Citations

Abstract A positive association has been reported between greater bone density and higher breast cancer risk, suggesting that these women could be at reduced risk of fracture. To estimate fracture risk among unselected community women with breast cancer and to systematically assess associations with various risk factors including breast cancer treatments, we conducted a population-based historical cohort study of 608 Olmsted County, MN, USA, women with invasive breast cancer first diagnosed in 1990 to 1999 (mean age 61.6 ± 14.8 years), who were followed for 5776 person-years. Altogether, 568 fractures were observed in 270 women (98 per 1000 person-years). Overall fracture risk was elevated 1.8-fold, but the absolute increase in risk was only 9%, and 56% of the women did not experience a fracture during follow-up. Excluding pathologic fractures (15%) and those found incidentally (24%), to allow for ascertainment bias, the standardized incidence ratio was 1.2 (95% confidence interval [CI] 0.99 to 1.3) for total fracture risk and 0.9 (95% CI 0.7 to 1.2) for osteoporotic fracture risk alone. Various breast cancer treatments were associated with an increased risk of fracture, but those associations were strongest for pathologic fractures, which were relatively more common among the women who were premenopausal when their breast cancer was diagnosed. Moreover, underlying clinical characteristics prompting different treatments may have been partially responsible for the associated fracture outcomes (indication bias). These data thus demonstrate that breast cancer patients in general are not at greatly increased risk of fracture but neither are they protected from fractures despite any determinants that breast cancer and high bone density may have in common. © 2012 American Society for Bone and Mineral Research.

Abstract Previous studies using dual-energy X-ray absorptiometry (DXA) have demonstrated that age is a major predictor of bone fragility and fracture risk independent of areal bone mineral density (aBMD). Although this aBMD-independent effect of age has been attributed to poor bone “quality,” the structural basis for this remains unclear. Because high-resolution peripheral quantitative computed tomography (HRpQCT) can assess bone microarchitecture, we matched younger and older subjects for aBMD at the ultradistal radius and assessed for possible differences in trabecular or cortical microstructure by HRpQCT. From an age-stratified, random sample of community adults, 44 women aged <50 years (mean age 41.0 years) were matched to 44 women aged ≥50 years (mean age 62.7 years) by ultradistal radius aBMD (mean ± SEM, younger and older aBMD 0.475 ± 0.011 and 0.472 ± 0.011 g/cm2, respectively), and 57 men aged <50 years (mean age 41.3 years) were matched to 57 men aged ≥50 years (mean age 68.1 years; younger and older aBMD both 0.571 ± 0.008 g/cm2). In these matched subjects, there were no sex-specific differences in trabecular microstructural parameters. However, significant differences were noted in cortical microstructure (all p < 0.05): Older women and men had increased cortical porosity (by 91% and 56%, respectively), total cortical pore volume (by 77% and 61%, respectively), and mean cortical pore diameter (by 9% and 8%, respectively) compared with younger subjects. These findings indicate that younger and older women and men matched for DXA aBMD have similar trabecular microarchitecture but clearly different cortical microstructure, at least at an appendicular site represented by the radius. Further studies are needed to define the extent to which this deterioration in cortical microstructure contributes to the aBMD-independent effect of age on bone fragility and fracture risk at the distal radius and other sites of osteoporotic fractures. © 2012 American Society for Bone and Mineral Research

Abstract There remains little consensus on the link between vitamin levels and muscle mass or strength. We therefore investigated the association of serum 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and parathyroid hormone (PTH) levels with skeletal muscle mass and strength. We studied 311 men (mean age, 56 years; range, 23–91 years) and 356 women (mean age, 57 years; range, 21–97 years) representing an age-stratified, random sample of community adults. Multivariate linear regression models were used to examine the association of skeletal muscle mass (by total body dual-energy X-ray absorptiometry) and strength (handgrip force and isometric knee extension moment) with each of 25(OH)D, 1,25(OH)2D, and PTH quartiles, adjusted for age, physical activity, fat mass, and season. We found no consistent association between 25(OH)D or PTH and any of our measurements of muscle mass or strength, in either men or women. However, in subjects younger than 65 years, there was a statistically significant association between low 1,25(OH)2D levels and low skeletal mass in both men and women and low isometric knee extension moment in women, after adjustment for potential confounders. Modestly low 25(OH)D or high PTH levels may not contribute significantly to sarcopenia or muscle weakness in community adults. The link between low 25(OH)D and increased fall risk reported by others may be due to factors that affect neuromuscular function rather than muscle strength. The association between low 1,25(OH)2D and low skeletal mass and low knee extension moment, particularly in younger people, needs further exploration. © 2011 American Society for Bone and Mineral Research

Background and Purpose —Case-control, cohort, and twin studies support a genetic contribution to ischemic stroke risk. Sibling pair linkage methods require identification of concordant or discordant siblings or both. We designed and tested a structured telephone interview to verify the stroke-free phenotype. Methods —A coordinator unaware of medical record data used an 8-item questionnaire to conduct a structured telephone interview of 70 outpatients aged >60 years. The questionnaire inquired about the sudden onset of deficits in strength, sensation, vision, and language. A subject was defined as stroke free by interview if responses to all items on the questionnaire were negative. Results of the telephone interview were compared with data obtained from a systematic medical record review (benchmark). Results —Interview time was 5 minutes or less for all subjects. All subjects who began the interview completed it. Records were reviewed in all subjects. Medical record review detected ischemic stroke or transient ischemic attack (TIA), or both, in 5 patients (7%). There were no significant differences in sex distribution or risk factor rates in patients who were designated stroke free or not stroke free by interview. Having 1 or more positive items on the questionnaire was significantly associated with finding stroke ( P <0.001), TIA ( P <0.001), or either stroke or TIA ( P <0.001), on medical record review. The telephone interview had a sensitivity of 1.0 (95% CI 0.48 to 1.0), specificity of 0.86 (95% CI 0.75 to 0.93), positive predictive value of 0.36 (95% CI 0.13 to 0.65), and negative predictive value of 1.0 (95% CI 0.94 to 1.0). Conclusions —Our instrument can identify the stroke-free individual with a high degree of confidence in a very efficient manner. It may be particularly suited for centralized verification of stroke discordancy in multicentered sib-pair genetic studies.

Abstract Recent studies in mice have demonstrated that osteocalcin (OCN) regulates testosterone (T) production in males but not in females. We hypothesized that this novel bone-testis axis may be most relevant during rapid skeletal growth to help maximize bone size. Thus we measured serum T, total and undercarboxylated (UC) OCN, and periosteal circumference at the radius in 56 boys (bone age 4 to 20 years). T was correlated with OCN (bone-age-adjusted r = 0.30, p = .024), with a similar trend for UC OCN. T began to increase in the boys at bone age 11 years, and OCN peaked at bone age 14 years. Thus we divided the boys into three groups: 4 to 10 years (n = 16), 11 to 14 years (n = 18), and 15 to 20 years (n = 22). In boys of bone age 11 to 14 years (but not the other two groups), OCN was correlated with T (r = 0.57, p = .013), with a similar trend for UC OCN; T, in turn, was correlated with periosteal circumference (r = 0.75, p &lt; .001). Collectively, these findings support the recent observations in mice of a novel bone-testis axis. Moreover, our data suggest that in human males, this axis may be most relevant during rapid skeletal growth, when T levels are rising under the influence of the hypothalamic-pituitary axis and OCN is increasing due to skeletal growth. During this phase, OCN may further stimulate testicular T production, which, in turn, contributes to an increase in bone size. © 2011 American Society for Bone and Mineral Research

Abstract Fractures are increased among men with prostate cancer, especially those on androgen-deprivation therapy (ADT), but few data are available on men with localized prostate cancer. The purpose of this investigation was to estimate fracture risk among unselected community men with prostate cancer and systematically assess associations with ADT and other risk factors for fracture. In a population-based retrospective cohort study, 742 Olmsted County, MN, men with prostate cancer first diagnosed in 1990–1999 (mean age 68.2 ± 8.9 years) were followed for 6821 person-years. We estimated cumulative fracture incidence, assessed relative risk by standardized incidence ratios, and evaluated risk factors in time-to-fracture regression models. All together, 482 fractures were observed in 258 men (71 per 1000 person-years). Overall fracture risk was elevated 1.9-fold, with an absolute increase in risk of 9%. Relative to rates among community men generally, fracture risk was increased even among men not on ADT but was elevated a further 1.7-fold among ADT-treated compared with untreated men with prostate cancer. The increased risk following various forms of ADT was accounted for mainly by associations with pathologic fractures (14% of all fractures). Among men not on ADT (62% of the cohort), more traditional osteoporosis risk factors were implicated. In both groups, underlying clinical characteristics prompting different treatments (indication bias) may have been partially responsible for the associations seen with specific therapies. To the extent that advanced-stage disease and pathologic fractures account for the excess risk, the effectiveness of fracture prevention among men with prostate cancer may be limited. © 2011 American Society for Bone and Mineral Research

Genome-wide association studies have identified an association between two intronic single nucleotide polymorphisms (SNPs), rs12722489 and rs2104286, in the interleukin-2 receptor alpha-chain gene ( IL2RA) and susceptibility to multiple sclerosis (MS). We studied these SNPs in association with susceptibility to and severity of MS in a population-based cohort of 220 patients from Olmsted County, Minnesota, compared with 442 matched controls. We sequenced the exons, splice sites and 5’ and 3’ untranslated regions in 27 randomly selected MS patients (powered for allele frequency ≥0.04) to search for mutations. No novel missense mutation was identified. Two patients (7.5%) had an exon 2 SNP ( rs4308625) and two patients had an exon 4 SNP ( rs2228149), both synonymous.

Background: Association of the HLA-DRB1*1501 allele with multiple sclerosis is well established, but its association with neuromyelitis optica has only been evaluated in small populations. Methods: We performed a case-control genetic association study to evaluate the association of HLA-DRB1*1501 with neuromyelitis optica. The single nucleotide polymorphism rs3135388, which tags HLA-DRB1*1501, was genotyped in 164 patients with neuromyelitis optica, 220 patients with multiple sclerosis and 959 controls matched for age, gender and ethnicity. Genotyping for rs3135388 was performed by Taqman-based 5' nuclease assay. Results: Rs3135388*A was positively associated with multiple sclerosis (OR = 3.93; 95% CI = 2.58—5.97, p = 1.18 × 10 -09 ) but negatively associated with NMO (OR = 0.57; 95% CI = 0.36—0.91, p = 0.01). Conclusions: Multiple sclerosis and neuromyelitis optica differ in their associations with DRB1*1501.

Abstract Because they are not reliably discriminated by areal bone mineral density (aBMD) measurements, it is unclear whether minimal vertebral deformities represent early osteoporotic fractures. To address this, we compared 90 postmenopausal women with no deformity (controls) with 142 women with one or more semiquantitative grade 1 (mild) deformities and 51 women with any grade 2–3 (moderate/severe) deformities. aBMD was measured by dual-energy X-ray absorptiometry (DXA), lumbar spine volumetric bone mineral density (vBMD) and geometry by quantitative computed tomography (QCT), bone microstructure by high-resolution peripheral QCT at the radius (HRpQCT), and vertebral compressive strength and load-to-strength ratio by finite-element analysis (FEA) of lumbar spine QCT images. Compared with controls, women with grade 1 deformities had significantly worse values for many bone density, structure, and strength parameters, although deficits all were much worse for the women with grade 2–3 deformities. Likewise, these skeletal parameters were more strongly associated with moderate to severe than with mild deformities by age-adjusted logistic regression. Nonetheless, grade 1 vertebral deformities were significantly associated with four of the five main variable categories assessed: bone density (lumbar spine vBMD), bone geometry (vertebral apparent cortical thickness), bone strength (overall vertebral compressive strength by FEA), and load-to-strength ratio (45-degree forward bending ÷ vertebral compressive strength). Thus significantly impaired bone density, structure, and strength compared with controls indicate that many grade 1 deformities do represent early osteoporotic fractures, with corresponding implications for clinical decision making. © 2010 American Society for Bone and Mineral Research