Quantification of age-related changes in the structure model type and trabecular thickness of human tibial cancellous bone

Structure model type and trabecular thickness are important characteristics in describing cancellous bone architecture. It has been qualitatively observed that a radical change of trabeculae from plate-like to rod-like occurs in aging, bone remodeling, and osteoporosis. Thickness of trabeculae has traditionally been measured using model-based histomorphometric methods on two-dimensional (2-D) sections. However, no quantitative study has been published based on three-dimensional (3-D) methods on the age-related changes in structure model type and trabecular thickness for human peripheral (tibial) cancellous bone. In this study, 160 human proximal tibial cancellous bone specimens from 40 normal donors, aged 16 to 85 years, were collected. These specimens were micro-computed tomography (micro-CT) scanned, then the micro-CT images were segmented using optimal thresholds. From accurate 3-D data sets, structure model type and trabecular thickness were quantified by means of novel 3-D methods. Structure model type was assessed by calculating the structure model index (SMI). The SMI was quantified based on a differential analysis of the triangulated bone surface of a structure. This technique allows quantification of structure model type, such as plate, rod objects, or mixture of plates or rods. Trabecular thickness is calculated directly from 3-D images, which is especially important for an a priori unknown or changing structure. Furthermore, 2-D trabecular thickness was also calculated based on the plate model. Our results showed that structure model type changed towards more rod-like in the elderly, and that trabecular thickness declined significantly with age. These changes become significant after 80 years of age for human tibial cancellous bone, whereas both properties seem to remain relatively unchanged between 20 and 80 years. Although a fairly close relationship was seen between 3-D trabecular thickness and 2-D trabecular thickness, real 3-D trabecular thickness was significantly underestimated using 2-D method.     

HRMRI对绝经后妇女骨质疏松症药物治疗效果的评价

目的通过MRI测量跟骨骨小梁微结构观察不同绝经后妇女骨质疏松患者的药物疗效。方法选择健康绝经后妇女按照绝经年限进行分组,通过计算OSTA得分及测量跟骨骨密度筛查,测腰椎正位骨密度,确诊为骨质疏松,共选择38例病例分为2组,做右跟骨MRI后开始服用药物治疗,分别于3个月和6个月重新测量跟骨骨密度,并做右侧跟骨MRI。结果所得骨小梁参数中骨小梁平均面积,骨小梁面积/总面积,节点数/总面积,节点至节点连接长度/骨架长,骨小梁总数,骨架长/总面积经治疗后均有不同程度的增长(P0.05),欧拉数/总面积经治疗后降低(P0.05)。绝经10年以内组骨小梁平均面积,骨小梁面积/总面积,节点数/总面积,小梁总数,骨架长/总面积增长幅度均高于绝经10年以后组(P0.05),欧拉数/总面积绝经10内组下降幅度高于绝经10年以后组(P0.05)。根骨骨密度治疗前后及两组间比较均无统计学意义(P0.05)。结论HRMRI对绝经后骨质疏松症疗效评价作用要优于骨密度测量,绝经后10年以内妇女治疗效果较绝经10年以后治疗效果要好。     

Static histomorphometry of human iliac crest and vertebral trabecular bone: a comparative study.

We recently developed a new, rapid method for conducting static histomorphometry on large histologic sections. This method has now been applied on both iliac crest and lumbar vertebral bone to compare the age-related changes at these two skeletal sites and to investigate the correlation between the histomorphometric measures at the iliac crest and the vertebral body. The material comprised matched sets of unilateral transiliac crest bone biopsies and lumbar vertebral bodies (L-2) from 24 women (19-96 years) and 24 men (23-95 years) selected from a larger autopsy material. Three female subjects (80, 88, and 90 years) had a known vertebral fracture of L-2. The iliac crest biopsies and 9-mm-thick mediolateral slices of half the entire vertebral bodies were embedded in methylmetacrylate, stained with aniline blue, and scanned into a computer with a flatbed image scanner at a high resolution. With a custom-made computer program the following static histomorphometric measures were determined: trabecular bone volume; marrow and bone space star volume; node-strut analysis; trabecular bone pattern factor; trabecular thickness; trabecular number; trabecular separation; and anisotropy of bone and marrow phase. In addition, connectivity density was measured (ConnEulor method). The results showed that the age-related changes in the static histomorphometric measures are generally similar in the iliac crest and the vertebral body, and that these age-related changes are independent of gender. An exception, however, is connectivity density, where the age-related changes are similar for women and men in the vertebral body but significantly different in the iliac crest. Furthermore, the results showed that the histomorphometric measures were weakly intercorrelated between the iliac crest and the vertebral body, despite the generally similar pattern in age-related changes at these two skeletal sites. The highest correlation coefficient was found for trabecular separation (Tb.Sp; r = 0.63). Trabecular bone volume showed a correlation coefficient of r = 0.59. It is concluded that static histomorphometry performed on one skeletal site does not automatically predict static histomorphometric measures at another skeletal site. Therefore, it is recommended that static histomorphometry be performed at the skeletal site of interest-if at all possible.     

Osteopenia in adolescent idiopathic scoliosis: a histomorphometric study

STUDY DESIGN: Bone biopsies from iliac crest and spinous process of adolescent idiopathic scoliosis patients were obtained intraoperatively for histology and histomorphometric analysis. OBJECTIVES: To study the histologic features of cancellous bone and to correlate the histomorphometric variables with preoperative bone mineral density in patients with adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Low bone mineral density has been reported in adolescent idiopathic scoliosis. However, there is limited information about the histopathologic changes. METHODS: Undecalcified and decalcified bone specimens from iliac crest and spinous process of adolescent idiopathic scoliosis patients obtained intraoperatively were stained with Goldner and hematoxylin & eosin stain, respectively. Results were correlated with bone mineral density of the lumbar spine (L2-L4) and proximal femur measured before surgery. RESULTS: Bone histology showed significant less osteocyte count in the trabecular bone characterized with smooth and continuous borders in patients with adolescent idiopathic scoliosis. Histomorphometry confirmed the lower static parameters. The results correlated well with the decreased bone mineral density. CONCLUSION: Bone biopsy study suggested disturbance of bone turnover in patients with adolescent idiopathic scoliosis. The abnormal metabolism might contribute to the low bone mineral density and play an important role in the etiology and pathogenesis of adolescent idiopathic scoliosis.     

Histomorphometric evidence for increased bone turnover without change in cortical thickness or porosity after 2 years of cyclical hPTH(1-34) therapy in women with severe osteoporosis

Parathyroid hormone (PTH) increases trabecular but may decrease cortical bone mass during treatment of postmenopausal osteoporosis. In a 2-year trial, PTH, with or without sequential calcitonin (CT), was given to 29 osteoporotic women (mean age 67 +/- 7 years), in 3-month cycles [28 days hPTH(1-34), 50 microg/day, +/-42 days CT, 75 units/day, 20 days "free"]. Over 2 years, lumbar spine bone mineral density measurements increased an average of 10%. Paired iliac crest biopsies were obtained 28 days and 2 years after starting the trial. The addition of CT made no difference to changes seen with cyclical PTH alone. Thus, the histomorphometric analyses for all 29 treated patients were compared with a separate group of biopsies from untreated osteoporotic control patients (n = 15). No significant increments in total bone volume or trabecular architecture were seen over 2 years of cyclical PTH treatment, although the light microscopic appearance of bone was normal. At the level of the bone remodeling unit, a twofold increase in total trabecular erosion surface over the control measurements was observed within the first 28 days of PTH treatment (10 +/- 5 vs. 5 +/- 3% trabecular surface, p < 0.01), which was sustained over 2 years. Trabecular bone formation rates (surface referent) were 11 +/- 7 microm(3)/microm(2)/year in control patients and threefold higher in treated patients both acutely (31 +/- 31 microm(3)/microm(2)/year, p < 0.01) and after 2 years (33 +/- 43 microm(3)/microm(2)/year, p < 0. 05). The activation frequency of trabecular remodeling was threefold higher than controls through 2 years of treatment (p < 0.05). The mean wall thickness of completed osteons after 2 years of treatment was significantly larger than controls (28 +/- 7 vs. 22 +/- 5 microm, p < 0.01), suggesting a positive remodeling balance, as well as the histomorphometric evidence of increased bone turnover and the increased resorption surfaces. Over 2 years of cyclical PTH therapy, cortical thickness remained significantly higher than controls (680 +/- 202 vs 552 +/- 218 microm, p < 0.05), without significant changes in cortical porosity. Thus, the histomorphometric changes during cyclical PTH therapy in patients with severe osteoporosis are consistent with increased trabecular bone turnover and a positive remodeling balance, with no evidence for detrimental changes in cortical bone.     

Image Analysis of the Distal Radius Trabecular Network Using Computed Tomography

Bone texture analysis might provide information about bone structure in a noninvasive manner. In a prospective case–control cross-sectional study we investigated the value of computed tomography (CT) image analysis of the distal radius in the assessment of osteoporosis. Twenty patients suffering from postmenopausal osteoporosis were studied and compared with 21 age-matched controls. Eight slices were selected in each patient: four consecutive coronal slices and four consecutive cross-sectional slices. Bone texture analysis was performed using statistical, fractal and structural methods leading to the measurement of 32 features. Structural variables derived from histomorphometric parameters were measured after segmentation from a binary or a skeletonized image. Bone mineral density was measured by dual-energy X-ray absorptiometry both at the lumbar spine and the femoral neck. Eight of the 9 statistical features were significantly different in osteoporotic women as compared with controls (coronal slices, p < 0.05). Seven structural variables were statistically different between the two groups on coronal slices (p < 0.05): valley surface area, bone volume/tissue volume, trabecular partition, Euler’s number, trabecular bone pattern factor, node-to-node strut count and terminus-to-terminus strut count. The most significant results on coronal slices (p < 0.01) concerned 4 structural features: trabecular partition, Euler’s number, trabecular bone pattern factor and terminus-to-terminus strut count. Three features were statistically different (p < 0.01) between the two groups on cross-sectional slices (skeletonization from gray levels). A few features yielded by texture analysis were correlated with both lumbar spine and femoral neck bone mineral density, but the level of these correlations was weak (r < 0.5). In conclusion, CT image analysis of the distal radius is a useful tool for characterizing bone texture alterations in osteoporotic women. These findings are in keeping with microarchitectural osteoporosis-related changes diagnosed on bone biopsies. Received: 8 April 1998 / Accepted: 14 September 1998     

Osteoprotegerin: a valid new marker of bone turnover in post-menopausal osteoporosis?

Abstract An increase of setum osteoprotegerin has been found in post-menopausal women, that is positively correlated with age and bone markers, negatively with bone mass. In 25 post-menopausal women (mean age, 63±8 years) we measured serum levels of osteoprotegerin, total and bone alkaline phosphatase, osteocalcin, urinary deoxypyridinoline and bone mineral density of the lumbar spine and femur.Osteoprotegerin and bone markers did not differ from range of normal values. Bone mineral density appeared markedly reduced both at the spine and the femur.A significant correlation between osteoprotegerin and age, duration of menopause, osteocalcin and bone alkaline phosphatase was found. No correlation was found between osteoprotegerin and bone mineral density in all measured skeletal sites. In conclusion, osteoprotegerin does not appear to be an interesting parameter for the evaluation of bone turnover in post-menopausal osteoporosis.     

A study of trabecular bones in ovariectomized goats with micro-computed tomography and peripheral quantitative computed tomography

Osteoporotic fractures occur most frequently in trabeculae-rich skeletal sites. The purpose of this study was to use a high-resolution micro-computed tomography (micro-CT) to investigate the changes in trabecular bone microarchitecture and to use a peripheral quantitative computed tomography (pQCT) to study changes in volumetric bone mineral density (BMD) in a large animal model resulted from ovariectomy (OVX). Ten adult goats were used for this study. The first iliac crest biopsy was harvested before OVX and served as baseline; the second biopsy was collected 6 months later from the opposite side for both pQCT and micro-CT measurements. Results showed that after 6 months of OVX, the BMD of the iliac crest biopsies decreased significantly by 16.3% (P < 0.05). The bone volume density (BV/TV), trabecular number (Tb.N), and connectivity density (Conn.D) measured with micro-CT decrease significantly after OVX, with an average decrease of 8.34%, 8.51%, and 18.52% (P < 0.05 each), respectively. The trabecular plate separation (Tb.Sp) was 8.26% (P < 0.05) greater than baseline after OVX. Significant correlations were found between the reduction of BMD and the decreases of BV/TV and Tb.N (r = 0.839 and 0.719, respectively; P< 0.001 both), as well as the increase of Tb.Sp (r = -0.758, P< 0.001) and SMI (r = -0.697, P< 0.001). In conclusion, this was the first experimental study in goat model to show that OVX-induced bone loss in goats was attributed by deterioration of trabecular microarchitecture.     

Evaluation and Development of Automatic Two-Dimensional Measurements of Histomorphometric Parameters Reflecting Trabecular Bone Connectivity: Correlations with Dual-Energy X-Ray Absorptiometry and Quantitative Ultrasound in Human Calcaneum

In osteoporosis, bone fragility results from both bone loss and changes in trabecular microarchitecture, which can be quantified by bone histomorphometric parameters. Twenty human calcaneum were collected after necropsy. All measurements were performed at the same anatomical location. Bone histomorphometric parameters were measured on histological slides with an automatic image analyzer. The aims of our study were (1) to develop automatic measurements of four additional parameters reflecting trabecular network connectivity and complexity, i.e., trabecular bone pattern factor (TBPf), Euler number/tissue volume (Euler) according to the three definitions previously reported and to a fourth one established in the laboratory (Euler_strut.cavity), marrow star volume, and interconnectivity index, and to determine their usefulness in microarchitecture characterization; and (2) to validate these parameters by evaluating their relationship with dual-energy X-ray absorptiometry and quantitative ultrasound (QUS) measurements performed on the same samples. The statistical analysis showed that TBPf and Euler_strut.cavity appeared to be the most significant connectivity parameters, independently of bone quantity (bone mineral density, apparent density, cancellous bone volume). For QUS, after adjustment for bone quantity, only speed of sound (SOS) was significantly and negatively correlated to Euler_strut.cavity. Broadband ultrasound attenuation depends only on bone quantity. In conclusion, TBPf (a strut analysis parameter extrapolable in three dimensions) and Euler_strut.cavity (the only bone connectivity parameter reflecting SOS) are two valid bone microarchitecture parameters. These new parameters were significantly correlated to the established trabecular structure parameters: trabecular thickness or trabecular spacing, being weakly correlated with SOS.     

Predicting human vertebral bone strength by vertebral static histomorphometry

The study investigates the relationship between static histomorphometry and bone strength of human lumbar vertebral bone. The ability of vertebral histomorphometry to predict vertebral bone strength was compared with that of vertebral densitometry, and also with histomorphometry and bone strength of iliac crest bone biopsies. The material comprised matched sets of second lumbar vertebrae, third lumbar vertebrae, and two iliac crest bone biopsies from each of 21 women (19--96 years) and 24 men (23--95 years). One of the iliac crest biopsies and 9-mm-thick mediolateral slices of half of each of the entire vertebral bodies (L-2) were used for histomorphometry. The other iliac crest biopsies and the L-3 were destructively tested by compression. High correlation was found between BV/TV or Tb.Sp and vertebral bone strength (absolute value of r = 0.86 in both cases). Addition of Tb.Th significantly improved the correlation between BV/TV and bone strength, and the addition of bone space star volume significantly improved the correlation between Tb.Sp and bone strength (from absolute value of r = 0.86 to absolute value of r = 0.89 in both cases). Bone structure (connectivity density) was not capable of improving the prediction of bone strength of the vertebral body. The correlations between BV/TV of L-2 and bone strength of L-3 were comparable with the correlation obtained by quantitative computed tomography (QCT), peripheral QCT (pQCT), and dual-energy X-ray absorptrometry (DEXA) of L-3 and bone strength of L-3. The iliac crest was found to have low predictive power of vertebral bone strength (iliac BV/TV: r = 0.62; iliac bone strength: r = 0.67). No gender-related differences were found in any of the relationships. It was shown that trabecular bone volume BV/TV and mean trabecular plate separation Tb.Sp are good predictors of vertebral bone strength. The ability of histomorphometry to predict vertebral bone strength was comparable to that of densitometry. Bone structure assessed by connectivity density did not improve the correlation between static histomorphometric measures and vertebral bone strength. No gender-related differences were found in any of the relationships. Neither static histomorphometry nor biomechanical testing of iliac crest bone biopsies is a good predictor of vertebral bone strength.     

Transmenopausal Changes in Trabecular Bone Quality

Bone strength depends on its amount and quality. Bone quality includes its structural and material properties. Bone material properties are dependent on bone turnover rates. Remodeling rates are significantly increased immediately after menopause. In the present study, we used Raman microspectroscopic analysis of double iliac crest biopsies with a spatial resolution of 1 µm obtained before and immediately after menopause (1 year after cessation of menses) in healthy females to investigate changes in material properties attributable to menopause. In particular, the mineral/matrix ratio, the relative proteoglycan and lipid content, the mineral maturity/crystallinity, and the relative pyridinoline collagen cross‐link content were determined in trabecular bone as a function of surface metabolic activity and tissue age. The results indicate that significant changes (specifically in mineral/matrix ratio) were evident at active bone forming surfaces, whereas the relative proteoglycan content was altered at resorbing surfaces. These changes were not accompanied by altered mineral content or quality as monitored by Raman microspectroscopic analysis. © 2014 American Society for Bone and Mineral Research.     

Immunosuppressive and postoperative effects of orthotopic liver transplantation on bone metabolism.

Bone loss occurs early after orthotopic liver transplantation (OLT) in all liver transplant recipients and leads to postoperative fractures, especially in cholestatic patients with the lowest bone mass. Little is known about the underlying changes in bone metabolism after OLT or about the etiology of these changes. Histomorphometric analysis of bone biopsies, a method that allows assessment of bone volume, resorption, and formation, has shown improved bone metabolism at 4 months after OLT. It has further suggested that accelerated posttransplant bone loss occurs in the first 1-2 months after OLT, probably by an additional insult to bone formation. This study attempts to correlate the histomorphometric bone changes in paired bone biopsies (OLT and 4 months after OLT) of 33 patients undergoing OLT for chronic cholestatic liver disease with the many clinical and biochemical changes in these patients over the same period. Cumulative steroid dosage early after OLT is shown to be important, presumably by decreasing bone formation rates. The actual effect of calcineurin inhibitors on this early phase of bone loss is less clear, although posttransplant histomorphometric findings suggest that tacrolimus-treated patients have an earlier recovery of bone metabolism and trabecular structure compared with cyclosporine patients. Other factors important in the recovery of bone metabolism after the early phase of bone loss are recovery of liver and gonadal function and better calcium balance.     

Oral Ibandronate Preserves Trabecular Microarchitecture: Micro-Computed Tomography Findings From the Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe Study

Micro-computed tomography (micro-CT) is a quantitative 3-dimensional (3D) scanning procedure used to assess trabecular architecture. In the 3-yr oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe (BONE) study, it was found that oral ibandronate administered daily (2.5 mg) or intermittently (20 mg) significantly reduced vertebral fracture risk by 62% (p = 0.0001) and 50% (p = 0.0006), respectively, vs placebo. Two-dimensional histomorphometric analysis of BONE study biopsies indicated that newly formed bone was of normal quality. In the current analysis, micro-CT was used to assess 3D trabecular microarchitecture. Rod and plate distribution was quantified by differential analysis of the triangulated bone surface. Biopsies were obtained from 110 patients, with 84 evaluable by micro-CT. Median structural model index (SMI; a lower SMI indicates an increased ratio of plates to rods and thus, improved trabecular microarchitecture) was 1.001 with ibandronate vs 1.365 with placebo (90% confidence interval [CI] for difference in medians: –0.626, –0.033), and connectivity density was higher in ibandronate-treated patients (median: 3.904 vs 3.112/mm³, 90% CI for difference in medians: 0.159, 1.517). This indicates that trabecular microarchitecture was better preserved in patients receiving ibandronate than placebo. Taken together with previous results from BONE, these findings indicate that ibandronate treatment preserves bone strength by maintaining good quality trabecular microarchitecture in women with postmenopausal osteoporosis.     

Are patterns of bone loss in anorexic and postmenopausal women similar? Preliminary results using high resolution peripheral computed tomography

This study intended to compare bone density and architecture in three groups of women: young women with anorexia nervosa (AN), an age-matched control group of young women, and healthy late postmenopausal women. Three-dimensional peripheral quantitative high resolution computed-tomography (HR-pQCT) at the ultradistal radius, a technology providing measures of cortical and trabecular bone density and microarchitecture, was performed in the three cohorts. Thirty-six women with AN aged 18–30 years (mean duration of AN: 5.8 years), 83 healthy late postmenopausal women aged 70–81 as well as 30 age-matched healthy young women were assessed. The overall cortical and trabecular bone density (D100), the absolute thickness of the cortical bone (CTh), and the absolute number of trabecules per area (TbN) were significantly lower in AN patients compared with healthy young women. The absolute number of trabecules per area (TbN) in AN and postmenopausal women was similar, but significantly lower than in healthy young women.The comparison between AN patients and post-menopausal women is of interest because the latter reach bone peak mass around the middle of the fertile age span whereas the former usually lose bone before reaching optimal bone density and structure. This study shows that bone mineral density and bone compacta thickness in AN are lower than those in controls but still higher than those in postmenopause. Bone compacta density in AN is similar as in controls. However, bone inner structure in AN is degraded to a similar extent as in postmenopause. This last finding is particularly troubling.     

Nondestructive determination of iliac crest cancellous bone strength by pQCT

The close relationship between apparent bone density and compressive strength is well established. In clinical situations, histomorphometry, and determination of the compressive strength on bone biopsies are destructive methods and require two separate biopsies from each patient. The aim of this study was to evaluate whether volumetric bone density measured by peripheral quantitative computed tomography (pQCT) could be used as a nondestructive method for estimating trabecular bone strength of iliac crest bone biopsies, thereby allowing the same biopsy to be used for subsequent histomorphometry. Materials consisted of trabecular bone samples prepared from unilateral transiliac crest bone samples obtained at autopsy [total 95 specimens; 41 females (21–90 years) and 54 males (23–87 years)]. From these, the apparent density of the cancellous bone was evaluated by pQCT in a 1-mm-thick slice in the middle of the biopsy and also by ash density measurement. Bone strength was measured by compression test. A strong power relationship was found between density measured by pQCT and compressive strength (r = 0.93, p < 0.00001). Likewise, there was a strong power relationship between ash density and compressive strength (r = 0.97, p < 0.00001). A linear correlation was found between pQCT measurement and ash density (r = 0.98, p < 0.00001), indicating a very high accuracy for the pQCT measurement. In conclusion, pQCT provides a very good estimate of cancellous bone strength. This nondestructive assessment of strength of iliac crest bone biopsies thereby enables biomechanical information as well as histomorphometric measurements to be obtained from the same biopsy.     

Stochastic simulation of vertebral trabecular bone remodeling

Bone remodeling changes bone mass, architecture, and thereby bone strength, during normal aging. These changes seem to be accelerated during the menopause. Several therapeutic agents have been used in order to delay the onset of the menopause-related changes. The effects of these agents on the remodeling process have been determined histomorphometrically in several short-term clinical studies, but data from long-term clinical studies are difficult to achieve, as are data on the influence on bone strength.

The aim of this study was to develop a computer simulation model that could assist in predicting the long-term effects of changes in the remodeling process on bone mass, trabecular thickness, and perforations. The paper presents such a stochastic model of the remodeling process in human vertebral trabecular bone. The computer model is based on histomorphometric and structural data from human studies. It is presented in terms of flow charts, and simulations performed with the model are discussed in relation to measurements on human vertebral bone samples.

The results show that a menopause-related doubling of the activation frequency causes a transient, mainly reversible bone loss. If the menopause is accompanied by an increase in both activation frequency and resorption depth, then the resulting bone loss will be more pronounced and with a larger part being irreversible bone loss (perforations). The two antiresorptive agents Etidronate and estrogen both cause a slight increase in bone mass (reducing remodeling space), and Etidronate also seems capable of preventing perforations. During fluoride therapy, an initial increase in remodeling space followed by a reduction is seen. Very few perforations are found to take place during fluoride therapy.

The present model has been validated by assessing the effects of the menopause and treatment with antiresorptive or anabolic agents. It was found that the results mirrored very closely the results (bone mass measurements) from short-term clinical studies. It is therefore concluded that the model provides a tool for evaluating existing and new therapeutic regimens.     

A histomorphometric determination of iliac bone structure and remodeling in obese subjects

Quantitative histomorphometric analyses of iliac crest biopsies were performed after tetracycline double labeling in 24 patients with morbid obesity and in 30 age- and sex-matched controls. The amount and structure of bone were determined from measurements of total biopsy length, fractional length of medullary space, fractional trabecular bone volume, trabecular thickness, and the intertrabecular distance. Static and dynamic variables of bone resorption and formation were determined, and the balance of the BMU level was estimated from final resorption depth and mean wall thickness of trabecular structural units. In the obese patients the total biopsy length was increased, with a normal proportion of medullary space to total biopsy length. The mean fractional trabecular bone volume was reduced due to an increased distance between trabeculae of normal mean thickness. The total biopsy length in the obese patients was found to be positively related to the intertrabecular distance and inversely related to the fractional trabecular bone volume. The remaining histomorphometric variables describing bone formation rate at tissue, BMU, and cellular levels, the amount of bone formed, the mineralization process, mineralization lag time, bone resorption, and the balance between resorption and formation were all normal in the obese group.     

Effects of salmon calcitonin on trabecular microarchitecture as determined by magnetic resonance imaging: results from the QUEST study.

The unique noninvasive MRI technique was used to assess trabecular microarchitecture at multiple skeletal sites in 91 postmenopausal osteoporotic women receiving nasal spray salmon calcitonin (CT-NS) or placebo over 2 years. In the distal radius and lower trochanter of the hip, individuals treated with CT-NS exhibited significant preservation of trabecular bone microarchitecture compared with placebo, where significant deterioration was shown. MRI analyses of os calcis or microCT/histomorphometric analyses of bone biopsies did not reveal consistent differences in architecture between CT-NS and placebo. INTRODUCTION: It is postulated that the reduction in osteoporotic fracture risk in response to certain antiresorptive osteoporosis therapies is caused less by effects on bone quantity than on bone quality (specifically trabecular microarchitecture). To test this hypothesis, the QUEST study was conducted to assess the effects of nasal spray salmon calcitonin (CT-NS) or placebo on parameters of trabecular microarchitecture at multiple skeletal sites using noninvasive MRI technology and iliac crest bone biopsies by microCT/histomorphometry. MATERIALS AND METHODS: Ninety-one postmenopausal osteoporotic women were followed for 2 years (n = 46 for CT-NS, n = 45 for placebo); all women received 500 mg calcium daily. MRI measurements at distal radius, hip (T2 relaxation time [T2*]), and os calcis (obtained yearly), iliac crest bone biopsies with 2D histomorphometry and 3D microCT (obtained at study onset and conclusion), DXA-BMD at spine/hip/wrist/os calcis (obtained yearly), and markers of bone turnover (obtained at 2-week to 12-month intervals) were analyzed, with an analysis of covariance model used to assess treatment effect for parameters of interest. RESULTS AND CONCLUSIONS: MRI assessment of trabecular microarchitecture at individual regions of the distal radius revealed significant improvement, or preservation (no significant loss), in the CT-NS-treated group compared with significant deterioration in the placebo control group, as reflected in apparent BV/TV (p < 0.03), apparent trabecular number (p < 0.01), and apparent trabecular spacing (p < 0.01). Also, at the hip, the CT-NS group exhibited preservation of trabecular microarchitecture at the lower trochanter (p < 0.05) as determined by T2* MRI technology. Significant deterioration of trabecular bone architecture was noted in the placebo group at the femoral neck, Ward's triangle, and lower trochanteric sites. Apart from a significant increase in apparent trabecular number in the CT-NS group, significant changes within or between groups were not noted at the os calcis. Combined microCT/histomorphometric analysis of iliac crest bone biopsies did not reveal significant differences between treated and placebo groups. In the CT-NS group, regardless of the change in BMD (gain or loss) at the spine, hip, or distal radius, preservation of parameters of trabecular microarchitecture was noted, whereas in the placebo group, regardless of the change in BMD (gain or loss) at the spine, hip, or distal radius, loss or preservation was noted; however, changes in DXA/BMD (of the spine, hip, wrist, os calcis) between CT-NS and placebo groups were not significant. Serum C-telopeptide (S-CTx), a specific bone resorption marker, was reduced by 22.5% at 24 months (p = 0.056). The results of the QUEST study suggest therapeutic benefit of CT-NS compared with placebo in maintaining trabecular microarchitecture at multiple skeletal sites and support the use of MRI technology for assessment of trabecular microarchitecture in clinical research trials. However, the results also highlight site specific differences in response to antiresorptive therapies and the importance of sufficiently large sampling volumes (areas) to obtain reliable assessment of bone architecture.