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Bone mineralization density and femoral neck fragility.
The traditional view of osteoporotic fractures is that they result from a reduction in bone mass combined with alterations in the micro-architecture. Apart from the effects of bone remodeling, the material properties of the remaining bone are thought to be unaffected. To test this, we compared the degree of matrix mineralization in femoral neck biopsies taken from cases of intracapsular hip fracture with age- and sex-matched postmortem controls. Whole femoral neck biopsies from seven female hip fracture cases (72-90 years) and nine controls (68-94 years) were embedded in methylmethacrylate, and sections stained with Solochrome Cyanin R for analysis of osteoid. The blocks were then diamond micro-milled, carbon coated, and analyzed for the degree of matrix mineralization using halogenated dimethacrylate standards for quantitative backscattered electron (qBSE) imaging (20 kV, entire block face, sampling interval 5 microm). The BSE gray scale was adjusted such that 0 corresponds to an electron backscattering coefficient of 0.1159 (approximately 1.70 g/ml) and 255-0.1519 (approximately 2.18 g/ml). Remodeling and mineralization data were analyzed for both the whole biopsy face and on a regional (anterior; inferior, posterior, or superior) basis. Over the whole biopsy, the level of mineralization was lower in the cases than the postmortem controls (-2.8%, P < 0.05). In both cases and controls, cortical mineralization was higher in the inferior (compressive) region compared with superior (tensile) region (P < 0.05). Mineralization was lower in all regions of the cases (inferior: -3.3%; posterior: -3.1%; anterior: -2.7%; superior: -1.6%) compared to the controls. Mineralization density in cancellous bone was not regionally dependent but was lower in the fracture cases (-3.5%; P = 0.001). Although there were weak relationships between osteoid formation (%O.Ar/B.Ar) and the mean level of mineralization in both cortical (P = 0.068) and cancellous (P < 0.01) bone, adjustment for this did not markedly affect the case-control differences. In conclusion, this study has shown that in cases of intracapsular hip fracture, matrix mineralization is reduced in the femoral neck. Unexpectedly, in view of the likely role of mild to moderate vitamin D deficiency osteopathy in hip fracture, this decreased mineralization was independent of osteoid indices and therefore potentially independent of bone age. This raises the possibility that alterations in the bone matrix such as excessive glycation or changes in the composition of the collagen fibrils affect its mineralization in hip fracture cases.
Increasing mineral density after menopause in individual lumbar vertebrae as a marker for incident degenerative disease: a pilot study for the effects of body composition and diet.
OBJECTIVE: To investigate the potential utility of dual x-ray absorptiometry (DXA) in incidence studies of lumbar spinal spondyloarthropathy. METHODS: Fifty-eight women recruited after menopause to a study of spinal bone loss were measured every 2 years for over a decade. Five developed scan image evidence of patchy calcification and 10 developed statistically significant (p < 0.05) nonparallelism of their bone loss (or gain) in L2, L3, and L4. The number of years since menopause at which these abnormal calcification trends (ACT) occurred was made the outcome in Cox proportional hazard modeling. At baseline, diet was assessed twice using 3-day weighed intakes. Nutrients estimated included carbohydrate, fat, protein, fiber, calcium and other minerals, and 6 vitamins. Measurements at baseline of fat mass and other anthropometric variables were made. RESULTS: The best single explanatory variable for developing ACT was whole body fat mass. Dietary fat was also predictive (p = 0.05) and adding dietary vitamin D (obtained substantially from oily fish) as a second predictor improved the diet model further (to p = 0.006 for model). These 2 dietary variables remained significantly predictive when fat mass was adjusted for (p = 0.0003 for model). CONCLUSION: Serial DXA measurements of the lumbar spine have the potential to provide a new, low radiation-dose approach to early identification of localized abnormal spinal calcification in epidemiology and trials. Alongside body fat, dietary fat intake and its components may warrant further investigation as risk factors for incident degenerative disease of the spine.
Nutritional and exercise-related determinants of bone density in elite female runners.
Although the female athletic triad is widely recognized clinically, there have been few studies quantitating the effect of disordered eating on bone mineral density. The purpose of this study was to explore the mechanisms through which disordered eating might influence the skeleton in nationally or internationally competitive runners. Fifty British national or higher standard middle and long-distance female runners aged under 36 years were recruited; 24 had amenorrhea (AM), nine had oligomenorrhea (OL) and the others were eumenorrheic (EU). Bone mineral density (BMD g.cm(-2)) of the proximal femur (femoral neck and trochanter) and lumbar spine (L2-L4) was measured by dual energy X-ray absorptiometry (DXA) and compared with population-based European reference data. Dietary eating patterns were assessed with the Eating Attitudes Test (EAT26) and Bulimia Investigatory Test Edinburgh (BITE) questionnaires. High eating disorder scores were common; the EAT26 score predicted menstrual disorders (P=0.014) and correlated with body mass index (BMI). BMD was generally low in the AM group, but was raised in the proximal femur in the EU group. In the AM group, younger age at start of training was associated with higher trochanteric BMD. In addition, years of eumenorrhea were positively associated with spine BMD. Although a high EAT26 score was associated with lower BMD in the proximal femur, this could be explained by the intermediary effect of menstrual disorders. Osteocalcin, a marker of bone formation, was reduced in the AM group and was also reduced by high VO2max and high BITE score, consistent with a central (hypothalamic) pathway for suppressing osteoblastic bone formation. Eumenorrheic runners had increased femoral BMD compared with European controls, consistent with a positive effect of increased mechanical loading. The effect of disordered eating to reduce BMD could be explained by its association with menstrual dysfunction. Lumbar spine BMD was reduced most in those athletes who menstruated for the shortest time in adolescence.
NOS isoforms in adult human osteocytes: multiple pathways of NO regulation?
Until now, eNOS has been considered to be the predominant osteocytic nitric oxide synthase (NOS) isoform in bone. We previously studied the distribution of eNOS protein expression in the human femoral neck because of its possible involvement in the response to load. Studies in rat and human fracture callus have shown that nNOS mRNA is expressed sometime after fracture, but no study has yet immunolocalized NOS isoforms in mature adult human bone. In this study, we have examined the distribution of NOS isoforms in iliac osteocytes. Frozen sections (10 microm) were cut from transiliac biopsies from 8 female osteoporotic patients (range, 56-80 years) and from 7 female postmortem femoral neck biopsies (range, 65-90 years). Sections were incubated overnight in antiserum for eNOS, nNOS, or iNOS followed by peroxidase/VIP substrate detection. We used eNOS and iNOS antisera directed against the C-terminus. For nNOS, three different antisera were used, two binding to different C-terminal epitopes and one binding to N-terminal epitope. Sections were then incubated in propidium iodide or methyl green to detect all osteocytes. eNOS antibody was able to detect eNOS epitopes in osteocytes. All three nNOS antibodies detected nNOS epitopes in osteocytes, but those directed against the C-terminus had higher detection rates. iNOS was rarely seen. In the iliac crest, the percentage of osteocytes positive for nNOS was higher than that for eNOS (cortical: nNOS 84.04%, eNOS 61.78%, P < 0.05; cancellous: nNOS 82.33%, eNOS 65.21%, P < 0.05). In the femoral neck, the percentage of osteocytes positive for nNOS (60.98%) was also higher than that for eNOS (40.41%), although this difference was not statistically significant. In conclusion, both eNOS and nNOS isoforms are present in osteocytes in the iliac crest and femoral neck.
Femoral neck fragility: genes or environment?
As with other diseases that show exponentially increasing rates, hip fracture probably requires multiple prior events to become manifest. It is common ground that there are genetic, environmental, lifestyle and perhaps dietary determinants of risk of osteoporotic fracture as well as interactions between them. The key to secondary prevention is the understanding of how these components can be integrated into an effective assessment of the major risks of hip fracture after a previous fracture has occurred. The key to primary prevention is to understand both the pathological and physiological basis of hip fragility. It is not unreasonable to suppose that in a western lifestyle our limited and stereotypic patterns of locomotion from middle age onwards may offer considerably less protection than, for example, the more physically demanding activity of subsistence farming.
Does hip strength analysis explain the lower incidence of hip fracture in the People's Republic of China?
To explore whether there are ethnic differences in calculated hip strength that might explain the low incidence of hip fracture in China, we used Lunar DPX 'beta' version of hip strength analysis (HAS) and hip axis length (HAL) programs to compare hip geometry, calculated strength and densitometric values from Chinese subjects in Shenyang to those of Caucasian subjects in Oslo and Leuven participating in the European Prospective Osteoporosis Study (EPOS). Subjects were 210 Chinese and 403 Caucasian men and women aged 53-77 years. Parameters investigated included bone mineral density (BMD), bone mineral content (BMC), bone area (BA), cross-sectional moment of inertia (CSMI) and section modulus (both indicating strength and rigidity of the femoral neck), HAL, neck length (NL), neck diameter, tensile stress (Tstress) and compressive stress (Cstress) (indicating the stress in the femoral neck at its weakest cross section arising from walking or a standard fall, respectively), safety factor (SF, indicating the resistance to fracture for forces generated during walking) and fall index (FI, indicating the resistance to fracture from force generated during a fall in the greater trochanter). The Chinese men and women were significantly shorter and lighter than their Caucasian counterparts (P<0.01) and had significantly lower BMD, BMC and BA of the femoral neck (P<0.01). After adjusting for BA, weight and height, there was no significant ethnic difference in either gender in BMC. CSMI and section modulus were significantly lower, and HAL, NL and neck diameter were significantly shorter in the Chinese men and women (P<0.01). These differences all remained after adjusting for weight and height. There were no significant differences in Tstress, Cstress, SF and FI between ethnic groups in either gender. Most of the parameters of calculated hip strength in the Chinese subjects were similar to or poorer than those in the Caucasian subjects. There was no evidence to indicate that Shenyang Chinese have superior BMD or BMC or better calculated hip strength. The short HAL and NL of the population, however, could be an independent factor contributing to the low incidence of hip fracture.
Broadband ultrasound attenuation (BUA) of the heel bone and its correlates in men and women in the EPIC-Norfolk cohort: a cross-sectional population-based study.
Osteoporotic fractures have substantial clinical and public health impact. Bone quality is an important determinant of fracture risk. Quantitative ultrasound (QUS) of bone measured as broadband ultrasound attenuation (BUA) has been shown to predict fracture risk. However, there have been very few large population studies, particularly in men. We investigated the correlates of calcaneal BUA using a CUBA clinical machine in 15,668 middle and older aged men and women (42-82 years) from the UK, EPIC-Norfolk cohort. At all ages mean BUA was significantly greater in men than women (men, 90.1+/-17.6; women 72.1+/-16.5). The age-related decline in BUA was five times greater in women than men (-0.77 vs. -0.15 dB/MHz per year). Pre- and post-menopausal bone loss was 0.39 and 0.85 dB/MHz per year, respectively. In univariate regression BUA increased with weight and height by 0.45 dB/MHz per kg and 0.68 per cm in women and 0.24 dB/MHz per kg and 0.33 per cm in men. BUA increased with body mass index (BMI) by 0.84 dB/MHz per kg/m2 in women and 0.55 in men. However, weight was twice as influential as height in men and seven times as great in women. Age, weight and height explained 27% of the variance of BUA in women, but only 3% in men. Adjusted BUA was significantly lower in men and women with an existing history of any hip, wrist or spinal fracture both overall and when analysed for specific site. Figures were: all fractures 66.8 vs. 72.5 dB/MHz ( P<0.001), women; 84.1 vs. 90.5 ( P<0.001), men; hip fractures 61.9 vs. 72.2 dB/MHz ( P<0.001), women; 81.5 vs. 90.2 ( P<0.001), men; wrist fractures 66.6 vs. 72.5 dB/MHz ( P<0.001), women; 81.5 vs. 90.2 ( P<0.001), men; spinal fractures 68.1 vs. 72.1 dB/MHz ( P<0.01), women; 85.1 vs. 90.2 ( P<0.01), men. These differences equate to reductions of 14, 9 and 6% and 10, 7 and 6% for fractures of the hip, wrist and spine in the BUA of women and men, respectively. Thus, despite the overall gender difference in BUA the relative magnitude of a previous history of fracture was equally important in both men and women. Adjusted BUA was also lower in those with previous history of osteoporosis. In women currently taking hormone replacement therapy (HRT) the adjusted BUA was 5 dB/MHz or one-third of an SD greater than in those who did not. The BUA of those with a current smoking habit was 1.7% lower in women and 3.2% lower in men. Overall, there are substantial sex differences in the relationship of the physical and osteoporotic risk factors associated with BUA. A better understanding of these determinants of heel ultrasound may provide insights into how some of the sex differences in bone health can be explained and bone loss in later life minimised.