the study is to determine if the geometry of the lower limb in individuals with neurofibromatosis type 1 (NF1) differs from controls, and to characterize the osseous components of the tibia in NF1. MethodsPeripheral quantitative computed tomography (pQCT) of the lower limb was performed (90 individuals with NF1 without tibial and/or fibular dysplasia: 474 healthy individuals without NF1). Subjects were 4–18 years of age. Individuals with NF1 were compared to controls using an analysis-of-covariance with a fixed set of covariates (age, weight, height, Tanner stage, and gender). ResultsUsing pQCT, NF1 individuals without bowing of the lower leg have smaller periosteal circumferences (p<0.0001), smaller cortical area (p<0.0001), and decreased tibial cortical and trabecular bone mineral content (BMC) (p<0.0001) compared to controls. DiscussionIndividuals with NF1 have a different geometry of the lower leg compared to healthy controls suggesting that NF1 haploinsufficiency impacts bone homeostasis although not resulting in overt anterolateral bowing of the lower leg.

Effect of Temporal Changes in Bone Turnover on the Bone Mineralization Density Distribution: A Computer Simulation Study

The heterogeneous distribution of mineral content in trabecular bone reflects the continuous renewal of bone material in bone remodeling and the subsequent increase in mineral content in the newly formed bone packets. The bone mineralization density distribution (BMDD) is typically used to describe this nonuniform mineral content of the bone matrix. Our mathematical model describes changes of the BMDD of trabecular bone as a function of bone resorption and deposition rates and the mineralization kinetics in a newly formed bone packet. Input parameters used in the simulations were taken from experimental studies. The simulations of the time evolution of the BMDD after increase in bone turnover (perimenopausal period) resulted in a shift of the BMDD toward lower values of the mineral content. Transiently, there was a broadening of the BMDD configuration partly showing two peaks, which points to a strongly heterogeneous distribution of the mineral. Conversely, when the remodeling rate was reduced (antiresorptive therapy), the BMDD shifted toward higher values of the mineral content. There was a transient narrowing of the distribution before broadening again to reach the new steady state. Results from this latter simulation are in good agreement with measurements of the BMDD of patients after 3 and 5 yr of treatment with risedronate. Based on available experimental data on bone remodeling, this model gives reliable predictions of changes in BMDD, an important factor of bone material quality. With the availability of medications with a known effect on bone turnover, this knowledge opens the possibility for therapeutic manipulation of the BMDD.

In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) affects bone tissue in rhesus monkeys

Bone tissue is one of the target tissues for dioxins and dioxin-like compounds. Therefore, the aim of this study was to investigate effects of in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), on bone tissue in rhesus monkey, the most human-like experimental model available. Pregnant rhesus monkeys ( Macaca mulatta; age 4–10 years) were exposed to TCDD with a total dose of 40.5–42.0 or 405–420 ng/kg bodyweight by repeated subcutaneous injections starting at gestational day 20 and followed by injections every 30 days until 90 days after delivery. At a mean age of 7 years the offspring were sacrificed and the femur bone dissected. Results from peripheral Quantitative Computed Tomography (pQCT) analyses of the metaphyseal part of the femur bones in female offspring showed significant increases in trabecular bone mineral content (BMC; +84.6%, p < 0.05, F-value ( F) = 5.9) in the low-dose treatment group compared with the controls. In the same animals, analysis of the mid-diaphyseal part revealed increases in total BMC (+21.3%, p < 0.05, F = 5.2) and cortical cross-sectional area (CSA; +16.4%, p < 0.01, F = 7.4) compared with the controls. In males, changes in biomechanical properties indicating more fragile bone were observed. Displacement at failure were significantly increased in the male low-dose group compared to the controls (+38.0%, p < 0.05, F = 11). The high dose of TCDD did not induce any significant changes in bone morphology. In conclusion, in utero and lactational low-dose, but not high-dose exposure to 2,3,7,8-TCDD induced disruption of bone tissue development in rhesus monkey, a result suggesting that similar effects might occur in humans also.

Preventive effects of Pueraria mirifica on bone loss in ovariectomized rats

Objective Effects of Pueraria mirifica on bone loss in fully mature ovariectomized rats are examined. Methods Two series of experiments were performed. In the first series, rats were kept with their ovaries intact and divided into two groups; initial control (IC) and sham control (SH). The IC rats were sacrificed on day 1 and their data were kept as baseline control. The SH rats were subjected to sham operation on day 0 and gavaged daily with distilled water for 90 days. In the second series, rats were subjected to ovariectomy, divided into five groups and gavaged daily with 0.1 mg/kg B.W./day of 17-alpha-ethinylestradiol (EE), 0, 10, 100 and 1000 mg/kg B.W./day of P. mirifica (P0, P10, P100 and P1000, respectively) for 90 days. Changes of bone mineral density and bone mineral content were measured using peripheral Quantitative Computerized Tomography. Results Bone loss was significantly induced by ovariectomy and it was dose-dependently prevented by P. mirifica treatment for 90 days. The preventive effects of P. mirifica on bone loss depended on bone types (axial or long bone), bone sites (metaphysis or diaphysis), and bone compartments (trabecular and cortical). At P100 and P1000, bone loss was completely prevented both in trabecular bone mineral density and content. The effects of P. mirifica were, as expected, comparable to that in the EE group. Conclusion These results suggest that P. mirifica may be applicable to treat the osteoporosis in menopausal women; however, an undesirable side effect on stimulating reproductive organs should be concerned.

Relationship of Circulating Total Homocysteine and C-Reactive Protein to Trabecular Bone in Postmenopausal Women

Homocysteine (Hcy) and C-reactive protein (CRP) are novel risk factors for osteoporosis. The purpose of this analysis was to determine the relationship of Hcy and CRP to volumetric trabecular bone, but also to assess their relationship to areal composite bone in healthy postmenopausal women (N = 184). We used peripheral quantitative computed tomography to assess volumetric bone at the distal tibia and dual-energy X-ray absorptiometry to assess areal composite bone at the proximal femur and lumbar spine. Multiple regression revealed that 22% of the variability in trabecular bone mineral content ( F = 9.59, p ≤ 0.0001) was accounted for by weight (12.4%; p ≤ 0.0001), hemoglobin (5.5%; p = 0.0006), uric acid (4.2%; p = 0.003), and blood glucose (1.5%; p = 0.07). Multiple regression revealed that 5.4% of the variability in trabecular bone mineral density ( F = 3.36; p = 0.020) was accounted for by hemoglobin (4.2%; p = 0.006) and Hcy (1.5%; not significant, p = 0.10). Total Hcy and CRP were not significantly related to trabecular bone, perhaps because these were nonosteoporotic women. However, our results suggested a weak but negative relationship between Hcy and trabecular bone. Further investigation is needed to examine the relationship of Hcy as an endogenous bioactive molecule to trabecular bone loss in early postmenopausal women and the response of trabecular bone to dietary intervention.

Effects of bisphosphonate on the mandible of rats in the growing phase with steroid‐induced osteoporosis

The objective of this study was to investigate the effects of bisphosphonate on the mandible of rats in the growing phase with steroid-induced osteoporosis, and to estimate the biomechanical response in the mandibular bone. Eight-week-old male Wistar rats (n = 50) were assigned to a 6-week control (Co-6) group, 6-week steroid (St) group, 9-week control (Co-9) group, 9-week steroid + standard diet (StSD) group, or 9-week steroid + standard diet + bisphosphonate (StSDBp) group. The mandibular bone was evaluated by two-dimensional bone density measurement (PDS-15), three-dimensional pQCT, and quantitative analysis of Ca, P, Mg, and Zn using a sequential high frequency plasma spectrometer (ICPS-8000). In PDS-15 analysis, the bone density converted to aluminum equivalent was higher in StSDBp group when compared with the StSD group, and no significant difference was observed in bone density between St group and Co-6 group. In pQCT analysis, trabecular bone density and mineral content were significantly higher, while all other bone parameters were significantly lower in St group when compared with the Co-6 group. The densities of trabecular and cortical bones, mineral content and cross-sectional area of cortical bone, and non-invasive stress strain index with reference to x and yaxes were higher in StSDBp group than in StSD group. In quantitative analyses, Ca and P were markedly higher in StSDBp group than in StSD group, while there were no differences in Mg and Zn. Bisphosphonate treatment increases trabecular and cortical bone parameters in the mandible of growing rats with steroid-induced osteoporosis.

Preventative ibandronate treatment has the most beneficial effect on the microstructure of bone in experimental tumor osteolysis

We investigated the effect of ibandronate on three-dimensional (3-D) microstructure and bone mass in experimentally induced tumor osteolysis. Walker carcinosarcoma cells were implanted into the left femur of female rats that received 26-day ibandronate pretreatment followed by continued therapy or ibandronate posttreatment only. A tumor-only group received isotonic saline. At endpoint, excised femurs were scanned using microcomputed tomography (microCT) to assess bone volume density, bone mineral content, trabecular number/thickness, and separation for cortical plus trabecular bone or trabecular bone alone. Compared with the nonimplanted right femur, bone volume and surface density and trabecular number and thickness were reduced in the distal left femur following tumor cell implantation. microCT analysis revealed greater cortical and trabecular bone mineral content in the preventative and interventional (pre-post tumor) ibandronate group, and the interventional (post-tumor) ibandronate group, versus the tumor-only group. Bone volume density was significantly higher in pre-post and post-tumor groups compared to the tumor-only group. After preventative and interventional ibandronate, bone volume density and trabecular thickness were 13% and 60% greater, respectively, than in the post-tumor treatment group. 3-D microCT images confirmed microstructural changes. We conclude that combined interventional and preventative ibandronate preserves bone strength and integrity more than intervention alone.