Thinking inside and outside the envelopes of bone

Introduction  Bone modeling and remodeling is the final common pathway expressing all genetic and environmental factors that influence the attainment and maintenance of bone’s material and structural strength. Modeling and remodeling require a surface, and during growth this cellular machinery fashions bone’s external size, shape, and internal architecture by depositing bone on, and removing bone from, both its periosteal (external) and endosteal (internal) envelopes. Bone is distributed and redistributed to achieve strength commensurate with its loading requirements. Methods  Advancing age is associated with: (1) a reduction in the volume of bone resorbed by each basic multicellular unit (BMU); (2) an even greater reduction in the volume of bone formed by each BMU so that each remodeling event, whether adaptive or reparative, removes bone from the bone; (3) increased remodeling (number of BMUs) on the three (endocortical, intracortical, and trabecular) components of its endosteal envelope in midlife in women and late in life in both sexes; and (4) reduced bone formation on the periosteal envelope. The net effect is cortical thinning, increased intracortical porosity, trabecular thinning, and loss of connectivity. Results  While remodeling intensity on an envelope determines structure (e.g., trabecular perforations), the surface area of the envelope determines remodeling intensity, and, so, structure. High remodeling on trabecular surfaces decreases as trabeculae (with their surface) are lost. Conversely, remodeling on the endocortical and intracortical envelopes increases their surface area, so remodeling intensity increases and bone loss becomes predominantly cortical. Conclusions  Understanding bone structural strength and its decay and the effects of genetic factors, exercise, nutrition, and drug therapy on bone requires thinking outside and inside these envelopes; their absolute and relative movements during growth and aging determine bone structure and its strength.     

The structural basis of bone fragility in men.

Understanding of the pathogenesis of bone fragility in men requires knowledge of its structural basis. There is no evidence that gender differences in fracture rates are explained by gender differences in bone mineral content (BMC) or areal bone mineral density (BMD). This is an untested assumption. The BMD measurement integrates the modeling and remodeling that occurs on the periosteal and endosteal surfaces of bone during growth and aging. The size, shape, and architecture of the bone so formed determine its breaking strength. None of these three-dimensional structural components is "seen" by the dual photons of the densitometer. Men and women attain a similar peak vertebral height during growth. Vertebral width is greater in men, conferring higher BMC and areal BMD, but trabecular number and thickness (trabecular volumetric BMD) is no greater in men than women. Blacks have shorter vertebra than whites, and vertebral width is similar. Trabecular thickness is greater in blacks than whites. Thus, at peak, gender differences in vertebral strength are likely to be size, not BMD, dependent. Racial differences in vertebral strength are likely to be BMD, not size, dependent. Greater periosteal expansion during growth in males than females, and blacks than whites, establishes the gender and racial differences in peak bone size. Men have wider long bones than women. Blacks have wider long bones than whites. The proximity of the endocortical surface to the periosteal surface determines peak cortical width, which is similar in men, women, blacks, and whites. It is the greater distance of the cortical mineral mass from the neutral axis of a long bone in males than in females, in blacks than in whites, and in men with, than men without, fractures, that partly accounts for the greater bone strength in the first mentioned in each group. Thus, at peak, racial and gender differences in long bone strength are likely to be size, not BMD dependent. Trabecular bone loss is similar in men and women. Loss of connectivity is greater in women. Endocortical resorption is greater in women than men, but men lose less cortical width because subperiosteal apposition during aging is greater in men than in women offsetting endocortical resorption. Men with spine fractures have smaller vertebrae because vertebral width is less. Men with hip fractures have smaller femoral neck width. In both types of fractures, there is less bone in the smaller bone-reduced volumetric BMD. The relative contributions of reduced accrual during growth, excessive bone loss during aging, or both to the deficit in volumetric BMD are undefined. No antifracture efficacy trials have been done in men. Reasonable approaches to treatment include the use of testosterone in hypogonadal men, and vitamin D if vitamin D deficiency is present. Calcium supplements may slow endocortical bone loss. Bisphosphonates may increase BMD.     

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.     

Growth hormone protects against ovariectomy‐induced bone loss in states of low circulating insulin‐like growth factor (IGF‐1)

Early after estrogen loss in postmenopausal women and ovariectomy (OVX) of animals, accelerated endosteal bone resorption leads to marrow expansion of long bone shafts that reduce mechanical integrity. Both growth hormone (GH) and insulin‐like growth factor (IGF‐1) are potent regulators of bone remodeling processes. To investigate the role of the GH/IGF‐1 axis with estrogen deficiency, we used the liver IGF‐1‐deficient (LID) mouse. Contrary to deficits in controls, OVX of LID mice resulted in maintenance of cortical bone mechanical integrity primarily owing to an enhanced periosteal expansion affect on cross‐sectional structure (total area and cortical width). The serum balance in LID that favors GH over IGF‐1 diminished the effects of ablated ovarian function on numbers of osteoclast precursors in the marrow and viability of osteocytes within the cortical matrix and led to less endosteal resorption in addition to greater periosteal bone formation. Interactions between estrogen and the GH/IGF‐1 system as related to bone remodeling provide a pathway to minimize degeneration of bone tissue structure and osteoporotic fracture. © 2010 American Society for Bone and Mineral Research     

Association of bone turnover markers with volumetric bone loss,periosteal apposition,and fracture risk in older men and women: the AGES-Reykjavik longitudinal study

Summary

Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk.

Introduction

We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study.

Methods

The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4–12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type.

Results

Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk.

Conclusion

This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.

     

Bone loss in elderly men: increased endosteal bone loss and stable periosteal apposition. The prospective MINOS study

Introduction Longitudinal studies on the age-related bone loss in men concerns the decrease in areal bone mineral density (aBMD), which can be qualified as “apparent bone loss” because it does not reflect the change in bone mineral content (BMC). Loss of BMC can be referred to as “net bone loss” because it does not take into account the morphological basis of the bone loss (decreased periosteal apposition; endosteal bone loss, i.e. bone loss on the trabecular, endocortical and intracortical surfaces). The aim of this study was to assess age-related apparent net and endosteal bone loss as well as their morphological basis and age-related changes during a prospective follow-up in a large cohort of elderly men. Methods This analysis was performed in 725 men aged 51–85 at baseline who were followed up for 90 months. Results Bone densitometry was carried out at the lumbar spine, hip and whole body by using the HOLOGIC QDR1500 device and at the distal forearm by using the Osteometer DTX100 device. Sixty-five men who abandoned the study after the first examination were older and had lower aBMC at most sites of measurement. Apparent bone loss was significant at the hip, distal forearm and whole body. Net bone loss was also significant at these sites, except for the femoral neck. Periosteal expansion was significant at all sites of measurement. Apparent and net bone loss accelerated with age, whereas the rate of periosteal expansion remained stable. At the distal radius and ulna, endosteal bone loss accelerated with age, whereas the rate of periosteal apposition remained stable. Conclusion In a large cohort of elderly men, age-related apparent bone loss (aBMD) at the hip, distal forearm and whole body was determined by the net bone loss (BMC), except for the femoral neck. Apparent and net bone loss accelerated with age, whereas the periosteal expansion rate (bone widening) remained constant. At the distal forearm, age-related acceleration of the apparent bone loss was determined by the higher endosteal bone loss, whereas the periosteal apposition rate (estimated mass of deposited bone) remained constant.     

Bone quality: the material and structural basis of bone strength

The material composition and structural design of bone determine its strength. Structure determines loads that can be tolerated but loads also determine structure. Bone modifies its material composition and structure to accommodate loads by adaptive modeling and remodeling. Adaptation is successful during growth but not aging because accumulating insults, including a reduction in the volume of bone formed in the basic multicellular unit (BMU), increased resorption in the BMU, increased remodeling rate in midlife in women and in some men because of sex hormone deficiency, and in both sexes in old age as a consequence of secondary hyperparathyroidism and reduced periosteal bone formation, all of which compromises the material composition of bone and its structure. An understanding of the mechanisms of adaptation and failed adaptation provides rational approaches to interventions that can prevent or restore bone fragility.     

Estrogen-specific action on bone geometry and volumetric bone density: Longitudinal observations in an adult with complete androgen insensitivity

IntroductionSex steroids have distinct effects on bone growth and maintenance in men and women, mediated through their respective steroid receptors. Though most evidence is derived from animal studies, several concepts have been confirmed in humans by detection of specific mutations. In this report we describe changes in bone size and volumetric bone density in a complete androgen insensitive subject (CAIS) due to a mutation in the androgen receptor during 5 years of estrogen treatment.Materials and methodsWe present a case report of a 31 year old XY female with CAIS with a longitudinal follow-up for 5 years of areal and volumetric bone parameters. Areal and volumetric bone parameters were determined using dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Sex steroids, LH, FSH and IGF-I were determined by immunoassay.ResultsComplete androgen insensitivity syndrome was genetically confirmed by detection of the mutation Asp767Tyr in the androgen receptor gene. Bone size at presentation was found to be intermediate between male and female reference values. Low areal and volumetric bone density (both trabecular and cortical) was observed at baseline and improved gradually with estrogen treatment (+ 2% to 6.5%). Upon estrogen treatment, endosteal contraction (? 1%) was demonstrated, with increasing cortical thickness (+ 3%), cortical area (+ 5%) and unchanged periosteal circumference.ConclusionsDuring adult life, estrogens mediate endosteal bone apposition and volumetric bone density, without marked influence on periosteal bone apposition. The finding of a bone size intermediate between male and female supports testosterone as an essential mediator for periosteal bone expansion, but not as the sole stimulus for bone expansion during growth.     

Cortical bone remodeling in normal rat

Summary Cortical bone remodeling along the femur diaphysis was determined in normal female rats (Sprague-Dawley) with the tetracycline technique.Three segments on the cortical bone circumference (the anterolateral, the medial, and the posterior) were found to be most suitable for the study of the remodeling process. Oxytetracycline was administered at age 60 and 75 days, and groups of animals were killed at age 75, 85, 95, and 105 days.The accumulated endosteal growth during age 60 to 75 days in the anterolateral segment was found to increase uniformly in the distal direction along the femur diaphysis. A method is described where this accumulated endosteal growth is used. This method eliminates the use of calipers to determine the section level and makes it possible to study comparable sections even after varying periods of time.The proximal part of the diaphysis showed periosteal apposition in all three segments. The periosteal apposition turned into resorption in the distal part of the diaphysis in the anterolateral and medial segments, whereas the periosteal appsition increased in the posterior segment.The endosteal growth increased in the distal direction in the anterolateral and medial segments. Irregular OTC bands made measurements of endosteal remodeling in the posterior segment impossible.The cortical width decreased in the distal direction along the femoral shaft. Comparison between the different age groups is described and also the relation between the accumulated endosteal growth and the diameter of the medullary cavity.     

Biochemical markers of bone formation reflect endosteal bone loss in elderly men--MINOS study

In the skeleton of elderly men, two opposite activities occur: bone loss at the endosteal envelope, which increases bone fragility, and periosteal apposition, which improves bending strength of bone. Both may contribute to serum bone formation markers although they have an opposite effect on bone fragility. The aim of this study was to determine if circulating bone formation markers reflect periosteal bone formation and endosteal bone remodelling in 640 men aged 55-85 years belonging to the MINOS cohort. We measured biochemical markers of bone formation (osteocalcin, bone alkaline phosphatase, N-terminal extension propeptide of type I collagen) and bone resorption (urinary and serum beta-isomerised C-terminal telopeptide of collagen type I, total and free deoxypyridinoline). Parameters of bone size (cross-sectional surface of third lumbar vertebral body measured by X-ray, projected areas of total hip, femoral neck, radius and ulna measured by dual-energy X-ray absorptiometry) increased with age (r = 0.20-0.32, P < 0.0001). In contrast, parameters related to bone loss (areal bone mineral density [aBMD], volumetric bone mineral density [vBMD] and cortical thickness) and determined mainly by bone resorption, decreased with ageing (r = -0.14 to -0.23, P < 0.005-0.0001). Men in the highest quartile of bone resorption markers had lower aBMD (3.8-10.2%, P < 0.05-0.0001), lower vBMD (3.9-13.0%, P < 0.05-0.0001), and lower cortical thickness (1.5-9.6%, P < 0.05-0.0001) than men in the lowest quartile. Markers of bone resorption were not significantly associated with estimates of bone size at any skeletal site. Markers of bone formation were not associated with estimates of periosteal formation after adjustment for covariates. In contrast, men in the highest quartile of the bone formation markers had significantly lower aBMD (4.0-11.7%, P < 0.05-0.0001), lower vBMD (4.2-16.3, P < 0.05-0.0001) and lower cortical thickness (4.0-7.4%, P < 0.05-0.0001) than men in the lowest quartile. In summary, serum levels of bone formation markers are negatively correlated with the estimates of endosteal bone loss. In contrast, they disclose no association with parameters reflecting periosteal apposition. Thus, in elderly men, bone formation markers reflect endosteal bone remodelling, probably because of the coupling between resorption and formation activities. In contrast, they do not reflect the periosteal bone formation, probably because the periosteal surface is smaller and has a slower remodelling rate than the endosteal surface.     

Short-Term effects of high dose estrogen on tibiae of growing male rats

The short-term effects of estrogen at a single high dose (4 mg/kg body weight/day for 14 days) were determined on tibiae in the normal (noncastrate) growing male rat. In cortical periosteal bone, at a middiaphyseal site devoid of resorbing activity, estrogen suppressed periosteal bone formation and apposition rates, resulting in a smaller cross-sectional area. In middiaphyseal endocortical bone, estrogen had no effect on apposition and formation rates and, because medullary area was unchanged, probably had no effect on endocortical bone resorption. In the proximal tibial metaphysis, estrogen greatly suppressed longitudinal growth rate. In a site within the metaphysis adjusted for the effects of growth, cancellous mineral apposition was greatly reduced by the hormone. Estrogen-treated rats retained more of a fluorochrome label deposited in cancellous bone at the beginning of the study than vehicle-treated animals, indicating a reduced net bone loss. As a result of the lowered resorption induced by estrogen, cancellous bone mass (area and perimeter) were both significantly higher in estrogen-treated rats. No evidence was found for an anabolic action of the hormone in the male rat; indeed, estrogen reduced indices of bone formation. Received: 31 December 1995 / Accepted: 3 May 1996     

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.     

Accelerated bone loss,but not low periosteal expansion,is associated with higher all-cause mortality in older men – prospective MINOS study

BackgroundLow bone mineral density (BMD), high bone resorption, fragility fractures and, possibly, accelerated bone loss are associated with higher mortality. However, it is not known if the higher mortality is related to lower volumetric BMD or lower bone width, to faster bone loss on endosteal surfaces (inside bone) or to slower periosteal apposition (formation of bone on the outer bone surface).MethodsWe assessed the association of 10-year mortality with bone width and bone loss in 782 men aged 50–85 years.ResultsLow bone width and slow periosteal apposition at the femoral neck, distal radius and distal ulna were not associated with higher mortality. Accelerated apparent bone loss (decrease in BMD), net bone loss (decrease in bone mineral content) and estimated endosteal bone loss were associated with a higher 10-year all-cause mortality after adjustment for age and other confounders. Accelerated apparent bone loss at the total hip (lowest quartile) was associated with a two-fold higher mortality (Hazard Ratio (HR)=1.96, 95% Confidence interval (CI): 1.33, 2.89, p<0.001).ConclusionLack of association between bone size and mortality shows that periosteal expansion is not an artifact induced by the selective mortality of men with narrow bones. We confirmed that poor bone status reflects poor health. These data should be interpreted with caution because of the study limitations, especially the lack of representativity of the cohort and dropout of older and sick men. However, they suggest that older men with low BMD or accelerated bone loss should obtain detailed diagnostic assessment to establish general factors that can contribute to their poor bone status.     

Tamoxifen prevents the skeletal effects of ovarian hormone deficiency in rats

To determine whether the nonsteroidal antiestrogen tamoxifen behaves as either an agonist or antagonist of estrogen on bone, the effects of ovariectomy, 17 beta-estradiol, and tamoxifen were compared on radial growth at the tibial diaphysis in young adult female rats. Ovariectomy and 17 beta-estradiol did not alter serum calcium, phosphate, or 25-hydroxyvitamin D. Ovariectomy increased serum 1,25-dihydroxyvitamin D in one experiment but not in the other. Tamoxifen increased the serum calcium and phosphate by itself and did not change serum 1,25-dihydroxyvitamin D in ovariectomized rats. Ovariectomy produced significant increases in medullary area, periosteal bone formation rate, and periosteal bone apposition rate compared to values in sham-operated animals and did not change endosteal bone formation rate. The increase in medullary area resulted from an increase in osteoclast number and resorbing surface length. Although endosteal forming surface length decreased, this was compensated for by an increase in the apposition rate. 17 beta-estradiol and tamoxifen each prevented the increases in bone formation rate and medullary area in ovariectomized rats. Tamoxifen reduced the length of the resorbing surface and osteoclast number to values observed in sham-operated animals. The findings demonstrate that in the rat, tamoxifen acts as an estrogen agonist by preventing the skeletal alterations that result from ovarian hormone deficiency.     

beta-Arrestin2 regulates the differential response of cortical and trabecular bone to intermittent PTH in female mice.

Cytoplasmic arrestins regulate PTH signaling in vitro. We show that female beta-arrestin2(-/-) mice have decreased bone mass and altered bone architecture. The effects of intermittent PTH administration on bone microarchitecture differed in beta-arrestin2(-/-) and wildtype mice. These data indicate that arrestin-mediated regulation of intracellular signaling contributes to the differential effects of PTH at endosteal and periosteal bone surfaces. INTRODUCTION: The effects of PTH differ at endosteal and periosteal surfaces, suggesting that PTH activity in these compartments may depend on some yet unidentified mechanism(s) of regulation. The action of PTH in bone is mediated primarily by intracellular cAMP, and the cytoplasmic molecule beta-arrestin2 plays a central role in this signaling regulation. Thus, we hypothesized that arrestins would modulate the effects of PTH on bone in vivo. MATERIALS AND METHODS: We used pDXA, muCT, histomorphometry, and serum markers of bone turnover to assess the skeletal response to intermittent PTH (0, 20, 40, or 80 mug/kg/day) in adult female mice null for beta-arrestin2 (beta-arr2(-/-)) and wildtype (WT) littermates (7-11/group). RESULTS AND CONCLUSIONS: beta-arr2(-/-) mice had significantly lower total body BMD, trabecular bone volume fraction (BV/TV), and femoral cross-sectional area compared with WT. In WT females, PTH increased total body BMD, trabecular bone parameters, and cortical thickness, with a trend toward decreased midfemoral medullary area. In beta-arr2(-/-) mice, PTH not only improved total body BMD, trabecular bone architecture, and cortical thickness, but also dose-dependently increased femoral cross-sectional area and medullary area. Histomorphometry showed that PTH-stimulated periosteal bone formation was 2-fold higher in beta-arr2(-/-) compared with WT. Osteocalcin levels were significantly lower in beta-arr2(-/-) mice, but increased dose-dependently with PTH in both beta-arr2(-/-) and WT. In contrast, whereas the resorption marker TRACP5B increased dose-dependently in WT, 20-80 mug/kg/day of PTH was equipotent with regard to stimulation of TRACP5B in beta-arr2(-/-). In summary, beta-arrestin2 plays an important role in bone mass acquisition and remodeling. In estrogen-replete female mice, the ability of intermittent PTH to stimulate periosteal bone apposition and endosteal resorption is inhibited by arrestins. We therefore infer that arrestin-mediated regulation of intracellular signaling contributes to the differential effects of PTH on cancellous and cortical bone.     

Bone mass and microarchitecture of irradiated and bone marrow-transplanted mice: influences of the donor strain

Summary  Total body irradiation and bone marrow transplantation induced dramatic trabecular bone loss and cortical thickening in mice. Transplanted cells were engrafted in bone marrow, along trabeculae, and in periosteal and endosteal envelopes. None of the osteocytes were of donor origin. Bone microarchitecture of transplanted mice changed to tend toward the donor phenotype. Introduction  Osteopenia and osteoporosis are complications of bone marrow transplants (BMT) attributed to related chemotherapy. However, the specific influence of total body irradiation (TBI) is unknown. Methods  We investigated the effects of TBI and BMT on bone mass and microarchitecture by micro-CT. Eighteen C57Bl/6 (B6) mice receiving lethal TBI had a BMT with marrow cells from green fluorescent protein--transgenic-C57Bl/6 (GFP) mice. Transplanted (T^GFPB6), B6, and GFP mice were euthanized 1, 3, and 6 months after BMT or at a related age. Results  T^GFPB6 presented a dramatic bone loss compared with B6 and did not restore their trabecular bone mass over time, despite a cortical thickening 6 months after BMT. Serum testosterone levels were not significantly reduced after BMT. During aging, GFP mice have less trabeculae, thicker cortices, but a narrower femoral shaft than B6 mice. From 3 months after BMT, cortical characteristics of T^GFPB6 mice differed statistically from B6 mice and were identical to those of GFP mice. GFP⁺ cells were located along trabecular surfaces and in periosteal and endosteal envelopes, but none of the osteocytes expressed GFP. Conclusion  Our findings suggest that engrafted cells did not restore the irradiation-induced trabecular bone loss, but reconstituted a marrow microenvironment and bone remodeling similar to those of the donor. The effects of irradiation and graft on bone remodeling differed between cortical and trabecular bone.     

Structural and biomechanical basis of racial and sex differences in vertebral fragility in Chinese and Caucasians

We conducted a cross-sectional study in 1868 healthy Chinese and Caucasian women and men aged 18 to 93 years to define the structural and biomechanical basis for racial and sex differences in vertebral body (VB) fragility. VB bone mineral content (BMC), cross-sectional area (CSA), and volumetric bone mineral density (vBMD) of the third lumbar vertebrae were measured using dual-energy X-ray absorptiometry. Using engineering principles, we calculated the load per unit CSA (stress), VB strength estimated from vBMD and the ratio of stress to strength (fracture risk index, FRI). Young adult Chinese women and men had a smaller VB with a higher vBMD than their Caucasian counterparts. In each race, women had a smaller VB than men but similar vBMD. From young adulthood (30 years) to old age (70 years), VB CSA increased more in Chinese than Caucasian women (8.6% vs. 5.8%) and increased less in Chinese than Caucasian men (8.7% vs. 11.8%). Estimated periosteal bone deposited was similar in Chinese and Caucasian women (2.64 vs. 2.63 g, 46% vs. 40% of peak BMC). Estimated endosteal bone lost was similar (3.94 vs. 4.05 g or 68% vs. 62% of peak BMC). As endosteal bone loss exceeded periosteal bone gain, net bone was lost from the VB, but this was similar in Chinese and Caucasian women (1.30 vs. 1.42 g or both lost 22% of peak BMC). For men, Chinese gained less periosteal bone than Caucasians (2.73 vs. 5.05 g or 34% vs. 56% of peak BMC) and lost less endosteal bone (3.07 vs. 5.49 g or 38% vs. 61% of peak BMC), so net bone loss was similar in Chinese and Caucasian men (0.34 vs. 0.44 g, both lost 5% of peak BMC). Comparing sexes, in Chinese, net bone loss was greater in women than in men because of greater endosteal bone loss in women (68% of peak BMC) than men (38% of peak BMC); periosteal bone gain was similar in women and men. In Caucasians, net bone loss was greater in women than men because periosteal bone gain was less in women (40%) than men (56%), endosteal bone loss was similar. The age-related increase in VB CSA reduced VB stress but vBMD decreased so the FRI increased; 25% of elderly Chinese and Caucasian women and 5% of elderly Chinese and Caucasian men had an FRI above unity. The structural basis of bone fragility differs by race and sex. Periosteal apposition plays a pivotal role in determining racial and sex differences in net bone loss, geometry, and strength.     

Free testosterone is a positive, whereas free estradiol is a negative, predictor of cortical bone size in young Swedish men: the GOOD study.

In this study, we evaluated the predictive roles of sex steroids for skeletal parameters in young men (n = 1068) at the age of peak bone mass. Serum free estradiol was a negative predictor, whereas free testosterone and SHBG were positive predictors of cortical bone size. INTRODUCTION: Previous studies have shown that free estradiol in serum is an independent predictor of areal BMD (aBMD) in elderly men. The aim of this study was to determine whether sex steroids are predictors of volumetric BMD (vBMD) and/or size of the trabecular and cortical bone compartments in young men at the age of peak bone mass. MATERIALS AND METHODS: The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study consists of 1068 men, 18.9 +/- 0.6 years of age. Serum levels of testosterone, estradiol, and sex hormone binding globulin (SHBG) were measured, and free levels of testosterone and estradiol were calculated. The size of the cortical bone and the cortical and trabecular vBMDs were measured by pQCT. RESULTS: Regression models including age, height, weight, free estradiol, and free testosterone showed that free estradiol was an independent negative predictor of cortical cross-sectional area (tibia beta = -0.111, p < 0.001; radius beta = -0.125, p < 0.001), periosteal circumference, and endosteal circumference, whereas it was a positive independent predictor of cortical vBMD (tibia beta = 0.100, p < 0.003; radius beta = 0.115, p = 0.001) in both the tibia and radius. Free testosterone was an independent positive predictor of cortical cross-sectional area (tibia beta = 0.071, p = 0.013; radius beta = 0.064, p = 0.039), periosteal circumference, and endosteal circumference in both the tibia and radius. Neither cortical nor trabecular vBMD was associated with free testosterone. SHBG was an independent positive predictor of parameters reflecting the size of the cortical bone, including cross-sectional area (beta = 0.078, p = 0.009), periosteal circumference, and endosteal circumference. CONCLUSIONS: Free estradiol is a negative, whereas free testosterone is a positive, predictor of cortical bone size in young men at the age of peak bone mass. These findings support the notion that estrogens reduce, whereas androgens increase, cortical bone size, resulting in the well-known sexual dimorphism of cortical bone geometry.     

Quantitative regional associations between remodeling, modeling, and osteocyte apoptosis and density in rabbit tibial midshafts

Evidence suggests that osteocyte apoptosis is involved in the adaptive response of bone, although the specific role of osteocytes in the signaling mechanism is unknown. Here, we examined and correlated regional variability in indices of remodeling, modeling, osteocyte apoptosis, and osteocyte density in rabbit tibia midshafts. Histomorphometric analysis indicated that remodeling parameters (BMU activation frequency, osteon density, forming osteon density, and resorption cavity density) were lower in the cranial region compared to other quadrants. In addition, pericortical subregions displayed less remodeling relative to intracortical and endocortical ones. Modeling indices also demonstrated regional variability in that periosteal surfaces exhibited a greater extent of bone forming surface than endosteal ones across all anatomic quadrants. In contrast, endosteal surfaces demonstrated significantly greater surface mineral apposition rates compared to periosteal surfaces in caudal, medial, and lateral but not cranial quadrants. Using TUNEL analysis to detect osteocytes undergoing apoptosis, the density of apoptotic osteocytes was found to be lower in cranial quadrants relative to medial ones. In addition, the densities of osteocyte lacunae, empty lacunae, and total osteocytes were higher in lateral fields relative to caudal quadrants. There was a strong, statistically significant linear correlation between the remodeling indices and apoptotic osteocyte density, supporting the theory that osteocytes undergoing apoptosis produce signals that attract or direct bone remodeling. In contrast, the modeling parameters did not exhibit a correlation with apoptotic osteocytes, although there was a strong correlation between the modeling indices and the density of empty osteocyte lacunae, corroborating previous studies that have found that osteocytes inhibit bone formation. It was found that osteocyte density and osteocyte lacunar density did not significantly correlate with modeling or remodeling parameters, suggesting that cell viability should be examined in studies correlating bone turnover parameters with the functional role of osteocytes in bone adaptation.     

Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model.

The relative importance of AR and ER activation has been studied in pubertal male AR knockout and WT mice after orchidectomy and androgen replacement therapy, either with or without an aromatase inhibitor. AR activation dominates normal trabecular bone development and cortical bone modeling in male mice. Moreover, optimal periosteal bone expansion is only observed in the presence of both AR and ER activation. INTRODUCTION: Androgen receptor (AR)-mediated androgen action has traditionally been considered a key determinant of male skeletal growth. Increasing evidence, however, suggests that estrogens are also essential for normal male bone growth. Therefore, the relative importance of AR-mediated and estrogen receptor (ER)-mediated androgen action after aromatization remains to be clarified. MATERIALS AND METHODS: Trabecular and cortical bone was studied in intact or orchidectomized pubertal AR knockout (ARKO) and male wildtype (WT) mice, with or without replacement therapy (3-8 weeks of age). Nonaromatizable (dihydrotestosterone [DHT]) and aromatizable (testosterone [T]) androgens and T plus an aromatase inhibitor (anastrazole) were administered to orchidectomized ARKO and WT mice. Trabecular and cortical bone modeling were evaluated by static and dynamic histomorphometry, respectively. RESULTS: AR inactivation or orchidectomy induced a similar degree of trabecular bone loss (-68% and -71%, respectively). Both DHT and T prevented orchidectomy-induced bone loss in WT mice but not in ARKO mice. Administration of an aromatase inhibitor did not affect T action on trabecular bone. AR inactivation and orchidectomy had similar negative effects on cortical thickness (-13% and -8%, respectively) and periosteal bone formation (-50% and -26%, respectively). In orchidectomized WT mice, both DHT and T were found to stimulate periosteal bone formation and, as a result, to increase cortical thickness. In contrast, the periosteum of ARKO mice remained unresponsive to either DHT or T. Interestingly, administration of an aromatase inhibitor partly reduced T action on periosteal bone formation in orchidectomized WT mice (-34% versus orchidectomized WT mice on T), but not in ARKO mice. This effect was associated with a significant decrease in serum IGF-I (-21% versus orchidectomized WT mice on T). CONCLUSIONS: These findings suggest a major role for AR activation in normal development of trabecular bone and periosteal bone growth in male mice. Moreover, optimal stimulation of periosteal growth is only obtained in the presence of both AR and ER activation.