Atkinson, Elizabeth J.

Background and Purpose — We sought to determine pedigree availability for a concordant sibling pair study of genetic risk factors in ischemic stroke. Methods — Probands with confirmed ischemic stroke were prospectively enrolled. Family histories were obtained by systematic interview. A study neurologist prospectively assigned stroke subtype. Results — Of 310 probands (median age, 75 years; range, 26 to 97 years; 48% women), 75% had at least 1 living sibling; 10%, at least 1 concordant living sibling; 2%, at least 1 concordant sibling living in the same city; and 7%, at least 1 concordant living and 1 discordant living sibling. Likelihood of having a concordant sibling increased significantly with proband age, even after adjustment for sibship size ( P =0.002). Positive family history of stroke was not related to either proband stroke subtype or risk factor profile. Conclusions — Approximately 10 probands were screened to find 1 potentially concordant living sibling. A concordant sibling pair study should be multicentered and enable enrollment of siblings from diverse geographic areas.

Abstract Vertebral fractures are more strongly associated with specific bone density, structure, and strength parameters than with areal BMD, but all of these variables are correlated. Introduction: It is unclear whether the association of areal BMD (aBMD) with vertebral fracture risk depends on bone density per se, bone macro- or microstructure, overall bone strength, or spine load/bone strength ratios. Materials and Methods: From an age-stratified sample of Rochester, MN, women, we identified 40 with a clinically diagnosed vertebral fracture (confirmed semiquantitatively) caused by moderate trauma (cases; mean age, 78.6 ± 9.0 yr) and compared them with 40 controls with no osteoporotic fracture (mean age, 70.9 ± 6.8 yr). Lumbar spine volumetric BMD (vBMD) and geometry were assessed by central QCT, whereas microstructure was evaluated by high-resolution pQCT at the ultradistal radius. Vertebral failure load (∼strength) was estimated from voxel-based finite element models, and the factor-of-risk (ϕ) was determined as the ratio of applied spine loads to failure load. Results: Spine loading (axial compressive force on L3) was similar in vertebral fracture cases and controls (e.g., for 90° forward flexion, 2639 versus 2706 N; age-adjusted p = 0.173). However, fracture cases had inferior values for most bone density and structure variables. Bone strength measures were also reduced, and the factor-of-risk was 35–37% greater (worse) among women with a vertebral fracture. By age-adjusted logistic regression, relative risks for the strongest fracture predictor in each of the five main variable categories were bone density (total lumbar spine vBMD: OR per SD change, 2.2; 95% CI, 1.1–4.3), bone geometry (vertebral apparent cortical thickness: OR, 2.1; 95% CI, 1.1–4.1), bone microstructure (none significant); bone strength (“cortical” [outer 2 mm] compressive strength: OR, 2.5; 95% CI, 1.3–4.8), and factor-of-risk (ϕ for 90° forward flexion/overall vertebral compressive strength: OR, 3.2; 95% CI, 1.4–7.5). These variables were correlated with spine aBMD (partial r, −0.32 to 0.75), but each was a stronger predictor of fracture in the logistic regression analyses. Conclusions: The association of aBMD with vertebral fracture risk is explained by its correlation with more specific bone density, structure, and strength parameters. These may allow deeper insights into fracture pathogenesis.

Abstract Bone structure, strength, and load-strength ratios contribute to forearm fracture risk independently of areal BMD. Introduction: Technological and conceptual advances provide new opportunities for evaluating the contributions of bone density, structure, and strength to the pathogenesis of distal forearm fractures. Materials and Methods: From an age-stratified random sample of Rochester, MN, women, we compared 18 with a distal forearm fracture (cases) to 18 age-matched women with no osteoporotic fracture (controls). High-resolution pQCT was used to assess volumetric BMD (vBMD), geometry, and microstructure at the ultradistal radius, the site of Colles' fractures. Failure loads in the radius were estimated from microfinite element (μFE) models derived from pQCT. Differences between case and control women were assessed, and the risk of fracture associated with each variable was estimated by logistic regression analysis. Results: Given similar heights, estimated loading in a fall on the outstretched arm was the same in cases and controls. However, women with forearm fractures had inferior vBMD, geometry, microstructure, and estimated bone strength. Relative risks for the strongest determinant of fracture in each of the five main variable categories were as follows: BMD (total vBMD: OR per SD change, 4.2; 95% CI, 1.4–12), geometry (cortical thickness: OR, 4.0; 95% CI, 1.4–11), microstructure (trabecular number: OR, 2.3; 95% CI, 1.02–5.1), and strength (axial rigidity: OR, 3.8; 95% CI, 1.4–10); the factor-of-risk (fall load/μFE failure load) was 24% greater (worse) in cases (OR, 3.0; 95% CI, 1.2–7.5). Areas under ROC curves ranged from 0.72 to 0.82 for these parameters. Conclusions: Bone geometry, microstructure, and strength contribute to forearm fractures, as does BMD, and these additional determinants of risk promise greater insights into fracture pathogenesis.

Abstract Elevated serum IGFBP-2 is associated with lower BMD in men and women. It is unknown whether IGFBP-2 serves as a negative regulator of bone metabolism by decreasing bone formation or increasing bone resorption. Studying an age-stratified community-based sample of 344 men and 276 women, IGFBP-2 was the strongest predictor of increased bone resorption among the IGF/IGFBPs studied. Introduction: Serum insulin-like growth factor binding protein-2 (IGFBP-2), which increases with age, is a predictor of low BMD among aging men and women. However, it is unknown whether IGFBP-2 negatively influences bone metabolism by decreasing bone formation or increasing bone resorption. Few have examined the relation between the insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) with bone turnover markers. Materials and Methods: In an age-stratified, random sample of the community, we examined the association between serum IGF-I, IGF-II, IGFBP-1, −2, and −3, and bone turnover markers before and after adjustment for potential confounders (age, body mass index, bioavailable estradiol and testosterone, and sex hormone binding globulin). Analyses were stratified by sex and menopausal status. Results: We studied 344 men (age range, 23–90 yr) and 276 women (age range, 21–93 yr; 166 postmenopausal) not on oral contraceptives or hormone replacement. Among the IGF/IGFBPs assessed, IGFBP-2 was the strongest and most consistent predictor of bone turnover in men and women. After adjustment for potential confounders, IGFBP-2 was positively associated with osteocalcin (OC) and urine and serum N-teleopeptide (NTX) in men (r = 0.20, 0.26, and 0.23, respectively; p < 0.001), serum C-telopeptide (CTX) in premenopausal women (r = 0.28; p < 0.01), and OC, urine NTX, and serum CTX in postmenopausal women (r = 0.24, 0.33, and 0.19, respectively; p < 0.05). Conclusions: Higher serum IGFBP-2, which is predictive of lower BMD, is associated with increased markers of bone resorption, independent of age, body mass, and sex hormones. The association between IGFBP-2 and markers of bone formation may reflect coupling with increased bone resorption, which is not adequate to maintain BMD.

Abstract After acute estrogen withdrawal in postmenopausal women, administration of anakinra or etanercept, specific blockers of IL-1 and TNF-α, respectively, reduced the rise in bone resorption markers to about one half of that in controls. This is consistent with an important role for these immune cytokines in mediating the effect of estrogen deficiency on bone. Introduction: Studies in rodents have implicated increased production of interleukin (IL)-1β and TNF-α as mediators of bone loss after ovariectomy, but their roles are unclear in humans whose immune system differs markedly from that of rodents. Materials and Methods: We administered transdermal estradiol, 0.1 mg/d, for 60 days to 42 early postmenopausal women. Estrogen treatment was discontinued, and subjects were randomly assigned to intervention groups receiving 3 wk of injections with 0.9% saline, anakinra 100 mg/d, or etanercept 25 mg/twice weekly. Bone turnover was assessed by measuring serum carboxyl-terminal telopeptide of type 1 collagen (CTX) and amino-terminal telopeptide of type 1 collagen (NTX), markers for bone resorption, and serum amino-terminal propeptide of type 1 collagen (P1NP), a marker for bone formation. Results were expressed as percent change in markers from baseline (last 2 days of estrogen treatment and days 20 and 21 of intervention). Results: The percent changes from baseline during intervention for serum CTX, urine NTX, and serum PINP, respectively, were 43.3 ± 8.0%, 12.0 ± 7.1%, and −41.0 ± 2.5% for the control group; 25.9 ± 6.3%, 9.5 ± 4.0%, and −37.8 ± 3.0% for the anakinra group; and 21.7 ± 5.0%, 0.32 ± 3.82%, and −34.5 ± 3.9% for the etanercept group. Compared with the control group, the blunting of the increase in serum CTX fell just below the level of significance (p = 0.10) after anakinra treatment, whereas the blunting of the increase in serum CTX (p = 0.034) and in urine NTX (p = 0.048) were significant after etanercept treatment. Other changes were not significant. Conclusions: The data are consistent with a role for TNF-α, and possibly for IL-1β, in mediating increased bone resorption during estrogen deficiency in women. Although either cytokine blocker reduced serum CTX by about one half, the effect of combined blockade could not be tested because of concerns about toxicity. The data do not exclude direct or indirect contributory roles for RANKL or for other cytokines.

Abstract We used QCT scans obtained in 687 men and women, 21–97 years of age, to estimate the factor of risk for vertebral fracture, Φvert, defined as the ratio of spinal loading to vertebral strength. With age, vertebral strength declined and Φvert increased significantly more in women than men. Age- and sex-specific differences in Φvert closely resembled previously reported vertebral fracture incidence. Introduction: Despite the high prevalence of vertebral fractures, little is known about the interaction between spinal loading and vertebral fragility. Materials and Methods: We assessed the ratio of spinal loading to vertebral strength (i.e., the factor of risk, Φvert) in an age- and sex-stratified population-based sample of 700 women and men 21–97 years of age. We measured volumetric BMD (vBMD, mg/cm3) and cross-sectional area (CSA, cm2) of the midvertebral bodies of L1–L3 using QCT and computed vertebral compressive strength from these data using engineering beam theory. A biomechanical model of the trunk was used to estimate compressive forces applied to the L3 vertebral body during standing, bending forward, and bending forward while lifting 10 kg. The factor of risk for fracture, Φvert, was computed as the ratio of spinal compressive force to vertebral strength for each activity. Results: Men had a higher vertebral strength at all ages, largely because of their greater CSA. Whereas both sexes exhibited a marked decline in vertebral compressive strength with age (p < 0.001), the decline was greater in women than men (−43% versus −31%, p = 0.008). Compressive forces on L3 were greater in men than women, because of their greater body weight and height. For both sexes, forces during bending and lifting were 8-fold higher than those experienced during upright standing. For all activities, Φvert increased with age, but significantly more so in women than men (p < 0.001). For bending and lifting, Φvert-bending exceeded 1.0 in 30% of women and 12% of men ≥50 years of age, values that are similar to the reported frequency of vertebral fracture. Conclusion: These findings illustrate potential mechanisms underlying vertebral fractures and provide strong rationale for further evaluation of this QCT-based biomechanical approach for assessment of fracture risk.

Abstract The NOF cost-effectiveness model, based on clinical risk factors and femoral neck aBMD, predicted overall fracture risk in a cohort of postmenopausal women followed for up to 22 years. Introduction: To assess the ability of a statistical model to predict long-term fracture risk for a population of postmenopausal women, we compared observed fractures to those predicted by the National Osteoporosis Foundation's (NOF) cost-effectiveness model. Materials and Methods: In this population-based study, 393 postmenopausal Rochester, MN, women had baseline measurements of femoral neck areal BMD (aBMD) and assessment of the clinical risk factors (personal fracture history, family history of osteoporotic fracture, low body weight, and smoking status) that were included in the NOF model. They were then followed prospectively for up to 22 years. Fractures were ascertained by periodic interview and review of community medical records. Standardized incidence ratios (SIRs) compared observed fractures to predicted numbers. Results: During 4782 person-years of follow-up, 212 women experienced 503 fractures, two-thirds of which were caused by moderate trauma. When undiagnosed (incidentally noted) vertebral and rib fractures were excluded, there was general concordance between observed and predicted fractures of the hip (SIR, 0.78; 95% CI, 0.56-1.01), distal forearm (SIR, 1.22; 95% CI, 0.86-1.68), spine (SIR, 0.76; 95% CI, 0.50-1.11), and all other sites combined (SIR, 1.18; 95% CI, 0.97-1.42). Fracture prediction by the NOF model was about as good after 10 years as it was earlier during follow-up. Conclusions: This study validates the ability of a statistical model based on femoral neck aBMD and common clinical risk factors to predict the actual occurrence of fractures in a cohort of postmenopausal white women.

Abstract In a population-based, cross-sectional study, we related age-associated changes in vBMD and in bone structural parameters to circulating bioavailable estradiol and testosterone levels in men. Associations between these bone mass/structural parameters and sex steroid levels were progressively stronger with age. Our previously postulated “threshold” for skeletal estrogen deficiency was most evident at cortical sites. Introduction: Serum sex steroids, particularly estrogen levels, are associated with bone mass in men, and previous work has suggested that there may be a “threshold” bioavailable estradiol (bio E2) level below which the male skeleton becomes estrogen deficient. However, previous studies addressing this issue have exclusively used DXA, which cannot separate trabecular from cortical bone or provide information on bone geometry or structure. Materials and Methods: In an age-stratified population sample of 314 men (age, 22-91 years), we assessed volumetric BMD (vBMD) and bone geometry by QCT at the lumbar spine, femoral neck, distal radius, and distal tibia and related these to circulating bio E2 and bio testosterone (T) levels. Results: Compared with young men (age, 20-39 years), middle-aged men (age, 40-59 years) had significantly lower bio T (−26%, p < 0.001) and bio E2 (−9%, p = 0.038) levels, and these decreases were even greater in the elderly men (age ≥ 60 years, −60% and −38% for bio T and bio E2, respectively, p < 0.001 for both). Reflecting their intact gonadal status, vBMD/structural parameters were not related to sex steroid levels in young men, whereas bio E2 levels were associated consistently with vBMD and variably with bone geometric parameters in the elderly men; middle-aged men showed associations with bio E2 and bio T at some sites. At all cortical sites, vBMD was associated with bio E2 at low (<30 pM, R = 0.27-0.41, p < 0.05-0.001) but not high (≥30 pM, R = −0.003 to 0.12, p = not significant) levels; no such differences were evident at trabecular sites. Conclusions: In men, bio E2 is the most consistent predictor of vBMD and some bone geometric variables as assessed by QCT. We also extend our previous findings on a possible “threshold” for skeletal estrogen deficiency by showing that this is most evident for cortical sites.

Abstract Several lines of evidence implicate estrogen deficiency as a cause of bone loss in elderly men. Thus, in 50 elderly men (mean age ± SD, 69.1 ± 6.0 years), we performed a randomized blinded study to assess the effect of 6 months of treatment with 60 mg/day of raloxifene (a selective estrogen receptor modulator [SERM] that has an agonist effect on bone but is not feminizing) versus placebo on bone turnover markers. The mean changes in bone turnover markers, serum sex steroid, or lipid levels with treatment did not differ between groups. However, changes in urinary cross-linked N-telopeptide of type I collagen (NTX) excretion were related directly to the baseline serum estradiol level in the raloxifene (r = 0.57; p = 0.004) but not in the placebo-treated (r = 0.15; p = 0.485) men (p = 0.015 for the difference between groups). Moreover, the men in whom NTX excretion decreased after raloxifene treatment had significantly lower baseline estradiol levels (mean ± SEM, 22 ± 2 pg/ml) than the men in whom urinary NTX excretion didn't change or increased after raloxifene therapy (30± 3 pg/ml; p = 0.03), and no such difference was found in the placebo group. Thus, raloxifene has no significant effect on bone turnover markers or lipid levels in elderly men. However, the association noted between baseline estradiol levels and the change in urine NTX excretion in the raloxifene-treated men suggests that a subset of men with low estradiol levels may respond to raloxifene or other SERMs, and further studies are needed to directly test this possibility.