Roger Zebaze

Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study.

BACKGROUND Osteoporosis research has focused on vertebral fractures and trabecular bone loss. However, non-vertebral fractures at predominantly cortical sites account for 80% of all fractures and most fracture-related morbidity and mortality in old age. We aimed to re-examine cortical bone as a source of bone loss in the appendicular skeleton. METHODS In this cross-sectional study, we used high-resolution peripheral CT to quantify and compare cortical and trabecular bone loss from the distal radius of adult women, and measured porosity using scanning electron microscopy. Exclusion criteria were diseases or prescribed drugs affecting bone metabolism. We also measured bone mineral density of post-mortem hip specimens from female cadavers using densitometry. Age-related differences in total, cortical, and trabecular bone mass, trabecular bone of cortical origin, and cortical and trabecular densities were calculated. FINDINGS We investigated 122 white women with a mean age of 62.8 (range 27-98) years. Between ages 50 and 80 years (n=89), 72.1 mg (95% CI 67.7-76.4) hydroxyapatite (68%) of 106.5 mg hydroxyapatite of bone lost at the distal radius was cortical and 34.3 mg (30.5-37.8) hydroxyapatite (32%) was trabecular; 17.1 mg (11.7-22.5) hydroxyapatite (16%) of total bone loss occurred between ages 50 and 64 years (n=34) and 89.4 mg (83.7-101.1) hydroxyapatite (84%) after age 65 years (n=55). Remodelling within cortex adjacent to the marrow accounted for 49.9 mg (45.4-53.7) hydroxyapatite (47%) of bone loss. Between ages 50-64 years (n=34) and 80 years and older (n=33), cortical density decreased by 127.8 mg (93.1-162.1) hydroxyapatite per cm(3) (15%, p<0.0001) before porosity trabecularising the cortex was included, but 374.3 mg (318.2-429.5) hydroxyapatite per cm(3) (43%, p<0.0001) after; trabecular density decreased by 18.2 mg (-1.4 to 38.2) hydroxyapatite per cm(3) (14%, p=0.06) before cortical remnants were excluded, but 68.7 mg (37.7-90.4) hydroxyapatite per cm(3) (52%, p<0.0001) after. INTERPRETATION Accurate assessment of bone structure, especially porosity producing cortical remnants, could improve identification of individuals at high and low risk of fracture and therefore assist targeting of treatment. FUNDING Australia National Health and Medical Research Council.

Cortical porosity identifies women with osteopenia at increased risk for forearm fractures.

Most fragility fractures arise among the many women with osteopenia, not the smaller number with osteoporosis at high risk for fracture. Thus, most women at risk for fracture assessed only by measuring areal bone mineral density (aBMD) will remain untreated. We measured cortical porosity and trabecular bone volume/total volume (BV/TV) of the ultradistal radius (UDR) using high‐resolution peripheral quantitative computed tomography, aBMD using densitometry, and 10‐year fracture probability using the country‐specific fracture risk assessment tool (FRAX) in 68 postmenopausal women with forearm fractures and 70 age‐matched community controls in Olmsted County, MN, USA. Women with forearm fractures had 0.4 standard deviations (SD) higher cortical porosity and 0.6 SD lower trabecular BV/TV. Compact‐appearing cortical porosity predicted fracture independent of aBMD; odds ratio (OR) = 1.92 (95% confidence interval [CI] 1.10–3.33). In women with osteoporosis at the UDR, cortical porosity did not distinguish those with fractures from those without because high porosity was present in 92% and 86% of each group, respectively. By contrast, in women with osteopenia at the UDR, high porosity of the compact‐appearing cortex conferred an OR for fracture of 4.00 (95% CI 1.15–13.90). In women with osteoporosis, porosity is captured by aBMD, so measuring UDR cortical porosity does not improve diagnostic sensitivity. However, in women with osteopenia, cortical porosity was associated with forearm fractures.

Teriparatide improves bone quality and healing of atypical femoral fractures associated with bisphosphonate therapy

Bone remodelling suppressants like the bisphosphonates reduce bone loss and slow progression of structural decay. As remodelling removes damaged bone, when remodelling suppression is protracted, bone quality may be compromised predisposing to microdamage accumulation and atypical femoral fractures. The aim of this study was to determine whether teriparatide therapy assists in fracture healing and improves bone quality in patients with bisphosphonate associated atypical femoral fractures. A prospective study was conducted involving 14 consecutive patients presenting during 2 years with atypical femoral fracture. All patients were offered teriparatide therapy unless contraindicated. Age and sex matched control subjects without fragility fractures or anti-resorptive treatment were recruited. High resolution peripheral micro-computed tomography (HRpQCT) scans of the distal radius and distal tibia were analysed for their cortical bone tissue mineralisation density using new software (StrAx1.0, StrAxCorp, Australia) at baseline and 6 months after teriparatide. Administration of 20 μg of teriparatide subcutaneously daily for 6 months to 5 of the 14 patients was associated with 2-3 fold increase in bone remodelling markers (p=0.01) and fracture healing. At the distal radius, the proportion of less densely mineralised bone increased by 29.5% (p=0.01), and the proportion of older, more densely mineralised bone decreased by 16.2% (p=0.03). Similar observations were made at the distal tibia. Of the nine patients managed conservatively or surgically, seven had poor fracture healing with ongoing pain, one sustained a contralateral atypical fracture and one had fracture union after 1 year. Teriparatide may assist in healing of atypical fractures and restoration of bone quality.

Rapid growth produces transient cortical weakness: A risk factor for metaphyseal fractures during puberty

Fractures of the distal radius in children have a similar incidence to that found in postmenopausal women but occur more commonly in boys than in girls. Fractures of the distal tibia are uncommon in children and show no sex specificity. About 90% of lengthening of the radius but only 30% of lengthening of the tibia during puberty occur at the distal growth plate. We speculated that more rapid modeling at the distal radial metaphysis results in a greater dissociation between growth and mineral accrual than observed at the distal tibia. We measured the macro‐ and microarchitecture of the distal radial and tibial metaphysis using high‐resolution peripheral quantitative computed tomography in a cross‐sectional study of 69 healthy boys and 60 healthy girls aged from 5 to 18 years. Bone diameters were larger but total volumetric bone mineral density (vBMD) was lower at the distal radius (not at the distal tibia) by 20% in boys and by 15% in girls at Tanner stage III than in children of the same sex at Tanner stage I (both p < .05). In boys at Tanner stage III, total vBMD was lower because the larger radial total cross‐sectional area (CSA) had a thinner cortex with lower vBMD than in boys at Tanner stage I. In girls at Tanner stage III, the larger total radial CSA was not associated with a difference in cortical thickness or cortical vBMD relative to girls in Tanner stage I. Cortical thickness and density at both sites in both sexes after Tanner stage III were greater than in younger children. Trabecular bone volume fraction (BV/TV) was higher in boys than in girls at both sites and more so after puberty because trabeculae were thicker in more mature boys but not in girls. There was no sex‐ or age‐related differences in trabecular number at either site. We infer that longitudinal growth outpaces mineral accrual in both sexes at the distal radius, where bone grows rapidly. The dissociation produces transitory low cortical thickness and vBMD in boys but not in girls. These structural features in part may account for the site and sex specificity of metaphyseal fractures during growth.

Differing effects of denosumab and alendronate on cortical and trabecular bone.

Vertebral fractures and trabecular bone loss are hallmarks of osteoporosis. However, 80% of fractures are non-vertebral and 70% of all bone loss is cortical and is produced by intracortical remodeling. The resulting cortical porosity increases bone fragility exponentially. Denosumab, a fully human anti-RANKL antibody, reduces the rate of bone remodeling more than alendronate. The aim of this study was to quantify the effects of denosumab and alendronate on cortical and trabecular bone. Postmenopausal women, mean age 61years (range 50 to 70), were randomized double blind to placebo (n=82), alendronate 70mg weekly (n=82), or denosumab 60mg every 6months (n=83) for 12months. Porosity of the compact-appearing cortex (CC), outer and inner cortical transitional zones (OTZ, ITZ), and trabecular bone volume/total volume (BV/TV) of distal radius were quantified in vivo from high-resolution peripheral quantitative computed tomography scans. Denosumab reduced remodeling more rapidly and completely than alendronate, reduced porosity of the three cortical regions at 6months, more so by 12months relative to baseline and controls, and 1.5- to 2-fold more so than alendronate. The respective changes at 12months were [mean (95% CI)]; CC: -1.26% (-1.61, -0.91) versus -0.48% (-0.96, 0.00), p=0.012; OTZ: -1.97% (-2.37, -1.56) versus -0.81% (-1.45, -0.17), p=0.003; and ITZ: -1.17% (-1.38, -0.97) versus -0.78% (-1.04, -0.52), p=0.021. Alendronate reduced porosity of the three cortical regions at 6months relative to baseline and controls but further decreased porosity of only the ITZ at 12months. By 12months, CC porosity was no different than baseline or controls, OTZ porosity was reduced only relative to baseline, not controls, while ITZ porosity was reduced relative to baseline and 6months, but not controls. Each treatment increased trabecular BV/TV volume similarly: 0.25% (0.19, 0.30) versus 0.19% (0.13, 0.30), p=0.208. The greater reduction in cortical porosity by denosumab may be due to greater inhibition of intracortical remodeling. Head to head studies are needed to determine whether differences in porosity result in differing fracture outcomes.

Construction of the Femoral Neck During Growth Determines Its Strength in Old Age

Study of the design of the FN in vivo in 697 women and in vitro in 200 cross‐sections of different sizes and shapes along each of 13 FN specimens revealed that strength in old age was largely achieved during growth by differences in the distribution rather than the amount of bone material in a given FN cross‐section from individual to individual.

Cortical Bone: A Challenging Geography

Trabecular bone loss and fractures of the trabecular-rich vertebral bodies are the hallmarks of osteoporosis and have dominated thinking and research into the structural basis of bone fragility during the past 70 years. Indeed, a reduction in vertebral fractures still forms the primary endpoint in almost all randomized trials. This trabeculo-centric view of bone fragility has diverted attention away from cortical bone despite evidence that: (1) 80% of all fractures are nonvertebral; (2) these fractures occur at predominantly cortical sites; (3) 70% of all age-related appendicular bone loss is cortical; and (4) most of this bone loss occurs by intracortical remodeling that cavitates the cortex producing porosity. As age advances, intracortical void volume, which is formed mainly by the enlargement and coalescence of these canals, doubles, and so reciprocally halves the mineralized bone matrix volume—changes that compromise bone strength. There are two challenges in the study of the effects of advancing age, menopause, disease, and therapy on cortical morphology. The first is to acquire high-resolution images of bone’s material composition, microstructure, and macrostructure. The second is to then accurately, reproducibly, and unambiguously quantify these determinants of bone strength. In this issue of the Journal of Bone and Mineral Research, three articles are published that used state-of-the-art methods of image acquisition and analysis to quantify the effects of therapy on cortical bone morphology. Examples from these articles and several others are given to identify challenges that result from low image resolution and limitations in image processing and analyses. We first summarize the observations reported and then discuss the difficulties in making inferences concerning the effects of therapy that result from limitations in image resolution and analysis. The Articles and the Challenges

Fracture risk and height: An association partly accounted for by cortical porosity of relatively thinner cortices

Taller women are at increased risk for fracture despite having wider bones that better tolerate bending. Because wider bones require less material to achieve a given bending strength, we hypothesized that taller women assemble bones with relatively thinner and more porous cortices because excavation of a larger medullary canal may be accompanied by excavation of more intracortical canals. Three‐dimensional images of distal tibia, fibula, and radius were obtained in vivo using high‐resolution peripheral quantitative computed tomography (HRpQCT) in a twin study of 345 females aged 40 to 61 years, 93 with at least one fracture. Cortical porosity <100 µm as well as >100 µm, and microarchitecture, were quantified using Strax1.0, a new algorithm. Multivariable linear and logistic regression using generalized estimating equation (GEE) methods quantified associations between height and microarchitecture and estimated the associations with fracture risk. Each standard deviation (SD) greater height was associated with a 0.69 SD larger tibia total cross‐sectional area (CSA), 0.66 SD larger medullary CSA, 0.50 SD higher medullary CSA/total CSA (i.e., thinner cortices relative to the total CSA due to a proportionally larger medullary area), and 0.42 SD higher porosity (all p < 0.001). Cortical area was 0.45 SD larger in absolute terms but 0.50 SD smaller in relative terms. These observations were confirmed by examining trait correlations in twin pairs. Fracture risk was associated with height, total CSA, medullary CSA/total CSA, and porosity in univariate analyses. In multivariable analyses, distal tibia, medullary CSA/total CSA, and porosity predicted fracture independently; height was no longer significant. Each 1 SD greater porosity was associated with fracture; odds ratios (ORs) and 95% confidence intervals (CIs) are as follows: distal tibia, OR = 1.55 (95% CI, 1.11–2.15); distal fibula, OR = 1.47 (95% CI, 1.14–1.88); and distal radius, OR = 1.22 (95% CI, 0.96–1.55). Taller women assemble wider bones with relatively thinner and more porous cortices predisposing to fracture.

Structural Decay of Bone Microarchitecture in Men with Prostate Cancer Treated with Androgen Deprivation Therapy

CONTEXT Androgen deprivation therapy (ADT) used in the treatment of prostate cancer reduces bone mineral density (BMD) and predisposes to fractures. The structural basis of the BMD deficit and bone fragility is uncertain. OBJECTIVE AND PATIENTS We investigated changes in bone microarchitecture in 26 men (70.6±6.8 yr) with nonmetastatic prostate cancer during the first year of ADT using the new technique of high-resolution peripheral quantitative computed tomography. DESIGN AND SETTING We conducted a 12-month prospective observational study in the setting of a tertiary referral center. RESULTS After 12 months of ADT, total volumetric density decreased by 5.2±5.4% at the distal radius and 4.2±2.7% at the distal tibia (both P<0.001). This was due to a decrease in cortical volumetric BMD (by 11.3±8.6% for radius and 6.0±4.2% for tibia, all P<0.001) and trabecular density (by 3.5±6.0% for radius and 1.5±2.3% for tibia, all P<0.01), after correcting for trabecularization of cortical bone. Trabecular density decreased due to a decrease in trabecular number at both sites (P<0.05). Total testosterone, but not estradiol, levels were independently associated with total and corrected cortical volumetric BMD at the tibia. CONCLUSIONS Sex steroid deficiency induced by ADT for prostate cancer results in microarchitectural decay. Bone fragility in these men may be more closely linked to testosterone than estradiol deficiency.

Role of cortical bone in bone fragility.

Purpose of reviewTrabecular bone loss and vertebral fractures are historical hallmarks of osteoporosis. During the past 70 years, this view has dominated research aiming to understand the structural basis of bone fragility. We suggest this notion needs to be revised to recognize and include the role of cortical bone deterioration as an important determinant of bone strength throughout life. Recent findingsAbout 80% of the fragility fractures involve the appendicular skeleton, at regions comprising large amounts of cortical bone. Up to 70% of the age-related bone loss at these locations is the result of intracortical remodeling that cavitates cortical bone producing porosity. It is now possible to accurately quantify cortical porosity in vivo and use this information to understand the pathogenesis of bone fragility throughout life, assist in identifying patients at risk for fracture, and use this as a potential marker to monitor the effects of treatment on bone structure and strength. SummaryCortical bone has an important role in determining bone strength. The loss of strength is the result of intracortical and endocortical remodeling imbalance that produces cortical porosity and thinning. Studies are needed to determine whether porosity is an independent predictor of fracture risk and whether a reduction in porosity serves as a surrogate of antifracture efficacy.