The effect of modelling and remodelling on human vertebral body architecture.

Vertebral bone strength is determined by several factors: cortical thickness, bone size, trabecular bone density, and microarchitecture. All these factors change with age as a result of the two dynamic processes: remodelling and modelling. When the changes become pronounced, osteoporotic fractures occur. There is a different aging pattern for men and women: 1. Men achieve a higher peak bone mass than women (mainly because of a larger cross-sectional area of their bones); 2. Men have no accelerated bone loss in middle age; and 3. Men seem to be able to compensate for their loss of cancellous bone strength by increasing their vertebral cross-sectional area with age. The general pattern, for both men and women is, though, that of an extreme (70-80%) decline in whole vertebral body strength during normal aging. The accompanying decline in bone density is much less pronounced (35-45%). This clearly illustrates the power relationship between bone density and strength. However, the role of changes in trabecular bone microarchitecture for vertebral bone strength during aging still needs to be determined.     

Use of calcaneal ultrasound and biochemical markers to assess the density and metabolic state of the bones of adults with hepatic cirrhosis

Bone loss has been shown to be associated with chronic liver disease (CLD) caused by ethanol consumption or viral infection, and trabecular bone is affected more than cortical bone. We therefore used calcaneal ultrasound to compare the bone status of 54 males and 20 females with CLD in northern Nigeria with 88 age- and gender-matched healthy controls. Serum levels of bone-specific alkaline phosphatase (BSAP) and the N-terminal telopeptide of type-1 collagen (NTx) were also measured to estimate relative rates of bone synthesis and turnover, respectively. The mean stiffness index (SI) of the males with CLD and the male controls were not different; however, the mean SI of the female subjects with CLD was lower than for the female controls (101 vs. 86, p=0.003). The levels of NTx and BSAP were markedly elevated in the males, but not in the females, with CLD. Liver function tests did not correlate with ultrasound parameters or biochemical markers of bone metabolism. These results show that Nigerian women, but not males, with CLD have decreased bone density as assessed by calcaneal ultrasound; however, the high rate of bone turnover in Nigerian males with CLD indicates that they are at risk for bone loss.     

In vivo high resolution 3D-QCT of the human forearm.

In vivo examinations of bone microarchitecture have become available recently through high resolution computed tomography (3D-QCT) and magnetic resonance imaging. The spatial resolution of the resulting images, however, is not sufficient to depict individual trabeculae in their true shape. Nevertheless, structural indices such as relative bone volume, trabecular number, mean thickness and mean separation can be extracted with the help of a ridge detection algorithm. Precision of the procedure is of the order of 1%, accuracy is ascertained using a micro-CT based calibration. In this work we report first results of time serial examinations. Eighteen healthy postmenopausal women (no HRT) were measured at months 0, 6, and 12, and the temporal changes were analyzed. Examination site was the distal radius. The above mentioned structural indices, the average densities and the thickness of the cortical shell were determined. Of the 18 women 6 showed no significant bone loss of any kind, 5 lost primarily cancellous bone, 4 lost primarily cortical bone, and 3 had a substantial loss of cortical as well as cancellous bone. We conclude that even in a homogenous group such as postmenopausal women, there are considerable differences in the reason why bone is weakened and that high resolution 3D-QCT allows to differentiate between various types of bone loss.     

Influence of pattern of menopausal transition on the amount of trabecular bone loss. Results from a 6-year prospective longitudinal study

INTRODUCTION: Bone density is lower in postmenopausal than in premenopausal women. Recent findings have suggested that accelerated bone loss already begins before menopause. Despite numerous cross-sectional studies on menopause-related bone density, longitudinal data on perimenopausal bone density changes are scarce. This study sought to characterize the dynamics of changes leading to postmenopausal osteopenia and to possibly find the time point at which accelerated bone loss begins. METHODS: We prospectively followed 34 pre-, peri- and early postmenopausal women without prior external hormone use, measuring their lumbar spine trabecular bone density with quantitative computer tomography at 0, 2 and 6 years. The analysis of the changes over time was done in a tri-parted fashion, since menopausal status changed variably for individual subjects: we grouped the participants according to their currently valid menopausal classification for prospective (baseline classification), interim (2 years) and retrospective (6-year classification) analysis. RESULTS: Six different patterns of menopausal transition were identified in our sample. Bone loss in the groups not reaching postmenopause during 6 years of observation was >50% of the maximum bone loss observed during the study period. Invariably for all analyses, the perimenopausal phase with estrogen levels still adequate was associated with the greatest reduction of trabecular bone mineral density, reaching 6.3% loss annually in the lumbar spine. By comparison, the average rate of loss was slower in the early postmenopause; total bone loss differed by pattern of menopausal transition (one-way ANOVA p<0.05). CONCLUSION: The presented data for the first time show the perimenopausal course of trabecular bone loss (as measured by QCT of the lumbar spine). Acceleration of bone loss during perimenopause reached half-maximal values of the total bone loss measured around menopause, despite adequate serum estradiol levels.     

Differential effect of long-term oestrogen therapy on trabecular and cortical bone

The effect of long-term oestrogen therapy has been assessed in 40 oophorectomised women. Twenty-one of the women had received mestranol (mean 26 micrograms/day) and 19 received placebo tablets for a mean duration of 14 yr. A newly developed gamma-ray computed tomography (CT) scanner was used to measure trabecular and cortical bone separately in the distal radius. Bone density in the lumbar spine was measured using dual photon absorptiometry (DPA). Prevention against bone loss was demonstrated at all sites for the mestranol treated group (P less than 0.01). The deficit of radial trabecular bone (27%) was greater than that for radical cortical bone (14%). The deficit for the spine was intermediate (20%). One-year follow-up radial measurements showed a significant 1.2% increase (P less than 0.01) in cortical bone for the treated group. The DPA measurement was found to be best correlated (r = 0.80) with a mixed trabecular and cortical bone parameter in the radius. We conclude that the degree of bone loss at any site is dependent on the proportion of trabecular bone present.     

Estrogen receptor alpha polymorphism as a genetic marker for bone loss, vertebral fractures and susceptibility to estrogen

OBJECTIVE: The purpose of the present study was to investigate the possible roles of PvuII and XbaI polymorphisms of the estrogen receptor alpha (ER(alpha)) in bone mineral density (BMD), vertebral fracture, bone loss rate after menopause and response to hormone replacement therapy (HRT). METHODS: All 286 women were grouped according to the genotypes of PvuII or XbaI polymorphisms of the ER(alpha) gene. We compared the BMD Z-score, incidence of vertebral fracture, changes in Z-score after menopause and response of BMD to HRT among the genotypes. RESULTS: Subjects with the PPxx genotype had significantly (P<0.05) lower Z-scores than did subjects with the other genotypes. A negative correlation was observed between the length of time after menopause and the decrease of the Z-score only in women with the pp genotype, suggesting faster bone loss in this group. In the analysis of the ER(alpha) polymorphism with regard to the effect of HRT on BMD, there appears to be a significantly greater increase of BMD (P<0.01 and 0.05) in women with the pp genotype than in those with the Pp or PP genotype. CONCLUSIONS: PvuII and XbaI polymorphisms of the ER(alpha) gene were associated with BMD in postmenopausal Japanese women. Also, the polymorphisms may be useful genetic markers for predicting vertebral fracture in relatively young postmenopausal women. The PvuII polymorphism may be associated with susceptibility to changes in estrogen level.     

Age-related changes in iliac crest cortical width and porosity: a histomorphometric study

Although age-related changes in cancellous bone structure in human are relatively well characterized, few studies have addressed changes in cortical bone. We have investigated age-related changes in iliac crest bone biopsy specimens from 54 normal subjects, 23 men and 31 women, aged 18-90 years. A significant decrease in cortical width and area was seen (P =0.002 and <0.001 respectively), with no difference between sexes. Haversian canal density increased significantly with age by approximately 9% per decade (P = 0.032) but Haversian canal area tended to be lower, resulting in no overall age-related difference in cortical porosity. Haversian canal area was significantly higher in the endosteal section than in the periosteal section of the cortex (P = 0.019) but the Haversian canal density was lower, resulting in similar overall porosity in the two sections. In conclusion, our results demonstrate an age-related decrease in iliac crest cortical width in men and women and an increase in Haversian canal density, but no overall change in cortical porosity.     

Constitutive modelling of inelastic behaviour of cortical bone

A visco-elasto-plastic constitutive model is formulated for investigating the mechanics of cortical bone tissue, accounting for an anisotropic configuration and post-elastic and time-dependent phenomena. The constitutive model is developed with reference to experimental data obtained from literature on the behaviour of cortical bone taken from multiple samples. Regarding the constitutive model, a specific procedure based on a coupled deterministic and stochastic method is applied in order to determine the values of the constitutive parameters with regard to human samples. The procedure entails processing of data deduced from mechanical tests to achieve relationships between permanent and total strain, elastic modulus and strain rate, and creep elastic modulus and time. Numerical results obtained by using a finite element model are compared with tensile experimental data on cortical bone including the post-elastic range and creep phenomena. The model shows an excellent capability to describe the tensile behaviour of the cortical bone for the specific mechanical condition analysed.     

Structural analysis of the human tibia by tomographic (pQCT) serial scans

This study analyses the evaluation of tomographic indicators of tibia structure, assuming that the usual loading pattern shifts from uniaxial compression close to the heel to a combined compression, torsion and bending scheme towards the knee. To this end, pQCT scans were obtained at 5% intervals of the tibia length (S5–S95 sites from heel to knee) in healthy men and women (10/10) aged 20–40 years. Indicators of bone mass [cortical area, cortical/total bone mineral content (BMC)], diaphyseal design (peri/endosteal perimeters, cortical thickness, circularity, bending/torsion moments of inertia – CSMIs), and material quality [(cortical vBMD (bone mineral density)] were determined. The longitudinal patterns of variation of these measures were similar between genders, but male values were always higher except for cortical vBMD. Expression of BMC data as percentages of the minimal values obtained along the bone eliminated those differences. The correlative variations in cortical area, BMC and thickness, periosteal perimeter and CSMIs along the bone showed that cortical bone mass was predominantly associated with cortical thickness toward the mid‐diaphysis, and with bone diameter and CSMIs moving more proximally. Positive relationships between CSMIs (y) and total BMC (x) showed men’s values shifting to the upper‐right region of the graph and women’s values shifting to the lower‐left region. Total BMC decayed about 33% from S5 to S15 (where minimum total BMC and CSMI values and variances and maximum circularity were observed) and increased until S45, reaching the original S5 value at S40. The observed gender‐related differences reflected the natural allometric relationships. However, the data also suggested that men distribute their available cortical mass more efficiently than women. The minimum amount and variance of mass indicators and CSMIs, and the largest circularity observed at S15 reflected the assumed adaptation to compression pattern at that level. The increase in CSMIs (successively for torsion, A–P bending, and lateral bending), the decrease in circularity values and the changes in cortical thickness and periosteal perimeter toward the knee described the progressive adaptation to increasing torsion and bending stresses. In agreement with the biomechanical background, the described relationships: (i) identify the sites at which some changes in tibial stresses and diaphyseal structure take place, possibly associated with fracture incidence; (ii) allow prediction of mass indicators at any site from single determinations; (iii) establish the proportionality between the total bone mass at regions with highly predominant trabecular and cortical bone of the same individual, suitable for a specific evaluation of changes in trabecular mass; and (iv) evaluate the ability of bone tissue to self‐distribute the available cortical bone according to specific stress patterns, avoiding many anthropometric and gender‐derived influences.     

Peripheral quantitative computed tomography (pQCT) is useful for monitoring bone mineral density of the patients who receive hormone replacement therapy

OBJECTIVE: A forearm fracture (Colles' fracture) is often the first sign of osteoporosis and should alert the patient and physician to the possibility of underlying skeletal fragility. Therefore, the establishment of a more accurate and reliable method for the measurement of bone mineral density (BMD) at the distal radius would be beneficial for the patients who suffer from osteoporosis. The objective of the present study was to evaluate the usefulness of peripheral quantitative computed tomography (pQCT) to assess the change of BMD at the distal radius in early postmenopausal women who receive hormone replacement therapy (HRT). METHODS: Twenty healthy early postmenopausal women who were diagnosed as osteoporosis or osteopenia were randomized to either HRT or placebo treatment. We analyzed BMD of the distal radius by pQCT, lumbar spine by dual-energy X-ray absorptiometry (DXA) and the biochemical markers of bone turn over (osteocalcin, deoxypyridinoline) every 6 months. RESULTS: The placebo group showed a significant decrease from the baseline in the trabecular BMD of the radius at 12 months (7.4+/-2.5%) (p<0.05), whereas the HRT group showed a slight increase (0.7+/-2.2%). The changes in the trabecular BMD of the radius between the HRT and placebo groups were statistically different at 12 months (p<0.05). On the other hand, in the cortical BMD of the radius, no significant differences were seen between the changes of bone densities in the HRT and control groups after 1 year of treatment. pQCT could detect a significant loss of BMD of the radius in early postmenopausal women after 1 year and HRT prevented its loss. CONCLUSION: Our preliminary clinical trial showed that pQCT might be useful for the early detection of bone loss in early postmenopausal women and for the monitoring BMD of the patients who receive HRT.     

Bone mineral content of the forearm in healthy Dutch women

Single energy photon absorptiometry is a reliable technique for assessing the bone mineral content (BMC) of cortical bone in the forearm. It can also be used for BMC measurement in the ultradistal part of the forearm, where there is a considerable proportion of trabecular bone. The results of a BMC survey at both sites in healthy Dutch women, aged 26-75 yr, are reported, and the differences and changes with age are discussed. The technique offers possibilities for a rational screening programme in post-menopausal women, because of its high precision, low radiation dose, speed and low cost. The validity of the ultradistal measurement for the detection of abnormally fast bone mineral loss from trabecular bone in the individual patient has yet to be proven.     

The effect of estrogen dose on postmenopausal bone loss

In order to establish whether the favorable effect of estrogen therapy on postmenopausal bone loss was dose related, we measured sequential changes in the cortical diameters of the metacarpals by radiographic morphometry in 120 normal postmenopausal women who were being treated with ethinyl estradiol in doses ranging from 5 to 50 micrograms daily. There was a net loss of bone at doses below 15 micrograms per day and a net gain at doses of 25 micrograms per day and above. At doses between 15 and 25 micrograms daily, bone was neither gained nor lost. The loss of bone with the low doses was due to expansion of the medullary cavity that was unaccompanied by any change in total bone width. There was no change in bone volume with the intermediate doses because endosteal resorption of bone was offset by periosteal apposition. The net gain of bone with the higher doses occurred because endosteal resorption was totally inhibited but periosteal bone apposition continued. Thus, in postmenopausal women the reduction in the rate of cortical bone loss in response to estrogen therapy depends on the dose administered.     

Continuing bone expansion and increasing bone loss over a two-decade period in men and women from a total community sample

As shown in 744 adult men and women aged 30–49 at entry and followed for 21.4 ± 0.9 years there is continuing subperiosteal expansion in both sexes as well as continuing and increasing endosteal surface resorption. In this longitudinal study, bone loss (as shown by medullary cavity expansion) begins by the 5th decade and increases thereafter. The smaller gains at the outer bone surface are essentially independent of the larger losses at the inner (endosteal) surface and neither functionally nor causally related. Though bone loss and net bone loss is nearly as great in men as in women, absolutely speaking, two-decade bone loss constitutes a larger percentage of the initially smaller bone mass in the female. In both sexes subperiosteal apposition (delta TA) and endosteal resorption (delta MA) are bone-size dependent though in diametrically opposite directions. These trends in two-decade bone change are not affected by smoking behavior, alcoholic beverage usage, antihypertensive usage, or early menopausal age. Similarly, the long-term bone changes prove to be independent of energy and mineral intakes and to long-term changes in calcium, phosphorus, magnesium, and vitamin D intake. Though dietary intakes do not predict long-term bone changes, the amount of tissue bone present at entry is highly correlated (> 0.93) with tissue bone 21.4 years later in men and women alike. Accordingly, only a small amount of intraindividual cortical variance in the later years still remains to be explained by life-style, dietary, medication, and error variables.     

Aging of bone density in the second metacarpal.

Bone weight, bone and cortical areas, and apparent and true bone densities (W/BV and W/CV) were measured on the second metacarpals of 114 male and 114 female Japanese, aged 30 to 98 years. Measurements were taken from midshaft cross-sections 2 mm thick, using an electron balance and an image analyzing system. The mean values of these variables were greater in men than in women at all ages. Bone area stayed almost unchanged regardless of age. Bone weight and cortical area decreased linearly with advancing age. The respective rates of decrease per decade observed for the these variables were 3.1% and 2.9% in men and 5.5% and 4.8% in women. Apparent bone density decreased gradually with age after the fourth decade in women. While, in men, it stayed almost unchanged or increased slightly until the fifth decade and then, decreased gradually with age. The rate of decrease per decade was accelerated after the fifth decade in women and after the sixth in men, being 10.3% and 8.1% in each gender, respectively. The mean loss of bone was about twice as great in women as in men. In women, significant differences (p less than 0.01) were found in these variables after the seventh decade compared with the preceding age group. However, true bone density (W/CV) stayed almost unchanged regardless of age, being about 2.0 in men and about 1.9 in women. Osteoporosis could be primarily a manifestation of normal aging, including the postmenopausal estrogen deficiency in women, regardless of gender or race.     

Risk factors for bone loss in the hip of 75-year-old women: A 4-year follow-up study

Risk factors for bone loss among the elderly are largely unknown. The objective of the study was to examine longitudinal bone loss in the hip in one-hundred and sixty-two 75-year-old women. Bone mineral density (BMD, g/cm²) was measured with dual X-ray absorptiometry (DXA) at baseline and after 4 years. The relationship between changes in BMD during follow-up and the following factors; baseline BMD, baseline weight, weight change, baseline lean and fat body mass (measured with DXA), serum values of biochemical markers and hormones, nutritional and lifestyle factors according to a questionnaire was assessed.     

Combined 2.25 MHz ultrasound velocity and bone mineral density measurements in the equine metacarpus and theirin vivo applications

A simple noninvasive ultrasound method is described for estimating the transverse cortical bone ultrasound velocity and the cross-sectional area of the equine third metacarpal bone (MC3). The method relies on measuring the time of flight of the ultrasound for each of two pathways, via the cortical shaft and through the central medulla. Ten metacarpal bones of approximately the same dimensions were selected to evaluate the method and to determine the practiocal correction factors Factors were established for the ovality of the external cortical boundary and the medullary cavity as well as corrections for the presence of the splint bones (second and fourth metacarpal bones, MC2 and MC4) which influence, the total cortical cross-sectional area. Conventional single-photon absorptiometry was used to measure the bone mineral content which, together with the cross-sectional area determined ultrasonically, was then used to estimate the bone mineral density. The bone mineral density was also determined for some bone sections from ash weight and volume. The compact bone density (i.e. relative density) together with the ultrasound velocity were then used to estimate a modulus of elasticity in the transverse direction.     

去睾丸大鼠骨形态计量学的研究

目的：探讨4月龄雄性大鼠去睾丸后骨量的变化，重点比较松质骨和皮质骨骨代谢的变化。方法：20只4月龄SD雄性大鼠，随机分为假手术组（A组）和去睾丸组（B组），同等条件下饲养90d后，取腰椎和胫骨中段行不脱钙制片进行骨形态计量学观察。结果：去睾丸组与假手术组比较，前者腰椎松质骨吸收增加、骨形成下降（P〈0．05），出现明显骨质疏松；皮质骨外膜的骨形成动态参数如矿化沉积率、骨形成率下降（P〈0．05），内膜骨形成和吸收均有增加趋势。结论：去睾丸90d能使大鼠松质骨出现骨质疏松，皮质骨丢失不如松质骨显著。松质骨对去睾丸敏感性比皮质骨高。     

Correlation between ultrasound velocity and densitometry in fresh and demineralized cortical bone

OBJECTIVE:To compare ultrasound propagation velocity with densitometry in the diaphyseal compact cortical bone of whole sheep metatarsals.METHODS:The transverse ultrasound velocity and bone mineral density of 5-cm-long diaphyseal bone segments were first measured. The bone segments were then divided into four groups of 15 segments each and demineralized in an aqueous 0.5 N hydrochloric acid solution for 6, 12, 24 or 36 hours. All measurements were repeated after demineralization for each time duration and the values measured before and after demineralization were compared.RESULTS:Ultrasound velocity and bone mineral density decreased with demineralization time, and most differences in the pre- and post-demineralization values within each group and between groups were significant: A moderate correlation coefficient (r=0.75956) together with a moderate agreement was determined between both post-demineralization parameters, detected by the Bland-Altman method.CONCLUSION:We conclude that both ultrasound velocity and bone mineral density decrease as a result of demineralization, thus indicating that bone mineral content is of great importance for maintaining the acoustic parameters of cortical bone, as observed for cancellous bone. Ultrasound velocity can be used to evaluate both compact cortical bone quality and bone mineral density.     

Age‐related Changes in Marmoset Trabecular and Cortical Bone and Response to Alendronate Therapy Resemble Human Bone Physiology and Architecture

In older humans, bone elongation ceases, periosteal expansion continues, and bone remodeling remains a dominant metabolic process. An appropriate animal model of type I and type II osteoporosis would be a species with sealed growth plates and persistence of bone remodeling. The rat is commonly used as a primary model, but due to delayed epiphyseal closure with continuous modeling and lack of Haversian remodeling, Food and Drug Administration guidelines recommend assessment of bone quality in an additional, nonrodent, remodeling species. This study investigated the skeletal characteristics of senescent marmosets to evaluate their suitability as an osteoporosis model. Animals were randomized across three experimental groups; controls for both sexes and marmosets receiving alendronate for either 30 or 60 days (28 μg/kg, sc, twice per week). Outcome measures included serum chemistry and bone biomarkers, DEXA, histomorphometry, micro‐computed tomography, and histopathology. Results showed that the adult marmoset skeleton has similar anatomical characteristics to the adult human, including the absence of growth plates, presence of Haversian system, and true remodeling of cancellous and cortical bone. Structural analyses of senescent marmoset cancellous bone demonstrated loss of trabecular mass and architecture similar to skeletal changes described for elderly men and women. Treatment with alendronate improved trabecular volume and number by reducing bone resorption, although bone formation was also reduced through coupling of bone remodeling. The common marmoset may provide a valuable model for research paradigms targeting human bone pathology and osteoporosis due to skeletal features that are similar to age‐related changes and response to bisphosphonate therapy reported for humans. Anat Rec, 2007. © 2007 Wiley‐Liss, Inc.     

Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures

The purinergic P2X7 receptor has a major role in the regulation of osteoblast and osteoclast activity and changes in receptor function may therefore affect bone mass in vivo. The aim of this study was to determine the association of non-synonymous single-nucleotide polymorphisms in the P2RX7 gene to bone mass and fracture incidence in post-menopausal women. A total of 1694 women (aged 45-58) participating in the Danish Osteoporosis Prevention Study were genotyped for 12 functional P2X7 receptor variants. Bone mineral density was determined at baseline and after 10 years. In addition, vertebral fracture incidence was documented at 10 years. We found that the rate of bone loss was clearly associated with the Arg307Gln amino acid substitution such that individuals heterozygous for this polymorphism had a 40% increased rate of bone loss. Furthermore, individuals carrying the Ile568Asn variant allele had increased bone loss. In contrast, the Gln460Arg polymorphism was associated with protection against bone loss. The Ala348Thr polymorphism was associated with a lower vertebral fracture incidence 10 years after menopause. Finally, we developed a risk model, which integrated P2RX7 genotypes. Using this model, we found a clear association between the low-risk (high-P2X7 function) alleles and low rate of bone loss. Conversely, high-risk (reduced P2X7 function) alleles were associated with a high rate of bone loss. In conclusion, an association was demonstrated between variants that reduce P2X7 receptor function and increased rate of bone loss. These data support that the P2X7 receptor is important in regulation of bone mass.