Epidemiology of fractures in adults of African ancestry with diabetes mellitus: A systematic review and meta-analysis.

Diabetes mellitus (DM) is associated with increased fracture risk in White adults. However, the impact of DM on fractures in Black adults is unknown. This systematic review and meta-analysis investigated the association between DM and fractures in adults of African ancestry. MEDLINE, Scopus, CINAHL and Embase databases were searched from their inception up to November 2023 for all studies in the English language investigating the epidemiology of fractures (prevalence, incidence, or risk) in Black men and women (age ≥ 18 years) with type 1 or type 2 DM. Effect sizes for prevalence of previous fractures (%) and incident fracture risk (hazard ratio [HR]) were calculated using a random-effects model on Stata (version 18.0). There were 13 eligible studies, of which 12 were conducted in Black adults from the United States, while one was conducted in adults of West African ancestry from Trinidad and Tobago. We found no fracture data in Black adults with DM living in Africa. Five studies were included in a meta-analysis of incident fracture risk, reporting data from 2926 Black and 6531 White adults with DM. There was increased risk of fractures in Black adults with DM compared to non-DM (HR = 1.65; 95 % confidence interval [CI]: 1.14, 2.39). The risk of fractures was also higher in White adults with DM compared to non-DM (HR = 1.31; 95 % CI: 1.06, 1.61) among these studies. Five studies were included in a meta-analysis of fracture prevalence, of which three also reported fracture prevalence in White adults. There were 175 previous fractures among 993 Black adults with DM and 384 previous fractures among 1467 White adults with DM, with a pooled prevalence of 17.5 % (95 % CI: 15.4, 19.6) and 25.8 % (95 % CI: 4.8, 46.8), respectively. Our results indicate a high burden of fractures in Black adults with DM.

Trabecular and cortical microstructure and fragility of the distal radius in women.

Fragility fractures commonly involve metaphyses. The distal radius is assembled with a thin cortex formed by fusion (corticalization) of trabeculae arising from the periphery of the growth plate. Centrally positioned trabeculae reinforce the thin cortex and transfer loads from the joint to the proximal thicker cortical bone. We hypothesized that growth- and age-related deficits in trabecular bone disrupt this frugally assembled microarchitecture, producing bone fragility. The microarchitecture of the distal radius was measured using high-resolution peripheral quantitative computed tomography in 135 females with distal radial fractures, including 32 girls (aged 7 to 18 years), 35 premenopausal women (aged 18 to 44 years), and 68 postmenopausal women (aged 50 to 76 years). We also studied 240 fracture-free controls of comparable age and 47 healthy fracture-free premenopausal mother-daughter pairs (aged 30 to 55 and 7 to 20 years, respectively). In fracture-free girls and pre- and postmenopausal women, fewer or thinner trabeculae were associated with a smaller and more porous cortical area (r = 0.25 to 0.71 after age, height, and weight adjustment, all p < 0.05). Fewer and thinner trabeculae in daughters were associated with higher cortical porosity in their mothers (r = 0.30 to 0.47, all p < 0.05). Girls and premenopausal and postmenopausal women with forearm fractures had 0.3 to 0.7 standard deviations (SD) fewer or thinner trabeculae and higher cortical porosity than controls in one or more compartment; one SD trait difference conferred odds ratio (95% confidence interval) for fracture ranging from 1.56 (1.01-2.44) to 4.76 (2.86-7.69). Impaired trabecular corticalization during growth, and cortical and trabecular fragmentation during aging, may contribute to the fragility of the distal radius.

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.

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.

Differences in the degree of bone tissue mineralization account for little of the differences in tissue elastic properties.

MINI-ABSTRACT: Study of postmortem samples of cortical bone from the trochanters of 12 Caucasian females revealed that tissue mineral density (TMD) and tissue elastic modulus correlate weakly within and between individuals. Other material properties need to be taken into account to more fully predict variation in tissue elastic modulus. INTRODUCTION: Bone is a composite material that varies in its material composition and structural organization at the macro-, micro-, and nano-scales. This hierarchical organization is essential for bone's resistance to crack initiation and propagation. We quantified the relationship between regional heterogeneity in TMD and tissue elastic modulus in cortical bone of the trochanter to determine whether TMD can be used as a predictor of tissue elastic modulus. METHODS: Measurements of tissue elastic modulus and hardness were made using nanoindentation at 5 × 20 indent points spaced 100 µm apart. TMD at the same location was computed from quantitative backscattered scanning electron microscopy imaging of cortical samples from trochanters obtained at postmortem from 12 Caucasian females (mean age: 69 years; range: 29 to 85 years). RESULTS: Within an individual, the variance in tissue elastic modulus (CV = 18.7%; range: 9 to 41.5%) was five times greater than the variance in TMD (3.6%, range: 1.8 to 5.7%). On average, only 45% of the variance in tissue elastic modulus was explained by TMD. From individual to individual, the proportion of the variance in tissue elastic modulus explained by TMD ranged from 0 to 64%. In 6 of 12 samples, TMD explained less than 30% of the variance in tissue elastic modulus. Results were similar for tissue hardness. CONCLUSION: Tissue mineral density is an incomplete surrogate for tissue elastic modulus. Other material properties need to be accounted for to more fully predict regional variation in tissue elastic modulus.

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.

Construction of the femoral neck during growth determines its strength in old age.

UNLABELLED: 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. INTRODUCTION: We studied the design of the femoral neck (FN) to gain insight into the structural basis of FN strength in adulthood and FN fragility in old age. MATERIALS AND METHODS: Studies in vivo were performed using densitometry in 697 women and in vitro using high-resolution microCT and direct measurements in 13 pairs of postmortem specimens. RESULTS: The contradictory needs of strength for loading yet lightness for mobility were met by varying FN size, shape, spatial distribution, and proportions of its trabecular and cortical bone in a cross-section, not its mass. Wider and narrower FNs were constructed with similar amounts of bone material. Wider FNs were relatively lighter: a 1 SD higher FN volume had a 0.67 (95% CI, 0.61-0.72) SD lower volumetric BMD (vBMD). A 1 SD increment in height was achieved by increasing FN volume by 0.32 (95% CI, 0.25-0.39) SD with only 0.15 (95% CI, 0.08-0.22) SD more bone, so taller individuals had a relatively lighter FN (vBMD was 0.13 [95% CI, 0.05-0.20 SD] SD lower). Greater periosteal apposition constructing a wider FN was offset by even greater endocortical resorption so that the same net amount of bone was distributed as a thinner cortex further from the neutral axis, increasing resistance to bending and lowering vBMD. This was recapitulated at each point along the FN; varying absolute and relative degrees of periosteal apposition and endocortical resorption focally used the same amount of material to fashion an elliptical FN of mainly cortical bone near the femoral shaft to offset bending but a more circular FN of proportionally more trabecular and less cortical bone to accommodate compressive loads adjacent to the pelvis. This structural heterogeneity was largely achieved by adaptive modeling and remodeling during growth-most of the variance in FN volume, BMC, and vBMD was growth related. CONCLUSIONS: Altering structural design while minimizing mass achieves FN strength and lightness. Bone fragility may be the result of failure to adapt bone's architecture to loading, not just low bone mass.

Depression in anorexia nervosa: a risk factor for osteoporosis.

CONTEXT: Both anorexia nervosa (AN) and depression are associated with osteoporosis. We hypothesized that adolescent girls with AN and depression will have lower bone mineral density (BMD) than anorexic girls without depression. OBJECTIVE: The objective of this study was to investigate whether depression is an independent risk factor for osteoporosis in anorexic adolescent girls. DESIGN: This study was cross-sectional. SETTING: This study was conducted at the University Children's Hospital (Bialystok, Poland) from October 2002 through September 2003. PARTICIPANTS: Forty-five Caucasian anorexic girls aged 13-23 yr, matched by age, Tanner stage, weight, height, calcium intake, and duration of AN, were studied, including 14 with comorbid depression (based on Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale) and 31 anorexic girls without depression. MAIN OUTCOME MEASURES: Total body and lumbar spine (LS) BMD, fat mass, and lean mass assessed using dual-energy x-ray absorptiometry were compared between AN girls with and without depression. RESULTS: BMD was reduced in both groups, relative to reference data, but girls with AN and depression had lower BMD than those with AN alone (LS Z-scores, -2.6 +/- 0.3 vs. -1.7 +/- 0.3; P = 0.02) (mean +/- sem). Quantitative assessment of depression correlated independently with total body BMD (r = -0.4; P < 0.05) and LS BMD (r = -0.6; P < 0.001). CONCLUSION: Anorexic girls with depression are at higher risk of osteoporosis than those without depression. The mechanisms responsible for decreased BMD in depression are not known. Independent treatment of the depressive disorder in AN may partly alleviate the bone fragility.

Femoral neck shape and the spatial distribution of its mineral mass varies with its size: Clinical and biomechanical implications.

The femoral neck (FN) is a cantilever with external and internal dimensions determining its size, shape, the spatial distribution of the mineralized cortical and trabecular bone tissue mass, and its strength. Geometric indices of FN strength are often derived using FN dimensions estimated in vivo from dual X-ray absorptiometry (DXA) assuming that the FN cross section approximates a circle or a square. As DXA does not measure FN depth, we examined whether circular, square, or elliptical models of FN cross sections predict FN depth, and so its external volume, shape, volumetric bone mineral density (vBMD), and geometric indices of strength. We studied paired FN specimens from 13 Caucasian female cadavers (mean age 69 years, range 29 to 85) using DXA, micro-computed tomography (mu-CT), and direct calliper measurements. DXA accurately measured FN width (supero-inferior diameter) but models assuming a circular and a square cross section overestimated FN depth (antero-posterior diameter) and volume, and so underestimated vBMD by 15.0 +/- 5.8% (circular cross section) and by 33.2 +/- 4.6% (square cross section) (both P < 0.05). As depth was less than the width, an elliptical model with a constant depth/width ratio of 0.75 reduced the accuracy error in vBMD to 14.0 +/- 8.5% (P = 0.10). However, as FN width increased, FN depth increased relatively less. An elliptical model using a quadratic equation to mimic this changing in shape with increasing size reduced the error in vBMD to 4.4 +/- 7.7% (NS). Circular cross-section models overestimated section modulus at the mid-FN by about 51%. The elliptical models reduced the error two- to three fold. Images from micro-CT scanning show that the FN cross-sectional shape resembles an ellipse with the long axis and the maximum moment of inertia (I(max)) oriented in the supero-inferior direction, and the cortical mass concentrated inferiorly. The larger the cross section, the more elliptical the shape, and the greater the I(max) supero-inferiorly, while I(min) (in the antero-posterior direction) remains relatively constant. The shape, spatial distribution of bone, and moments of inertia are likely to be adaptations to bending moments during bipedalism. Assuming the FN cross section approximates a circle or square produces errors in FN depth, volume, vBMD, and geometric indices of bone strength. Studies are needed to determine the effects of age, sex, and race on FN size and shape in health and disease.

Loss of regularity in the curvature of the thoracolumbar spine: a measure of structural failure.

UNLABELLED: Departure from regularity (smoothness) in the curvature of the spine was quantified and correlated with the number of fractures, deficits in height, BMD, and identified women with vertebral fractures. INTRODUCTION: Differences in anterior and posterior vertebral heights (VHs) form the thoracolumbar curvature needed for stability in bipedal gait. Modest differences in VHs within and between adjacent vertebrae allow the spine curve to change its trajectory gently. Large differences in VHs, as occur following a fracture, produce abrupt changes in the direction of the curve, producing a departure from regularity (i.e., irregularity or loss of smoothness). MATERIALS AND METHODS: VHs and BMD were measured using DXA in 697 Lebanese women 20-87 years of age. Regularity of the spinal curvature was measured by comparing the ratio of the anterior to the posterior VHs of one vertebra to this ratio of adjacent vertebrae. If these ratios are similar, there is a smooth transition in the trajectory of the spinal curve. Departure from this regularity (smoothness) was measured at each pair of adjacent vertebrae in each individual and expressed as the spinal curvature irregularity index (SCII) for the entire thoracolumbar spine. RESULTS AND CONCLUSIONS: In premenopausal women, the mean SCII was 8.5% (range, 4-15%); that is, regularity was 91.5%. Only 0.8% of women had a SCII >17%. In postmenopausal women, the mean SCII was 10% (range, 4-36%) and was correlated with age (r = 0.25), height (r = -0.21), BMD (r = -0.13), and the number of deformities assessed by quantitative vertebral morphometry (QVM; r = 0.31-0.60; all p < 0.001). About 5% of women had an SCII >17%, and this group had 3- to 9-fold more deformities (as defined by QVM) than women with SCII <17%, reduced lumbar spine BMD (-1.01 SD), and 2- to 4-fold greater height deficits (-0.5 SD) than women with deformities (by QVM). The SCII is a robust method of identifying structural failure that is easy to compute and does not require controls.