Intracortical remodeling during human bone development--a histomorphometric study

Although intracortical bone remodeling is a key aspect of bone physiology, very little is known about this process during human bone development. In this study, we examined transiliac bone samples from 56 individuals between 1.5 and 22.9 years of age (31 female; tetracycline labeling present in 42 subjects) who did not have evidence of metabolic bone disease. Parameters of osteonal structure (osteon diameter, wall thickness, diameter of osteonal canals) and dynamic measures of intracortical remodeling were determined separately for the external and internal cortex. We found that measures of osteonal structure were independent of age. However, the percentage of osteons showing metabolic activity was lower in the older study subjects, corresponding to a slowdown in the turnover of cortical bone. Most dynamic parameters of bone metabolism were higher in the internal cortex than in the external cortex. Cortical porosity was negatively associated with age on the external, but not on the internal cortex. The bone forming activity that refills the remodeling cavities seemed to favor the side of the osteonal canal that faced towards the periosteum. In summary, intracortical remodeling activity varies markedly during bone development, and is slightly asymmetric between the two cortices of an iliac bone specimen. Remodeling during development is thus an age-dependent process that varies with location even within the same bone.     

The bone formation defect in idiopathic juvenile osteoporosis is surface-specific

We have previously shown that idiopathic juvenile osteoporosis (IJO) is characterized by a decreased cancellous bone volume and a very low bone formation rate on cancellous surfaces. Whether IJO similarly affects cortical bone is unknown. We therefore compared tetracycline double-labeled transfixing iliac-crest bone biopsies from eight children with typical clinical features of IJO (six girls; age 10-12 years) and from nine children (four girls; age 9-12 years) without metabolic bone disease. No differences in intracortical remodeling activity were detected. Both structural parameters reflecting intracortical remodeling (cortical porosity, active canal diameter, and quiescent canal diameter) and bone surface-based metabolic parameters (osteoid, osteoblast, mineralizing, osteoclast and eroded surfaces, and bone formation rate) were similar in IJO patients and controls (p > 0.2 each, t-test). Although the internal cortex of the biopsy was thinner in IJO patients than in controls (660 +/- 170 microm vs. 980 +/- 320 microm; p = 0.02), there was no difference in the width of the external cortex (p = 0.36). In growing children, both cortices exhibit an external modeling drift. Therefore, the difference in internal cortical width point to a decreased modeling activity on the endocortical surface of the internal cortex. In fact, bone formation rate on this surface was 48% lower in IJO patients than in controls (82 +/- 45 microm(3)/microm(2) per year vs. 159 +/- 162 microm(3)/microm(2) per year). However, this difference did not achieve statistical significance (p = 0.21) due to the high variability of bone formation rate on modeling surfaces. The disturbance of bone remodeling in IJO is limited to cancellous bone, but there may be a modeling defect affecting the internal cortex. Thus, the process causing IJO appears to mainly affect bone surfaces that are in contact with the bone marrow cavity.     

Structural and cellular changes during bone growth in healthy children

Normal postnatal bone growth is essential for the health of adults as well as children but has never been studied histologically in human subjects. Accordingly, we analyzed iliac bone histomorphometric data from 58 healthy white subjects, aged 1.5-23 years, 33 females and 25 males, of whom 48 had undergone double tetracycline labeling. The results were compared with similar data from 109 healthy white women, aged 20-76 years, including both young adult reference ranges and regressions on age. There was a significant increase with age in core width, with corresponding increases in both cortical width and cancellous width. In cancellous bone there were increases in bone volume and trabecular thickness, but not trabecular number, wall thickness, interstitial thickness, and inferred erosion depth. Mineral apposition rates declined on the periosteal envelope and on all subdivisions of the endosteal envelope. Because of the concomitant increase in wall thickness, active osteoblast lifespan increased substantially. Bone formation rate was almost eight times higher on the outer than on the inner periosteum, and more than four times higher on the inner than on the outer endocortical surface. On the cancellous surface, bone formation rate and activation frequency declined in accordance with a fifth order polynomial that matched previously published biochemical indices of bone turnover. The analysis suggested the following conclusions: (1) Between 2 and 20 years the ilium grows in width by periosteal apposition (3.8 mm) and endocortical resorption (3.2 mm) on the outer cortex, and net periosteal resorption (0.4 mm) and net endocortical formation (1.0 mm) on the inner cortex. (2) Cortical width increases from 0.52 mm at age 2 years to 1.14 mm by age 20 years. To attain adult values there must be further endocortical apposition of 0.25 mm by age 30 years, at a time when cancellous bone mass is declining. (3) Lateral modeling drift of the outer cortex enlarges the marrow cavity; the new trabeculae filling this space arise from unresorbed cortical bone and represent cortical cancelization; (4) Lateral modeling drift of the inner cortex encroaches on the marrow cavity; some trabeculae are incorporated into the expanding cortex by compaction. (5) The net addition of 37 microm of new bone on each side of a trabecular plate results from a <5% difference between wall thickness and erosion depth and between bone formation and bone resorption rates; these small differences on the same surface are characteristic of bone remodeling. (6) Because the amount of bone added by each cycle of remodeling is so small, the rate of bone remodeling during growth must be high to accomplish the necessary trabecular hypertrophy.     

Effects of a one-month treatment with PTH(1-34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human ilium.

Using bone histomorphometry, we found that a 1-month treatment with PTH(1-34) [hPTH(1-34)] stimulated new bone formation on cancellous, endocortical, and periosteal bone surfaces. Enhanced bone formation was associated with an increase in osteoblast apoptosis. INTRODUCTION: The precise mechanisms by which hPTH(1-34) increases bone mass and improves bone structure are unclear. Using bone histomorphometry, we studied the early effects of treating postmenopausal women with osteoporosis with hPTH(1-34). MATERIALS AND METHODS: Tetracycline-labeled iliac crest bone biopsies were obtained from 27 postmenopausal women with osteoporosis who were treated for 1 month with hPTH(1-34), 50 microg daily subcutaneously. The results were compared with tetracycline-labeled biopsies from a representative control group of 13 postmenopausal women with osteoporosis. RESULTS: The bone formation rate on the cancellous and endocortical surfaces was higher in hPTH(1-34)-treated women than in control women by factors of 4.5 and 5.0, respectively. We also showed a 4-fold increase in bone formation rate on the periosteal surface, suggesting that hPTH(1-34) has the potential to increase bone diameter in humans. On the cancellous and endocortical surfaces, the increased bone formation rate was primarily caused by stimulation of formation in ongoing remodeling units, with a modest amount of increased formation on previously quiescent surfaces. hPTH(1-34)-stimulated bone formation was associated with an increase in osteoblast apoptosis, which may reflect enhanced turnover of the osteoblast population and may contribute to the anabolic action of hPTH(1-34). CONCLUSIONS: These findings provide new insight into the cellular basis by which hPTH(1-34) improves cancellous and cortical bone architecture and geometry in patients with osteoporosis.     

Normative data for iliac bone histomorphometry in growing children

Many insights into normal and pathologic bone development can only be gained by bone histomorphometry. However, the use of this technique in pediatrics has so far been hampered by the lack of reference data. Therefore, we obtained transfixing iliac bone samples from 58 individuals between 1.5 and 22.9 years of age (25 male; tetracycline labeling performed in 48 subjects), who underwent surgery for reasons independent of abnormalities in bone development and metabolism. The results of histomorphometric analyses of cancellous parameters and cortical width are presented as means and standard deviations, as well as medians and ranges in five age groups. In addition, the original data are available from the authors. There were significant age-dependent increases in both cortical width and cancellous bone volume, the latter being due to an increase in trabecular thickness. Osteoid thickness did not vary significantly with age. Bone surface-based indicators of bone formation showed an age-dependent decline, reflecting similar changes in activation frequency. Mineral apposition rate decreased continuously with age. Parameters of bone resorption did not vary significantly between age groups. Paired biopsies from adjacent sites, obtained in eight subjects, were used to examine the reproducibility of histomorphometric parameters in children. The lowest coefficients of variation (<10%) were found for structural measures, as well as mineral apposition rate and wall thickness. The highest variability was found for cellular parameters. The availability of reference material will greatly facilitate the use of histomorphometry in pediatrics.     

Bone fragility: failure of periosteal apposition to compensate for increased endocortical resorption in postmenopausal women.

The increase in bone fragility after menopause results from reduced periosteal bone formation and increased endocortical resorption. Women with highest remodeling had greatest loss of bone mass and estimated bone strength, whereas those with low remodeling lost less bone and maintained estimated bone strength. INTRODUCTION: Bone loss from the inner (endocortical) surface contributes to bone fragility, whereas deposition of bone on the outer (periosteal) surface is believed to be an adaptive response to maintain resistance to bending. MATERIALS AND METHODS: To test this hypothesis, changes in bone mass and estimated indices of bone geometry and strength of the one-third distal radius, bone turnover markers, and fracture incidence were measured annually in 821 women 30-89 years of age for 7.1 +/- 2.5 years. The analyses were made in 151 premenopausal women, 33 perimenopausal women, 279 postmenopausal women, and 72 postmenopausal women receiving hormone replacement therapy (HRT). RESULTS: In premenopausal women, periosteal apposition increased the radius width, partly offsetting endocortical resorption; therefore, the estimated cortical thickness decreased. Outward displacement of the thinner cortex maintained bone mass and cortical area and increased estimated bending strength. Estimated endocortical resorption accelerated during perimenopause, whereas periosteal apposition decreased. Further cortical thinning occurred, but estimated bending strength was maintained by modest outward cortical displacement. Endocortical resorption accelerated further during the postmenopausal years, whereas periosteal apposition declined further; cortices thinned, but because outward displacement was minimal, estimated cortical area and bending strength now decreased. Women with highest remodeling had the greatest loss of bone mass and strength. Women with low remodeling lost less bone and maintained estimated bone strength. In HRT-treated women, loss of bone strength was partly prevented. These structural indices predicted incident fractures; a 1 SD lower section modulus doubled fracture risk. CONCLUSIONS: Periosteal apposition does not increase after menopause to compensate for bone loss; it decreases. Bone fragility of osteoporosis is a consequence of reduced periosteal bone formation and increased endocortical resorption. Understanding the mechanisms of the age-related decline in periosteal apposition will identify new therapeutic targets. On the basis of our results, it may be speculated that the stimulation of periosteal apposition will increase bone width and improve skeletal strength.     

Skeletal effects of constant and terminated use of risedronate on cortical bone in ovariectomized rats

To study the skeletal effects of continual and terminated use of risedronate treatment on cortical bone in ovariectomized (Ovx) rats, we used risedronate (Ris), 5 μg · kg⁻¹, by subcutaneous injections, twice per week. The middle part of the tibial shafts (Tx) were processed undecalcified for quantitive bone histomorphometry. Cortical bone and the marrow areas of the tibial shaft did not change in either sham-Ovx or Ovx rats during the 150-day experimental period. Continued administration of Ris for 150 days decreased the marrow area and increased the percentage of cortical area compared with the matching sham and Ovx group. A decrease in bone formation indices in both periosteal and endocortical surfaces of Tx in sham-operated rats between the age of 5 and 8 months was seen. Ovariectomy increased the percentage of labeled perimeter in the periosteal area, and markedly increased the percentage of eroded perimeter in the endocortical surface compared with sham control groups in 81 and 150 days. Bone formation indices of Ris treatment were increased in periosteal surfaces, and percentages of eroded perimeter were decreased more in endocortical surfaces in 150 days than in the matching sham and Ovx groups. These data matched our static data, which showed a significantly increased percentage of cortical bone area and decreased percentage of marrow area. These bone gains were not maintained in the 90-day Ris withdrawal group. For cancellous bone, the 60-day Ris-treated high bone mass was maintained in the withdrawal group and not maintained in Ris continmuously treated group. These results indicate the effects of constant and terminated use of Ris in cortical bone were different from those in trabecular bone in the proximal tibial metaphysis. Received: Jan. 20, 1998 / Accepted: June 16, 1998     

Structural and biomechanical basis of sexual dimorphism in femoral neck fragility has its origins in growth and aging.

The structural basis for sex differences in femoral neck (FN) fragility was studied in 1196 subjects and 307 patients with hip fracture. The absolute and relative patterns of modeling and remodeling on the periosteal and endocortical envelopes during growth and aging produce changes in FN geometry and structure that results in FN fragility in both sexes and sexual dimorphism in hip fracture risk in old age. INTRODUCTION: Femoral neck (FN) fragility in old age is usually attributed to age-related bone loss, while the sex differences in hip fracture rate are attributed to less bone loss in men than in women. The purpose of this study was to define the structural and biomechanical basis underlying the increase in FN fragility in elderly men and women and the structural basis of sex differences in hip fracture incidence in old age. MATERIALS AND METHODS: We measured FN dimensions and areal bone mineral density in 1196 healthy subjects (801 females) 18-92 years of age and 307 patients (180 females) with hip fracture using DXA. We then used the DXA-derived FN areal bone mineral density (BMD) and measured periosteal diameter to estimate endocortical diameter, cortical thickness, section modulus (a measure of bending strength), and buckling ratio (indices for structural stability). RESULTS: Neither FN cortical thickness nor volumetric density differed in young adult women and men after height and weight adjustment. The sex differences in geometry were confined to the further displacement of the cortex from the FN neutral axis in young men, which produced 13.4% greater bending strength than in young women. Aging amplified this geometric difference; widening of the periosteal and endocortical diameters continued in both sexes but was greater in men, shifting the cortex even further from the neutral axis maintaining bending strength in men, not in women. In both sexes, less age-related periosteal than endocortical widening produced cortical thinning increasing the risk for structural failure by local buckling of the enlarged thin walled FN. Relative to age-matched controls, women and men with hip fractures had reduced cortical thickness, but FN periosteal diameter was increased in women and reduced in men, differences are likely to be originated in growth. CONCLUSIONS: The absolute and relative patterns of modeling and remodeling on the periosteal and endocortical envelopes during growth and aging produce changes in FN diameters, cortical thickness, and geometry that results in FN fragility in both sexes and sexual dimorphism in hip fracture risk in old age.     

Prostaglandin E2 enhances cortical bone mass and activates intracortical bone remodeling in intact and ovariectomized female rats

To assess the efficacy of prostaglandin E2 (PGE2) in augmenting cortical bone mass, graded doses of PGE2 were subcutaneously administered for 30 days to seven-month old sham-ovariectomized (SHAM) and ovariectomized (OVX) rats. Both groups were operated at three months of age. Histomorphometric analyses of double fluorescent labeled tibial shafts were performed on basal control, OVX, and SHAM rats treated with 0, 0.3, 1, 3, and 6 mg PGE2/kg/d for 30 days. Baseline aging data showed increased cortical tissue and cortical bone area and reduced bone formation parameters at the periosteal and endocortical bone envelopes between three and eight months of age. The tibial shafts of OVX rats compared to SHAM controls showed elevated periosteal mineral apposition rate and endocortical bone formation parameters. PGE2 administration to OVX and SHAM rats increased cortical bone by the addition of new circumferential bone on the endocortical and periosteal surfaces, as well as woven cancellous bone in the marrow region. Stimulated osteoblastic recruitment and activity enhanced bone formation at all bone surfaces. The new bone was both lamellar and woven in nature. PGE2 treatment also activated intracortical bone remodeling (not seen in untreated eight-month old rats), creating a porous cortex. Thus, PGE2 administration activated cortical bone modeling in the formation mode (A----F), as well as intracortical bone remodeling (A----R----F). PGE2 administration to OVX rats resulted in more intracortical bone remodeling, periosteal bone formation, and new cancellous bone production than observed in PGE2 treated controls. The findings that PGE2 administration to OVX and intact female rats increases cortical bone mass, coupled with observations that mouse, rat, dog, and man respond similarly to PGE2, suggest that PGE2 administration may be useful in the prevention and treatment of postmenopausal osteoporosis.     

Spatial Differences in the Distribution of Bone Between Femoral Neck and Trochanteric Fractures

There is little knowledge about the spatial distribution differences in volumetric bone mineral density and cortical bone structure at the proximal femur between femoral neck fractures and trochanteric fractures. In this case‐control study, a total of 93 women with fragility hip fractures, 72 with femoral neck fractures (mean ± SD age: 70.6 ± 12.7 years) and 21 with trochanteric fractures (75.6 ± 9.3 years), and 50 control subjects (63.7 ± 7.0 years) were included for the comparisons. Differences in the spatial distributions of volumetric bone mineral density, cortical bone thickness, cortical volumetric bone mineral density, and volumetric bone mineral density in a layer adjacent to the endosteal surface were investigated using voxel‐based morphometry (VBM) and surface‐based statistical parametric mapping (SPM). We compared these spatial distributions between controls and both types of fracture, and between the two types of fracture. Using VBM, we found spatially heterogeneous volumetric bone mineral density differences between control subjects and subjects with hip fracture that varied by fracture type. Interestingly, femoral neck fracture subjects, but not subjects with trochanteric fracture, showed significantly lower volumetric bone mineral density in the superior aspect of the femoral neck compared with controls. Using surface‐based SPM, we found that compared with controls, both fracture types showed thinner cortices in regions in agreement with the type of fracture. Most outcomes of cortical and endocortical volumetric bone mineral density comparisons were consistent with VBM results. Our results suggest: 1) that the spatial distribution of trabecular volumetric bone mineral density might play a significant role in hip fracture; 2) that focal cortical bone thinning might be more relevant in femoral neck fractures; and 3) that areas of reduced cortical and endocortical volumetric bone mineral density might be more relevant for trochanteric fractures in Chinese women. © 2017 American Society for Bone and Mineral Research.     

Varying contributions of growth and ageing to racial and sex differences in femoral neck structure and strength in old age

The structural basis of racial and sex differences in femoral neck (FN) fragility in old age was assessed in a cross-sectional study of 829 healthy Chinese and 1181 healthy Caucasian subjects aged 18 to 93 years in Melbourne, Australia. We measured FN bone mineral density (BMD), periosteal diameter, and estimated endocortical diameter, cortical thickness, volumetric BMD (vBMD), section modulus, and buckling ratio using dual X-ray absorptiometry. Racial and sex differences in structural and strength indices were adjusted for age, bone length and body weight and were expressed in standard deviation (SD) unit. In young adulthood, Chinese women had a 0.85 SD narrower FN, a 0.47 SD thinner cortex and a 0.79 SD shorter FN axis length (FNAL) than Caucasian women. Across age, Chinese and Caucasian women had similar increments in endocortical and periosteal diameters and similar decrements in cortical thickness and vBMD (both 20%). In young adult males, FN periosteal diameter did not differ by race, but cortical thickness was 0.35 SD lower in Chinese than Caucasians. Across age, increments in periosteal and endocortical diameters were less in Chinese than Caucasian men so cortical thickness and vBMD diminished less in Chinese than in Caucasian men. In both races, young adult women had narrower FN than men. As Chinese women had a greater increment in periosteal diameter than Chinese men across age, the sex difference in FN periosteal diameter established in young adulthood diminished in old age. As Caucasian men had a greater increment in periosteal diameter than Caucasian women, the sex difference in FN periosteal diameter established in young adulthood increased with age. In old age, for both sexes, Chinese had a higher fracture risk in bending than Caucasians, but a lower fracture risk by buckling. For both races, women had a higher fracture risk in bending than men. Racial and sexual dimorphism in the absolute and relative behavior of the periosteal and endocortical surfaces throughout life produce race- and sex-specific differences in FN size, cortical thickness, and indices of bone strength in old age.     

Osteoblast-specific targeting of soluble colony-stimulating factor-1 increases cortical bone thickness in mice.

The soluble and membrane-bound forms of CSF-1 are synthesized by osteoblasts and stromal cells in the bone microenvironment. Transgenic mice, generated to selectively express sCSF-1 in bone, showed increased cortical thickness in the femoral diaphysis caused by new bone formation along the endosteal surface. The ability of sCSF-1 to enhance bone cell activity in vivo is potentially relevant for increasing cortical bone in a variety of disorders. INTRODUCTION: The soluble form of colony-stimulating factor-1 (sCSF-1) and the membrane-bound form of CSF-1 (mCSF-1) have been shown to support osteoclastogenesis in vitro; however, the effect of each peptide on bone remodeling in vivo is unclear. To determine the effect of sCSF-1, selectively expressed in bone, the skeletal phenotype of transgenic mice harboring the human sCSF-1 cDNA under the control of the osteocalcin promoter was assessed. METHODS: At 5 and 14 weeks, mice were analyzed for CSF-1 protein levels, weighed, and X-rayed, and femurs were removed for peripheral quantitative computed tomography, histology, and histomorphometry. RESULTS: High levels of human sCSF-1 were detected in bone extracts and, to a lesser extent, in plasma. Adult transgenic mice showed normal body weight and increased circulating monocytic cells. At 5 weeks, the femoral diaphysis was similar in CSF-1T and wt/wt littermates. However, by 14 weeks, the femoral diaphysis in CSF-1T mice showed increased cortical thickness and bone mineral density. In contrast to the diaphysis, the femoral metaphysis of CSF-1T mice showed normal cancellous bone comparable with wt/wt littermates at each time point. Histological sections demonstrated increased woven bone along the endosteal surface of the diaphysis and intracortical remodeling. Fluorochrome-labeling analysis confirmed endocortical bone formation in CSF-1T, with a 3.1-fold increase in the percentage of double-labeled surfaces and a 3.6-fold increase in the bone formation rate compared with wt/wt mice. Although remodeling resulted in a slightly porous cortex, sCSF-1 preferentially stimulated endocortical bone formation, leading to increased cortical thickness. CONCLUSIONS: These findings indicate that sCSF-1 is a key determinant of bone cell activity in the corticoendosteal envelope.     

Changes in cortical width with bone turnover in the three different endosteal envelopes of the ilium in postmenopausal osteoporosis.

Histological indicators of bone turnover were compared in the three endosteal envelopes (cancellous, endocortical, and intracortical) of iliac bone specimens obtained from 82 osteoporotic women, to assess the correlation between bone turnover and bone volume in different remodeling sites. Although there was a significant but weak correlation between the mineral apposition rate (MAR), a histological indicator of bone formation at the basic multicellular unit (BMU) level, and the three endosteal envelopes, the bone formation rate corrected for bone surface (BFR/BS) and mineralizing surface (MS/BS), indicators of the rate of bone formation reflecting activation frequency, in the cancellous and endocortical envelopes was more closely related to the rate in the intracortical envelope. The endocortical BFR/BS and MS/BS were higher than the rate in the cancellous envelope (1.6-2.1 times and 2.0-2.4 times, respectively), indicating a higher turnover rate in the endocortical envelope. According to stepwise regression analysis of the significant determinants contributing to bone mass, several histological determinants relating to bone turnover were identified: (1) trabecular thickness (Tb.Th) was a positive determinant, whereas age and cancellous bone volume referent BFR (BFR/BV) were negatively correlated determinants of the cancellous bone volume (BV/TV) (R2 = 0.50, p < 0.001); and (2) the endocortical wall thickness (W.Th) of the given side and the cortical width (Ct.Wi) of the opposite side were positive determinants, whereas the cancellous osteoid surface (OS/BS), cancellous MAR, and endocortical eroded surface (ES/BS) of the given side were the negatively correlated determinants of the Ct.Wi of the thicker cortex (R2 = 0.62, p < 0.001). In the thinner cortex, the endocortical W.Th of the given side and Ct.Wi of the opposite side were only used as the positive determinants of the Ct.Wi of the given side (R2 = 0.55, p < 0.001). In addition: (3) a significant but weak correlation was found using the intracortical BFR/BV as a positively correlated determinant of the cortical porosity (Ct.Po) in the thicker cortex (R2 = 0.17, p < 0.01). Although these histological determinants do not fully explain the mechanisms of bone loss, an increased rate of bone turnover contributes to bone loss not only in the cancellous and intracortical envelopes, but also in the endocortical envelope, indicating increased endocortical bone resorption in osteoporosis.     

Correlation between microradiodensitometric data on the second metacarpal and histomorphometric values on biopsied iliac spongiosa

We compared the results of microdensitometry of the second metacalpal with those of histomorphometry of the biopsied iliac spongiosa in metabolically normal subjects, thirty seven females and twenty males, with the mean age of 44.7 years. Correlation coefficient with bone area was 0.681 for MCI (p<0.001), ?0.679 for d (p<0.001), 0.650 for ΔGSmin (p<0.001), 0.635 for E (p<0.001), 0.600 for ΔGSmax (p<0.001), 0.563 for ΣGS/D (p<0.001), ?0.226 for D (N.S.), 0.179 for F · GS(N.S.). Correlation between parameters of histomorphometry of iliac biopsy specimen and each index of metacalpal microdensitometry was generally high.     

Cortical Bone Histomorphometry of the Iliac Crest in Normal Black and White South African Adults

Fragility fracture rates in South African blacks (B) are lower than in whites (W). Since bone strength in many parts of the skeleton depends mainly on cortical bone, we examined iliac crest cortical bone from 97 B (49 male, 48 female) aged 22–80 and 111 W (60 male, 51 female) aged 21–84 histomorphometrically for differences between B and W and effects of age. B had thicker (P = 0.02) and less porous (P = 0.0007) cortices, fewer haversian (H) osteons (P < 0.0001), and greater endocortical (Ec) wall thickness (P < 0.0001). B also had thicker H (P = 0.0005) and Ec osteoid seams (P < 0.0001); greater Ec osteoid surface (P = 0.0005), Ec mineral apposition rate (P < 0.0001), and Ec bone formation rate (P = 0.038); and lower H (P = 0.0002) and Ec eroded surfaces (P = 0.029). Some of the differences were already present in subjects aged 21–30 years. Although cortical structure deteriorated with age in B and W, after age 40 Ec wall thickness declined only in W. Greater Ec mineral apposition and bone formation rates, i.e., greater osteoblast efficiency at the cellular and tissue levels, suggest better Ec bone preservation that may contribute to lower fragility fracture rates in B.     

Cortical Bone Loss in Androgen‐Deficient Aged Male Rats Is Mainly Caused by Increased Endocortical Bone Remodeling

Introduction : Hypogonadism is considered to be one of the major risk factors for osteoporosis in men. Here, we sequentially studied the effects of androgen deficiency on cortical bone in aged orchiectomy (ORX) rats. Materials and Methods : One hundred seventy 13‐mo‐old male Fischer‐344 rats were either ORX or sham‐operated. After in vivo fluorochrome labeling, groups of 8–15 SHAM and ORX rats each were killed at 2 wk and 1, 2, 3, 4, 6, and 9 mo after surgery. To examine the effects of testosterone replacement therapy, 9‐mo‐old ORX rats were supplemented with testosterone undecanoate at a weekly dose of 6 mg/kg for 4 mo. Cortical bone changes in the tibial shaft were monitored by pQCT analysis and by bone histomorphometry. Results : SHAM rats did not show age‐related bone loss at the tibial diaphysis. pQCT analysis and bone histomorphometry showed cortical bone osteopenia in ORX rats, beginning from 2 mo after surgery until the end of the study. Androgen deficiency induced a sustained decrease in periosteal bone formation during the first 4 mo after ORX. However, although periosteal expansion of the tibial shaft tended to be slower in ORX rats compared with SHAM controls, the reduction in total cross‐sectional area in ORX animals reached statistical significance only at 4 mo after surgery. The major mechanism for cortical bone loss in aged ORX rats was a progressive expansion of the marrow cavity, which was associated with an initial increase in endocortical eroded perimeter at 1 and 2 mo after surgery, followed by a sustained increase in endocortical bone formation until the end of the study. All these changes were prevented in aged ORX rats receiving testosterone supplementation in an insulin‐like growth factor system–independent fashion. Conclusions : We conclude that androgen deficiency–induced cortical bone loss in aged, nongrowing rats is mainly caused by augmented endocortical bone remodeling.     

Interindividual and intraspecimen variability of 3-D bone microarchitectural parameters in iliac crest biopsies imaged by conventional micro-computed tomography

Bone microarchitecture of the iliac bone is used to characterize the properties of bone tissue in osteoporosis, particularly in pharmacological studies. Trabecular bone is known to be heterogeneous media. For a few years, the analysis of three-dimensional (3-D) bone microarchitecture has been based on micro-computed tomography (micro-CT). To assess the interindividual variability (inter-indVar) and the intrasample variability (intra-sampVar) of iliac crest biopsies, we used a Bordier needle trephine in 35 postmenopausal female cadavers (mean age, 74.4 +/- 10.4 years). Finally, we had at our disposal 32 individual iliac crests to assess the inter-indVar and 21 oriented specimens to assess the intra-sampVar. All the samples were chemically defatted, and the images were performed with a desktop micro-CT with a voxel size of 10.77 mum. We measured trabecular bone parameters: bone volume/tissue volume (BV/TV %), trabecular thickness and spacing (Tb. Th*, Tb.Sp* mum), bone surface/bone volume (BS/BV, 1/mm), the trabecular number (Tb.N, 1/mm), structure model index (SMI), trabecular pattern factor (Tb.Pf), and degree of anisotropy (DA). We also measured cortical bone parameters: cortical thickness (Cort.Th), porosity (PoV/TV), and pore diameter (Po.Dm). For the inter-indVar, we analyzed a fixed volume of interest corresponding to 119.8 mm(3) centered on each iliac crest. To assess the intra-sampVar, we divided the whole trabecular volume into three equal height parts (external, middle, internal). BV/TV, Tb.N, and PoV/TV were negatively correlated with age and Tb.Sp* and SMI were positively correlated. The mean difference of absolute individual variations in percentage with the middle area used as a reference, comparatively to external and internal areas, ranged from 6.6% (Tb.Sp*) to 27.8% (BV/TV), except Tb.Pf, which showed large variability. There was no difference between external and internal areas, with a tendency for lower values of BV/TV, Tb.Th*, and Tb.N in the middle of the iliac crest and higher values of Tb.Sp* and BS/BV. The evaluation of bone microarchitecture of iliac crest samples on micro-CT images is reliable. The heterogeneity of bone inside the iliac crest is noticeable as leading to analyzing the largest possible quantity of bone, with standardized location, according to cortex but without any assumption of orientation.     

Transient effects of subcutaneously administered prostaglandin E2 on cancellous and cortical bone in young adult dogs

The transient effects of prostaglandin E2 (PGE2) on cancellous and cortical bone in iliac crests and mid-tibial shafts of nine intact young adult dogs were evaluated following 31 days of treatment. Histomorphometric bone changes were characterized from in vivo fluorescent double-labeled undecalcified bone specimens. PGE2 caused an increase in cancellous bone remodeling evidence by increased in activation frequency; increased percent eroded and formation surfaces; increased mineral apposition and bone formation rates; and shortened resorption, formation, and total bone remodeling periods. Activated cancellous bone remodeling did not lead to decreased cancellous bone mass, indicating an imbalance between bone resorption and formation in favor of formation (activation----resorption----stimulated formation; A----R----F increases) at remodeling sites. The PGE2 treatment activated bone modeling in the formation mode (activation----formation; A----F) at the periosteal and endocortical surfaces and increased activation frequency of intracortical bone remodeling in the tibial shaft. Increased modeling activation converted quiescent bone surfaces to formation surfaces with stimulated osteoblastic activity (i.e., increased percent labeled periosteal and endocortical surfaces, mineral apposition rates, and woven and lamellar trabecular bone formation) leading to 9- to 26-fold increases in newly formed bone mass in subperiosteal, subendosteal, and marrow regions, compared to controls. However, increased intracortical bone remodelling elevated remodeling space (i.e., increased cortical porosity), producing a bone loss that partially offsets the bone gain. The combined events lead to a positive bone balance in PGE2-treated cortical bone, compared to a negative bone balance in control bones. Collectively our data suggest that in vivo PGE2 is a powerful activator of cancellous and cortical bone formation, which may be able to build a peak bone mass to prevent and/or correct the skeletal defects to cure osteoporosis.     

Long-term disuse osteoporosis seems less sensitive to bisphosphonate treatment than other osteoporosis.

We sought to determine whether risedronate can preserve cortical bone mass and mechanical properties during long-term disuse in dogs, assessed by histomorphometry and biomechanics on metacarpal diaphyses. Risedronate slowed cortical thinning and partially preserved mechanical properties, but it was unable to suppress bone loss to the degree seen in other osteoporoses. INTRODUCTION: Disuse induces dramatic bone loss resulting from greatly elevated osteoclastic resorption. Targeting osteoclasts with antiresorptive agents, such as bisphosphonates, should be an effective countermeasure for preventing disuse osteoporosis. MATERIALS AND METHODS: Single forelimbs from beagles (5-7 years old, n = 28) were immobilized (IM) for 12 months. Age-matched, non-IM dogs served as controls. One-half the animals received either risedronate (RIS, 1 mg/kg) or vehicle daily. Histomorphometry was performed on second metacarpal mid-diaphyses. Cortical mechanical properties were determined by testing third metacarpal diaphyses in four-point bending. RESULTS: IM caused marked reduction in cortical area (-42%) and cortical thinning (-40%) through endocortical resorption, extensive intracortical tunneling, and periosteal resorption; both bone resorption and formation were significantly elevated over control levels on all envelopes. IM also decreased maximum load and stiffness by approximately 80% compared with controls. RIS reduced both periosteal bone loss and marrow cavity expansion; however, cortical area remained significantly lower in RIS-treated IM animals than in untreated non-IM controls (-16%). RIS also increased resorption indices in all envelopes compared with nontreated IM, indicating that RIS suppressed osteoclast activity but not osteoclast recruitment. RIS did not affect bone formation. RIS treatment conserved some whole bone mechanical properties, but they were still significantly lower than in controls. There were no significant differences in tissue level material properties among the groups. CONCLUSION: RIS treatment reduces cortical bone loss at periosteal and endocortical surfaces caused by long-term immobilization, thus partially conserving tissue mechanical properties. This modest effect contrasts with more dramatic actions of the bisphosphonate in other osteoporoses. Our results suggest that risedronate impairs osteoclastic function but cannot completely overcome the intense stimulus for osteoclast recruitment during prolonged disuse.     

Physical and histomorphological characteristics of iliac crest bone differ according to the grade of osteoarthritis at the hand

The amount of cortical and trabecular bone was studied in 32 iliac crest necropsy specimens from women 60-75 years of age and examined according to the grade of osteoarthritis. Three different methods to evaluate bone mass were used: dual photon absorptiometry, physical assessment according to Archimedes' principle, and histomorphometry. Patients were divided into groups--with or without osteoarthritis--according to the presence of osteoarthritis on hand x rays. A significantly increased amount of cortical and trabecular bone mass was found in those who had osteoarthritis at the hands. Percent pure/crude bone volume and trabecular width were found to be increased with osteoarthritic grade, indicating that primary osteoarthritis is probably part of a generalized bone disease.