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.     

A new method of comprehensive static histomorphometry applied on human lumbar vertebral cancellous bone

The aim of the present study was to assess age-related changes in the human spine by use of established static histomorphometry, and to determine how these static histomorphometric measures are interrelated in human cancellous bone tissue. The material comprised normal human lumbar vertebral bodies (L-2) from 12 women (19-96 years) and 12 men (23-91 years) selected from a larger autopsy material to give an even age and gender distribution. In addition, L-2 from three female subjects (80, 88, and 90 years) with a known vertebral fracture of L-2 were considered. Approximately 9-mm-thick frontal (mediolateral) slices were embedded in methylmetacrylate, stained with aniline blue, and scanned into a computer with a flatbed image scanner at a high resolution (2400 dpi). With a custom-made computer program the following static histomorphometric measures were determined: trabecular bone volume; marrow space star volume; bone space star volume; anisotropy of bone and marrow phase (star length distribution method); node-strut analysis (node:terminus ratio); trabecular thickness; trabecular number; trabecular separation; and trabecular bone pattern factor. In addition, connectivity density was determined (by the ConnEulor method). All 11 histomorphometric measures, except bone space star volume and the two measures of anisotropy, showed a significant correlation with age. Marrow space star volume (r = 0.82) and trabecular bone volume (r = -0.81) showed the highest correlation with age. Furthermore, it was found that all of the histomorphometric measures were correlated, to different degrees. Trabecular bone volume correlated significantly with all ten histomorphometric measures, whereas the two anisotropy measures were poorly correlated to the other measures. Finally, we found the histomorphometric values in this study to be in excellent accordance with various previously published results from studies of human trabecular vertebral bone, the sole exception being marrow space star volume, which was probably due to the small (artificial) region of interest (ROI) that was used in the earlier studies. In conclusion, the new method applied herein allows for easy assessment of age-related changes and also for assessment of relationships between histomorphometric measures in human vertebral cancellous bone.     

Zone-dependent changes in human vertebral trabecular bone: clinical implications

We have previously shown that there are pronounced age-related changes in human vertebral cancellous bone density and microarchitecture. However, the magnitude of these changes seemed to be dependent on zone location in the vertebral body-the central third vs. the areas adjacent to the endplates. The aim of the present study was, therefore, to investigate whether such zone-specific differences could be identified by static histomorphometric measures. The material comprised 48 individuals (24 women aged 19-97 years, and 24 men aged 23-95 years). Three of the women had a known fracture of the L-2. From each L-2, thick frontal sections of half of the vertebra were embedded undecalcified in methylmethacrylate, cut into 10-microm-thick sections, and stained with aniline blue. The sections were scanned into a computer, and classic static histomorphometry was performed on the images. The histomorphometry was performed on both the whole section and on the separate zones (central and sub-endplate zone). The results showed that trabecular bone volume, trabecular number, and connectivity density decreased significantly faster with age, whereas marrow space star volume increased significantly faster with age in the zones adjacent to the endplates than in the central zone. The other histomorphometric measures showed no zone specificity in relation to aging. However, trabecular thickness and trabecular separation were both higher at all ages in the central zone than in the sub-endplate zone, although this was significant only for trabecular separation. The described differences might have significant clinical implications concerning quantitative computed tomography (QCT) scanning, X-ray analyses, and assessment of fracture liability in the human spine, but the underlying pathogenesis is still not known. This study shows that the human vertebral body can be described as two distinct zones with very specific age-related changes in density and microstructure. This zone-specificity is important for the correct interpretation of clinical data.     

Interrelationships between bone microarchitecture and strength in ovariectomized monkeys treated with teriparatide.

Bone microarchitecture measured at the iliac crest at 6 mo was confirmed to be a reasonable surrogate for, and a predictor of, architecture and strength of the femoral neck and lumbar vertebra after 18 mo of teriparatide treatment. However, the data taken together showed the importance of cortical bone volume for vertebra to assess pharmacological effects on bone quality. INTRODUCTION: Improvements in bone architecture with teriparatide treatment are suggested to contribute to fracture risk reduction in osteoporotic patients. Teriparatide significantly improves microarchitecture in the iliac crest of humans by stimulating bone modeling and remodeling processes that differ dramatically from those induced by antiresorptives. The relationship between improvements of bone microarchitecture and improvements of bone strength with teriparatide treatment has not yet been fully studied. MATERIALS AND METHODS: Ovariectomized monkeys were administered vehicle (n = 20); teriparatide 1.0 microg/kg/d (n = 19); or teriparatide 5.0 microg/kg/d (n = 21) for 18 mo. Iliac crest biopsies were obtained at 6 and 15 mo after initiation of treatment. Animals were killed after 18 mo of treatment, and adjacent vertebrae or contralateral proximal femora were processed for biomechanical or histomorphometric analyses. Pearson correlation analyses were performed to assess the relationship between biomechanical and static histomorphometric parameters of lumbar vertebra, femoral neck, and iliac crest biopsies. RESULTS: Static histomorphometric parameters of the 6- and 15-mo biopsies were significantly correlated with the vertebral and femoral neck parameters obtained at 18 mo of teriparatide treatment. Iliac crest biopsy parameters at 6 and 15 mo also correlated with vertebral and femoral neck strength at 18 mo. Static histomorphometry of the lumbar vertebra and femoral neck at 18 mo also significantly correlated with strength at these sites. However, cortical bone volume of the lumbar vertebrae had the strongest correlation with vertebral and femoral neck strength (r = 0.74 and 0.71, respectively). CONCLUSIONS: Teriparatide dose dependently improved cortical and trabecular microarchitecture of vertebra and femoral neck, as well as trabecular microarchitecture of the iliac crest. Bone microarchitecture at all sites was significantly correlated with lumbar vertebra and femoral neck strength. Cortical bone volume of vertebra had the strongest correlation with vertebral and femoral neck strength. Therefore, structural improvement seemed to be part of the mechanism for improved strength observed with teriparatide treatment. Trabecular bone architecture of the iliac crest at 6 mo also correlated with vertebral and femoral neck strength, as did femoral neck (cortical and trabecular) histomorphometry and trabecular histomorphometry of vertebra after 18 mo of treatment. Because clinical assessment of cortical bone volume is not readily possible for vertebra noninvasively, these findings confirm the importance of iliac crest biopsies to monitor skeletal health and show that biopsies are a reasonable surrogate to assess spine and femoral neck structure and function.     

Iliac crest trabecular bone volume as predictor for vertebral compressive strength, ash density and trabecular bone volume in normal individuals

Whole vertebral bodies (L2) and cylindrical trabecular bone samples from the central part of the first lumbar vertebral body (L1) were obtained from 42 normal individuals aged 15-87 years (27 females and 15 males). These bone samples were analyzed by a compression test, and maximum load and stress values were calculated from the load deformation curves. After the compression the ash density of the samples was estimated. For histomorphometric measurements trabecular bone samples from L1 (n = 42) and from the iliac crest (n = 25) were embedded undecalcified, cut in 8 microns sections and stained with Masson trichrome. Trabecular bone volume (TBV) was measured by means of point counting. A significant and parallel age-related decrease in TBV was found in the iliac crest and in the vertebral trabecular bone specimens (p less than 0.001). Highly significant positive correlations were observed between iliac crest TBV and the quantitative vertebral parameters: TBV and ash density (p less than 0.001). Furthermore, the iliac crest TBV was significantly correlated to the qualitative vertebral strength parameters: Vertebral trabecular bone stress, whole vertebral body stress and whole vertebral body load (p less than 0.001). Multiple regression analyses revealed that the vertebral trabecular bone strength was unrelated to bone volume when the influence of age was considered but significantly inversely correlated to age when bone volume was taken into account. This indicates that age-related structural changes other than bone mass affect the vertebral bone strength strongly.     

Relationships between bone structure in the iliac crest and bone structure and strength in the lumbar spine

The purpose of this study was to examine the relationship between histomorphometric variables of cancellous bone structure and ultimate compressive strength (UCS) in the second lumbar vertebra (L2) and to determine whether structural variables in the iliac crest are predictive of the same variables and of UCS in L2. At autopsy, 7.5 mm diameter cores were removed from the iliac crest and from L2 of 29 subjects who had died suddenly without bone disease. Cancellous bone volume (BV/TV, %) was significantly lower in L2 than in iliac crest due to lower trabecular number (Tb.N, per mm) and thickness (Tb.Th, µm). There were significant correlations between iliac crest and L2 for BV/TV, Tb.N and trabecular separation (Tb.Sp, µm), but not for Tb.Th. BV/TV was negatively correlated, and Tb.Sp was positively correlated with age at both sites. Tb.Th was not significantly correlated with age in the iliac crest, but a significant negative correlation was observed in L2. The UCS of vertebral cores was negatively correlated with age. BV/TV and Tb.Th in L2 were positively correlated with UCS in L2. Cortical width and BV/TV in iliac crest were positively correlated with UCS in L2. We conclude that: (1) cancellous bone volume in the iliac crest is higher than in the lumbar spine due to thicker, more closely spaced trabecular plates, (2) the changes in structural variables with age are generally similar in the iliac crest and lumbar vertebra, but trabecular thinning with age is more evident in the spine than in the ilium, and (3) the compressive strength of cancellous bone in the lumbar spine is correlated with histomorphometric variables of bone structure, as measured both in the lumbar spine and in the iliac crest.     

Histomorphometric analysis of vertebral and iliac crest bone samples. A correlated study

Iliac crest and corresponding second vertebral body specimens were obtained from 20 cadavers. Of these, ten underwent histopathologic evaluation and histomorphometry in a blind fashion followed by statistical evaluation of the results. In this study, the authors found the iliac crest biopsy specimens to be highly correlated and predictive of osteoid and resorptive parameters in the spine and less so for trabecular bone volume. Whereas the transileal bone biopsy is a useful tool in diagnosing and typing metabolic bone disease, its predictive value of bone volume at other sites in the skeleton requires further evaluation.     

Comparison of histomorphometry and computerized tomography of the spine in quantitating trabecular bone in renal osteodystrophy

Computerized tomography (CT) has the advantage of allowing the isolation of trabecular bone of the axial skeleton, which is the more sensitive to metabolic changes. By means of single-energy X-ray CT we have devised a method for assessing trabecular bone mass (TBM) at L-4 vertebral body, which has an acceptable reproducibility (CV = 2.76%). Normal values where obtained after studying 29 normal individuals from both sexes and different ages. In order to know if the method is accurate, TBM was assessed in 17 patients (6 with creatinine clearance less than 6 ml/min and 11 on chronic hemodialysis), and in all of them the results were compared with the histomorphometry of the iliac crest bone biopsy. TBM assessed by CT correlated with trabecular bone volume (TBV; mineralized bone + osteoid) (r = 0.82; p less than 0.001) and this correlation was not improved after adding the volume of marrow fibrosis to TBV. TBM assessed by CT also correlated with mineralized bone volume but at a lower level of significance (r = 0.72; p = 0.001), and no correlation was found with relative osteoid volume alone. These findings suggest that final CT value is an integral of mineralized bone and osteoid but with a higher influence of mineralized bone. Osteomalacia and osteitis fibrosa were seen in situations of normal, decreased, or increased TBM assessed by CT, although the 2 patients with severe osteosclerosis suffered osteomalacia. We conclude that the assessment of TBM by CT at the axial skeleton of uremic patients has an acceptable reproducibility and accuracy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sex differences of human trabecular bone microstructure in aging are site-dependent.

In this study, we characterize bone microstructure, specifically sex differences, at multiple skeletal sites in 165 subjects >52 yr of age, using microCT technology in vitro. Significant sex differences are observed at the distal radius, femoral neck, and femoral trochanter, but not at the iliac crest, calcaneus, and lumbar vertebral body. Correlations in BV/TV between sites ranged from r = 0.13 to 0.56. INTRODUCTION: The goals of this study were (1) to assess potential sex differences of bone microstructure and their difference between skeletal sites and (2) to explore the relationship of trabecular microstructural properties between relevant skeletal sites. MATERIALS AND METHODS: Trabecular bone microstructural properties were measured in vitro in 165 subjects 52-99 yr of age using microCT. Defined volumes of interest (cylinders with 6 mm diameter and 6 mm length) were scanned at a resolution of 26 microm (isotropic) in six different anatomical sites: distal radius, femoral neck and trochanter, iliac crest, calcaneus, and second lumbar vertebral body. RESULTS: At the radius and femoral neck, trabecular bone displayed a more plate-like structure, thicker trabeculae, smaller separation/higher trabecular number, higher connectivity, and a higher degree of anisotropy in men than in women (p < 0.05). At the trochanter, men displayed more plate-like structure and thicker trabeculae (p < 0.05), but no differences in trabecular separation or other parameters compared with the women. At the calcaneus, iliac crest, and second lumbar vertebra none of the bone parameters displayed significant differences between sexes. The BV/TV at one site explained a range of only 2-32% of the variability at other sites. CONCLUSIONS: These results suggest that trabecular bone microstructural properties are remarkably heterogeneous throughout the skeleton. Significant differences between men and women are observed at some, but not at all, sites. The magnitude of sex differences in trabecular microstructure coincides with that of fracture incidence observed for some of the sites in epidemiological studies.     

Age-related changes in trabecular architecture differ in female and male C57BL/6J mice.

We used microCT and histomorphometry to assess age-related changes in bone architecture in male and female C57BL/6J mice. Deterioration in vertebral and femoral trabecular microarchitecture begins early, continues throughout life, is more pronounced at the femoral metaphysis than in the vertebrae, and is greater in females than males. INTRODUCTION: Despite widespread use of mice in the study of musculoskeletal disease, the age-related changes in murine bone structure and the relationship to whole body BMD changes are not well characterized. Thus, we assessed age-related changes in body composition, whole body BMD, and trabecular and cortical microarchitecture at axial and appendicular sites in mice. MATERIALS AND METHODS: Peripheral DXA was used to assess body composition and whole body BMD in vivo, and microCT and histomorphometry were used to measure trabecular and cortical architecture in excised femora, tibia, and vertebrae in male and female C57BL/6J mice at eight time-points between 1 and 20 mo of age (n = 6-9/group). RESULTS: Body weight and total body BMD increased with age in male and female, with a marked increase in body fat between 6 and 12 mo of age. In contrast, trabecular bone volume (BV/TV) was greatest at 6-8 wk of age and declined steadily thereafter, particularly in the metaphyseal region of long bones. Age-related declines in BV/TV were greater in female than male. Trabecular bone loss was characterized by a rapid decrease in trabecular number between 2 and 6 mo of age, and a more gradual decline thereafter, whereas trabecular thickness increased slowly over life. Cortical thickness increased markedly from 1 to 3 mo of age and was maintained or slightly decreased thereafter. CONCLUSIONS: In C57BL/6J mice, despite increasing body weight and total body BMD, age-related declines in vertebral and distal femoral trabecular bone volume occur early and continue throughout life and are more pronounced in females than males. Awareness of these age-related changed in bone morphology are critical for interpreting the skeletal response to pharmacologic interventions or genetic manipulation in mice.     

Histomorphometric Approach of Bone Loss in Men

From a review of the published literature the authors have described the histomorphometric changes observed in human iliac bone corresponding to the age-related bone loss in 'males and in "idiopathic" male osteoporosis. Age-related bone loss of about 30% is histomorphometrically characterized in males by a reduction in iliac cancellous bone volume between ages 20 and 70-80 years, less marked than in women (-42%). The age-related thinning of trabecular packets wall width is the same between males and females, but trabecular separation is lower in aged males than in aged females, suggesting a better preservation of the trabecular microarchitecture in elderly males. Trabecular eroded surfaces increase with age in females but not in males. The rare studies comparing bone formation parameters in males and females did not show any major difference, with a trend for a decrease in mineralization apposition rate and an increase in activation frequency in both sexes. Bone histomorphometry in "idiopathic" male osteoporosis is characterized by a mean decrease in cancellous bone volume of 35% compared with age-matched controls, similar to the mean decrease observed in females (-38%). Most, but not all authors have found an increase in bone resorption parameters and a decrease in bone static and dynamic formation indices (osteoid surfaces, mineralizing surfaces, bone formation rate).     

Treatment with a sclerostin antibody increases cancellous bone formation and bone mass regardless of marrow composition in adult female rats

The current report describes the skeletal effects of a sclerostin monoclonal antibody (Scl-AbIII) treatment at a yellow (fatty) marrow skeletal site in adult female rats. Ten-month-old female Sprague–Dawley rats were treated with vehicle or Scl-AbIII at 5 or 25 mg/kg, twice per week by s.c. injection for 4 weeks. Trabecular bone from a yellow (fatty) marrow site, the 5th caudal vertebral body (CVB), was processed undecalcified for quantitative bone histomorphometric analysis. Compared to vehicle controls, Scl-AbIII at both doses significantly increased bone formation parameters and trabecular bone volume and thickness and decreased bone resorption parameter in the trabecular bone of the CVB. As a reference, we also found that the Scl-AbIII at both doses significantly decreased bone resorption and increased bone formation and bone volume in a red (hematopoietic) marrow site, the 4th lumber vertebral body (LVB). It appears that the percentage of increase in trabecular bone volume induced by Scl-AbIII treatment was slightly larger in the LVB than in the CVB. In summary, these preclinical findings show that antibody-mediated sclerostin inhibition has significant bone anabolic effects at both red and yellow marrow skeletal sites.     

Intratrabecular tunneling increases trabecular number throughout the skeleton of ovariectomized rhesus monkeys treated with parathyroid hormone 1-84

Daily treatment of ovariectomized (OVX) adult rhesus monkeys with human parathyroid hormone (PTH) 1-84 for 16 months increases trabecular bone volume (BV/TV), number (Tb.N) and connectivity at lumbar vertebra-3 (L3) and thoracic vertebra-10. We proposed that the increased Tb.N and connectivity was achieved by stimulation of intratrabecular tunneling. Using histomorphometry to determine frequency of events, we have now quantified intratrabecular tunneling at L3 and extended it to investigate the effects of PTH(1-84) treatment on trabecular bone at the proximal femur, distal radius and iliac crest of these animals. At L3, tunneling frequency was low in control sham and OVX animals ( approximately 0.05/mm(2)) but increased significantly in PTH(1-84)-treated animals (0.27, 0.49 and 0.95/mm(2) with the 5, 10 and 25 microg/kg doses, respectively). Very similar tunneling frequencies were observed at all skeletal sites in all groups. Iliac crest biopsies were also collected at baseline and after 6 months of treatment and showed significant time- and dose-related increases in tunnels. Although the pattern and magnitude of response varied slightly from site to site, PTH(1-84) treatment significantly increased Tb.N, as well as BV/TV and bone formation rate at all skeletal sites. A modest but statistically significant increase in trabecular thickness occurred only at the iliac crest. In summary, intratrabecular tunneling is rare in control monkeys, but increased substantially with PTH(1-84) treatment. This phenomenon provides a plausible explanation for the PTH(1-84)-induced increase in Tb.N observed in OVX monkeys. Moreover, these analyses allowed a comparison of the effects PTH(1-84) treatment on trabecular bone at multiple locations.     

Correlation between the compressive strength of iliac and vertebral trabecular bone in normal individuals

Intrabone and interbone variations and age-related changes in vertical and horizontal trabecular bone compressive strength (CS) were evaluated for loadbearing (vertebral) and nonloadbearing (iliac crest) trabecular bone from 30 normal individuals, 17 females and 13 males, aged 15-87 years. All had died suddenly. The vertebral bodies of Th6, L1, and L3 and the right and left iliac crests were frozen at -20 degrees C immediately after removal. Cylindrical bone samples in the vertical and horizontal direction were taken from the frozen bone, and load-deformation curves were recorded by a materials testing machine. For all vertebral bodies, the vertical CS was much larger than the horizontal CS (P less than 0.01), whereas no significant difference was found for the iliac crests. The anisotropy expressed as an index of vertical to horizontal CS, therefore, was higher in the vertebrae than in the iliac crest. The anisotropy index (Al) increased with age in the vertebrae but not in the iliac crest (r = 0.56, P less than 0.01). Age related, almost identical decreases in CS were observed in the vertebrae (vertical direction) (r = 0.81, P less than 0.01) and in the iliac crest (horizontal direction) (r = -0.69, P less than 0.01). In spite of the pronounced differences in the architecture between the vertebral body and iliac trabecular bone, the vertical vertebral CS could be predicted from the horizontal iliac crest CS (r = 0.88, P less than 0.01, SEE = 0.9 MPa). The vertical iliac crest CS showed a less significant correlation to the average vertical vertebral CS (r = 0.53, P less than 0.05, SEE = 1.25 MPa).     

Trabecular architecture in women and men of similar bone mass with and without vertebral fracture: II. Three-dimensional histology

We recently developed a simple and inexpensive method that complements established bone histomorphometry procedures by enabling the two-dimensional imaging of cancellous bone to be viewed within its three-dimensional context with the marrow tissue in place and without detriment to the material for other histological purposes. The method, based on the preparation and superficial staining of slices 300 microm thick, enables "real" (i.e., unstained) trabecular termini to be separated from "artifactual" (i.e., stained) termini, providing a direct measure of cancellous connectivity in osteopenic bone. The technique was applied to osteopenic age-matched, white, postmenopausal women (31 with and 22 without vertebral compression fractures) with a similar bone status, as measured at the spine by absorptiometry and at the iliac crest by histology (see part I of this study). Despite the similarity in the mass of trabecular bone at either site, the results showed a significant difference (p < 0. 05) in the number of "real" trabecular termini between the groups, such that the fracture group had almost four times as many termini (mean +/- SE: 1.98 +/- 0.51/30 mm(2)) at the iliac crest as the nonfracture group (mean +/- SE: 0.53 +/- 0.31/30 mm(2)). Previous histomorphometry of the same material failed to detect a structural distinction between the two groups using established variables. It was concluded that a mass-independent trabecular discontinuity contributes to skeletal failure and that determination of the number of "real" disconnections (i.e., unstained termini) by the direct method proposed may provide a more sensitive discriminant of fracture than the present indirect procedures. A group of fracture and nonfracture men (see part I) suggested a similar distinction (fracture: 0.69 +/- 0.30/30 mm(2); nonfracture: 0.18 +/- 0.18/30 mm(2)), although the difference was not significant.     

Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure.

Histomorphometry and microCT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone plate-like structure, and cortical thickness, and a reduction in marrow star volume. INTRODUCTION: We studied the ability of teriparatide (rDNA origin) injection [rhPTH(1-34), TPTD] to improve both cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural data. METHODS: Fifty-one paired iliac crest bone biopsy specimens (placebo [n = 19], 20 microg teriparatide [n = 18], and 40 microg teriparatide [n = 14]) were analyzed using both two-dimensional (2D) histomorphometry and three-dimensional (3D) microcomputed tomography (microCT). Data for both teriparatide treatment groups were pooled for analysis. RESULTS AND CONCLUSIONS: By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, -24%; p = 0.001) and reduced marrow star volume (teriparatide, -16%; placebo, 112%; p = 0.004). Teriparatide administration was not associated with osteomalacia or woven bone, and there were no significant changes in mineral appositional rate or wall thickness. By 3D cancellous and cortical bone structural analyses, teriparatide significantly decreased the cancellous structure model index (teriparatide, -12%; placebo, 7%; p = 0.025), increased cancellous connectivity density (teriparatide, 19%; placebo, - 14%; p = 0.034), and increased cortical thickness (teriparatide, 22%; placebo, 3%; p = 0.012). These data show that teriparatide treatment of postmenopausal women with osteoporosis significantly increased cancellous bone volume and connectivity, improved trabecular morphology with a shift toward a more plate-like structure, and increased cortical bone thickness. These changes in cancellous and cortical bone morphology should improve biomechanical competence and are consistent with the substantially reduced incidences of vertebral and nonvertebral fractures during administration of teriparatide.     

Comparative study of iliac crest and subchondral femoral bone in osteoarthritic patients.

This is a study of trabecular bone changes in selected regions of the femoral head. Iliac crest bone from osteoarthritic (OA) and control groups is compared to the bone from regions in the femoral head. The regions are the subchondral principal compressive and tensile areas. These areas of highest and lowest stress undergo dramatic change with OA. The compressive region has total cartilage loss and eburnation. Bone histomorphometry was done on undecalcified tissue sections stained by the von Kossa silver method and counter-stained with haematoxylin and eosin. Iliac crest histomorphometry is similar for the OA and control groups. The femoral trabecular structure in the stress regions changes in opposing directions with OA. In the compressive region the structural variables (BV/TV and BS/TV) increase [corrected], and in the tensile region decrease. Femoral bone turnover indices (OV/TV, OS/BS, and ES/BS) are no different, but femoral bone structure is different from that of the iliac crest. In OA patients there is no significant increase in iliac crest trabecular bone volume. The iliac crest is not useful to assess the bony changes in femoral OA.     

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.     

The relationship between spinal trabecular bone mineral content and iliac crest trabecular bone volume

Summary The relationship between spinal trabecular bone mineral density and iliac crest trabecular bone volume has been studied in 84 patients, 23 with primary osteoporosis, 19 with osteoporosis secondary to inflammatory bowel disease, and 42 with nonsteroid-treated rheumatoid arthritis. Spinal trabecular bone mineral density was measured in the first three lumbar vertebrae by quantitative computed tomography, and iliac crest trabecular bone volume was assessed histomorphometrically in sections from trans-iliac biopsies using computerized techniques. In all 84 patients, there was a significant positive correlation between the two measurements (r=0.60,P<0.001). However, when the three patient groups were analyzed separately, a significant correlation was found in the group with secondary osteoporosis (r=0.65,P<0.01) but not in the patients with primary osteoporosis (r=0.07) or rheumatoid arthritis (r=0.19). These results indicate that the relationship between spinal trabecular bone mineral density and iliac crest trabecular bone volume differs according to the underlying disease process, these differences possibly reflecting variations in skeletal patterns of bone loss in different types of osteoporosis.     

Comparison of bone mass measured by histomorphometry on iliac biopsy and by dual photon absorptiometry of the lumbar spine

In a prospective study we compared bone mass measured independently by dual photon absorptiometry (DPA) on lumbar spine and by histomorphometry on transiliac biopsy. Measurements were done in 83 patients (23 males, 60 females) with various generalized bone diseases, including spinal osteoporosis, primary hyperparathyroidism and osteopetrosis. Iliac bone density was analyzed on bone biopsy with an automatic image analyzer and expressed as the trabecular bone volume (TBV), the cortical thickness (CT) and the total bone density (TBD) which includes the density of both spongy and cortical bone within the periosteal envelope. The bone mineral content (BMC) and density (BMD) were measured from L2 to L4 with a Novo Lab 22a device. For the 83 patients, there were significant correlations between values given by both methods, with r values ranging from 0.74 to 0.43, according to the bone mass parameters analyzed. In the 37 patients with untreated vertebral osteoporosis, the TBV--but not the CT nor the TBD--correlated significantly with the BMD of the spine (r = 0.53, p less than 0.001). In conclusion, there is a significant correlation between bone density of the iliac crest assessed histomorphometrically and spinal density measured by DPA. Despite the fact that DPA measures both trabecular and cortical bone of the spine, it correlates better with iliac trabecular bone mass than with the overall iliac bone density.