Fish consumption,bone mineral density,and risk of hip fracture among older adults: The cardiovascular health study

Marine n‐3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may be beneficial for bone health, but few studies have investigated the association with fish consumption. Our aim was to study associations of fish and EPA + DHA consumption with bone mineral density (BMD) and hip fracture risk and determine whether high linoleic acid (LA) intake, the major dietary n‐6 PUFA, modifies the associations. The study population consisted of 5045 participants aged 65 years and older from the Cardiovascular Health Study. Data on BMD were available for 1305 participants. Food‐frequency questionnaire was used to assess dietary intake, and hip fracture incidence was assessed prospectively by review of hospitalization records. After multivariable adjustment, femoral neck BMD was 0.01 g/cm² lower in the highest versus lowest tuna/other‐fish intake category (p = .05 for trend). EPA + DHA intake (higher versus lower median of 0.32 g/day) was associated with lower femoral neck BMD (0.66 versus 0.71 g/cm², p < .001) among those with LA intake greater than the median 12.1 g/day (p = .03 for interaction). No significant associations were found with total‐hip BMD. During mean follow‐up of 11.1 years, 505 hip fractures occurred. Fish or EPA + DHA consumption was not significantly associated with fracture incidence [hazard ratio (HR) for extreme categories: HR = 1.23, 95% confidence interval (CI) 0.83–1.84 for tuna/other fish; HR = 1.16, 95% CI 0.91–1.49 for fried fish; and HR = 0.98, 95% CI 0.71–1.36 for EPA + DHA]. High LA intake did not modify these associations. In this large prospective cohort of older adults, fish consumption was associated with very small differences in BMD and had no association with hip fracture risk. © 2010 American Society for Bone and Mineral Research.     

The association of red blood cell n‐3 and n‐6 fatty acids with bone mineral density and hip fracture risk in the women's health initiative

Omega‐3 (n‐3) and omega‐6 (n‐6) polyunsaturated fatty acids (PUFA) in red blood cells (RBCs) are an objective indicator of PUFA status and may be related to hip fracture risk. The primary objective of this study was to examine RBC PUFAs as predictors of hip fracture risk in postmenopausal women. A nested case‐control study (n = 400 pairs) was completed within the Women's Health Initiative (WHI) using 201 incident hip fracture cases from the Bone Mineral Density (BMD) cohort, along with 199 additional incident hip fracture cases randomly selected from the WHI Observational Study. Cases were 1:1 matched on age, race, and hormone use with non–hip fracture controls. Stored baseline RBCs were analyzed for fatty acids using gas chromatography. After removing degraded samples, 324 matched pairs were included in statistical analyses. Stratified Cox proportional hazard models were constructed according to case‐control pair status; risk of fracture was estimated for tertiles of RBC PUFA. In adjusted hazard models, lower hip fracture risk was associated with higher RBC α‐linolenic acid (tertile 3 [T3] hazard ratio [HR]: 0.44; 95% confidence interval [CI], 0.23–0.85; p for linear trend 0.0154), eicosapentaenoic acid (T3 HR: 0.46; 95% CI, 0.24–0.87; p for linear trend 0.0181), and total n‐3 PUFAs (T3 HR: 0.55; 95% CI, 0.30–1.01; p for linear trend 0.0492). Conversely, hip fracture nearly doubled with the highest RBC n‐6/n‐3 ratio (T3 HR: 1.96; 95% CI, 1.03–3.70; p for linear trend 0.0399). RBC PUFAs were not associated with BMD. RBC PUFAs were indicative of dietary intake of marine n‐3 PUFAs (Spearman's rho = 0.45, p < 0.0001), total n‐6 PUFAs (rho = 0.17, p < 0.0001) and linoleic acid (rho = 0.09, p < 0.05). These results suggest that higher RBC α‐linolenic acid, as well as eicosapentaenoic acid and total n‐3 PUFAs, may predict lower hip fracture risk. Contrastingly, a higher RBC n‐6/n‐3 ratio may predict higher hip fracture risk in postmenopausal women. © 2013 American Society for Bone and Mineral Research.     

Assessment of incident spine and hip fractures in women and men using finite element analysis of CT scans

Finite element analysis of computed tomography (CT) scans provides noninvasive estimates of bone strength at the spine and hip. To further validate such estimates clinically, we performed a 5‐year case‐control study of 1110 women and men over age 65 years from the AGES‐Reykjavik cohort (case = incident spine or hip fracture; control = no incident spine or hip fracture). From the baseline CT scans, we measured femoral and vertebral strength, as well as bone mineral density (BMD) at the hip (areal BMD only) and lumbar spine (trabecular volumetric BMD only). We found that for incident radiographically confirmed spine fractures (n = 167), the age‐adjusted odds ratio for vertebral strength was significant for women (2.8, 95% confidence interval [CI] 1.8 to 4.3) and men (2.2, 95% CI 1.5 to 3.2) and for men remained significant (p = 0.01) independent of vertebral trabecular volumetric BMD. For incident hip fractures (n = 171), the age‐adjusted odds ratio for femoral strength was significant for women (4.2, 95% CI 2.6 to 6.9) and men (3.5, 95% CI 2.3 to 5.3) and remained significant after adjusting for femoral neck areal BMD in women and for total hip areal BMD in both sexes; fracture classification improved for women by combining femoral strength with femoral neck areal BMD (p = 0.002). For both sexes, the probabilities of spine and hip fractures were similarly high at the BMD‐based interventional thresholds for osteoporosis and at corresponding preestablished thresholds for “fragile bone strength” (spine: women ≤ 4500 N, men ≤ 6500 N; hip: women ≤ 3000 N, men ≤ 3500 N). Because it is well established that individuals over age 65 years who have osteoporosis at the hip or spine by BMD criteria should be considered at high risk of fracture, these results indicate that individuals who have fragile bone strength at the hip or spine should also be considered at high risk of fracture. © 2014 American Society for Bone and Mineral Research.     

Use of DXA‐based finite element analysis of the proximal femur in a longitudinal study of hip fracture

Bone mineral density (BMD) measured by dual‐energy X‐ray absorptiometry (DXA) is used for clinical assessment of fracture risk; however, measurements that incorporate bone strength could improve predictive ability. The aim of this study was to determine whether bone strength derived from finite element (FE) analysis was associated with hip fracture risk in a longitudinal study. We studied 728 women (mean age 82 years), 182 with subsequent hip fracture. FE models were generated from baseline DXA scans of the hip to determine femoral bone strength and load‐to‐strength ratio (LSR). The baseline LSR was significantly higher in fracture cases (median 1.1) compared with controls (0.7, p < 0.0001). Femoral strength and BMD were also significantly lower in cases (median 1820 N, 0.557 g/cm²) compared with controls (2614 N, 0.618 g/cm²) both p < 0.0001. Fracture risk increased per standard deviation decrease in femoral strength (odds ratio [OR] = 2.2, 95% confidence interval [CI] 1.8–2.8); femoral neck (FN) BMD (OR = 2.1, 95% CI 1.7–2.6); total hip BMD (OR = 1.8, 95% CI 1.5–2.1); and per SD increase in LSR (OR = 1.8, 95% CI 1.5–2.1). After adjusting for FN BMD, the odds ratio for femoral strength (OR = 1.7, 95% CI 1.2–2.4) and LSR (OR = 1.4, 95% CI 1.1–1.7) remained significantly greater than 1. The area under the curve (AUC) for LSR combined with FN BMD (AUC 0.69, 95% CI 0.64–0.73) was significantly greater than FN BMD alone (AUC 0.66, 95% CI 0.62–0.71, p = 0.004). Strength and LSR remained significant when adjusted for prevalent fragility fracture, VFA, and FRAX score. In conclusion, the DXA‐based FE model was able to discriminate incident hip fracture cases from controls in this longitudinal study independently from FN BMD, prior fracture, VFA, and FRAX score. Such an approach may provide a useful tool for better assessment of bone strength to identify patients at high risk of hip fracture who may benefit from treatment to reduce fracture risk. © 2013 American Society for Bone and Mineral Research.     

Risk Factors for Severity and Type of the Hip Fracture

More severe hip fractures such as displaced femoral neck (FN) fractures and unstable intertrochanteric (IT) fractures lead to poorer outcomes, but risk factors for severe fractures have not been studied. To identify risk factors for severe types of hip fracture, we performed a prospective cohort study and obtained preoperative hip radiographs from women who sustained an incident hip fracture (excluding traumatic fractures). A single radiologist scored the severity of FN fractures by the Garden System: grades I and II, undisplaced; grades III and IV, displaced. The severity of IT hip fractures was rated by the Kyle System: grades I and II, stable; grades III and IV, unstable. A total of 249 women had FN fractures: 75 (30%) were undisplaced. A total of 213 women had IT fractures: 59 (28%) were stable. Both types of hip fracture increased with age, but older age was even more strongly associated with more severe hip fractures. Low BMD was more strongly related to undisplaced FN fractures (p interaction BMD × FN type, p = 0.0008) and stable IT fractures (p interaction BMD × IT type, p = 0.04). Similar findings were observed for estimated volumetric BMD and hip geometric parameters. Corticosteroid use was only associated with displaced FN fractures, and Parkinson's disease was only associated with stable IT fractures. Little difference was reported in the self‐reported circumstances surrounding each type of fracture. In conclusion, the lower the BMD, the greater the likelihood of experiencing a hip fracture that is less displaced and more stable.     

Plasma Choline,Nicotine Exposure,and Risk of Low Bone Mineral Density and Hip Fracture: The Hordaland Health Study

Choline, obtained from diet and formed by biosynthesis, is the immediate precursor of betaine. Animal studies suggest an impact of choline on bone metabolism. We examined the associations of plasma choline and betaine with bone mineral density (BMD), the risk of hip fractures, and possible effect‐modification by nicotine exposure. The Hordaland Health Study (1998 to 2000) included 7074 women and men (ages 46 to 49 or 71 to 74 years). In 5315, BMD was measured. The oldest (n = 3311) were followed for hip fractures through 2009. Risk associations were studied by logistic and Cox regression by comparing the lowest and middle tertiles with the highest, as well as trends across tertiles of plasma choline and betaine. In analyses adjusted for sex and age, participants in the lowest (odds ratio [OR] = 2.00, 95% confidence interval [CI] 1.69–2.37) and middle (OR = 1.39, CI 1.17–1.66) tertiles of plasma choline had an increased risk of low BMD (lowest quintile) (p trend < 0.001). Separate analyses for sex and age groups revealed the strongest relations in elderly women (lowest tertile: OR = 2.84, CI 1.95–4.14; middle tertile: OR = 1.80, CI 1.22–2.67, p trend < 0.001), and highest OR among those in the lowest tertile who were exposed to nicotine (OR = 4.56, CI 1.87–11.11). Low plasma choline was also associated with an increased risk of hip fracture in elderly women and men (lowest tertile: hazard ratio [HR] = 1.45, CI 1.08–1.94; middle tertile: HR = 1.13, CI 0.83–1.54, p trend = 0.012). In elderly women, the HR for hip fracture was 1.90 (CI 1.32–2.73) and 1.36 (CI 0.92–1.99) (p trend < 0.001) for lowest and middle tertiles of choline, and the highest HR was found among women in the lowest tertile exposed to nicotine (HR = 2.68, CI 1.16–6.19). Plasma betaine was not related to BMD or hip fracture. Low plasma choline was associated with low BMD in both sexes and increased the risk of hip fracture in elderly women. These results should motivate further studies on choline, nicotine exposure, and bone metabolism. © 2014 American Society for Bone and Mineral Research.     

Prediction of Incident Hip Fracture with the Estimated Femoral Strength by Finite Element Analysis of DXA Scans in the Study of Osteoporotic Fractures

A bone fractures only when loaded beyond its strength. The purpose of this study was to determine the association of femoral strength, as estimated by finite element (FE) analysis of dual‐energy X‐ray absorptiometry (DXA) scans, with incident hip fracture in comparison to hip bone mineral density (BMD), Fracture Risk Assessment Tool (FRAX), and hip structure analysis (HSA) variables. This prospective case‐cohort study included a random sample of 1941 women and 668 incident hip fracture cases (295 in the random sample) during a mean ± SD follow‐up of 12.8 ± 5.7 years from the Study of Osteoporotic Fractures (n = 7860 community‐dwelling women ≥67 years of age). We analyzed the baseline DXA scans (Hologic 1000) of the hip using a validated plane‐stress, linear‐elastic finite element (FE) model of the proximal femur and estimated the femoral strength during a simulated sideways fall. Cox regression accounting for the case‐cohort design assessed the association of estimated femoral strength with hip fracture. The age–body mass index (BMI)‐adjusted hazard ratio (HR) per SD decrease for estimated strength (2.21; 95% CI, 1.95–2.50) was greater than that for total hip (TH) BMD (1.86; 95% CI, 1.67–2.08; p < 0.05), FN BMD (2.04; 95% CI, 1.79–2.32; p > 0.05), FRAX scores (range, 1.32–1.68; p < 0.0005), and many HSA variables (range, 1.13–2.43; p < 0.005), and the association was still significant (p < 0.05) after further adjustment for hip BMD or FRAX scores. The association of estimated strength with incident hip fracture was strong (Harrell's C index 0.770), significantly better than TH BMD (0.759; p < 0.05) and FRAX scores (0.711–0.743; p < 0.0001), but not FN BMD (0.762; p > 0.05). Similar findings were obtained for intracapsular and extracapsular fractures. In conclusion, the estimated femoral strength from FE analysis of DXA scans is an independent predictor and performs at least as well as FN BMD in predicting incident hip fracture in postmenopausal women. © 2014 American Society for Bone and Mineral Research.     

Dietary Calcium and Serum 25‐Hydroxyvitamin D Status in Relation to BMD Among U.S. Adults

A higher calcium intake is still the primary recommendation for the prevention of osteoporosis, whereas vitamin D deficiency is often not addressed. To study the relative importance of dietary calcium intake and serum 25‐hydroxyvitamin D [25(OH)D] status in regard to hip BMD, 4958 community‐dwelling women and 5003 men ≥20 yr of age from the U.S. NHANES III population‐based survey were studied. Calcium supplement users and individuals with a prior radius or hip fracture were excluded. We calculated standardized means for BMD by quartiles of sex‐specific calcium intake for three 25(OH)D categories (<50, 50–74, and 75+ nM) among men and women, separately controlling for other important predictors of BMD. A higher calcium intake was significantly associated with higher BMD (p value for trend: p = 0.005) only for women with 25(OH)D status <50 nM, whereas calcium intake beyond the upper end of the lowest quartile (>566 mg/d) was not significantly associated with BMD at 25(OH)D concentrations >50 nM. Among men, there was no significant association between a higher calcium intake beyond the upper end of the lowest quartile (626 mg/d) and BMD within all 25(OH)D categories. Among both sexes, BMD increased stepwise and significantly with higher 25(OH)D concentrations (<50, 50–74, 75+ nM; p value for trend: women < 0.0001; men = 0.0001). Among men and women, 25(OH)D status seems to be the dominant predictor of BMD relative to calcium intake. Only women with 25(OH)D concentrations <50 nM seem to benefit from a higher calcium intake.     

Subgroup Variations in Bone Mineral Density Response to Zoledronic Acid After Hip Fracture

Minimizing post‐fracture bone loss is an important aspect of recovery from hip fracture, and determination of factors that affect bone mineral density (BMD) response to treatment after hip fracture may assist in the development of targeted therapeutic interventions. A post hoc analysis of the HORIZON Recurrent Fracture Trial was done to determine the effect of zoledronic acid (ZOL) on total hip (TH) and femoral neck (FN) BMD in subgroups with low‐trauma hip fracture. A total of 2127 patients were randomized (1:1) to yearly infusions of ZOL 5 mg (n = 1065) or placebo (n = 1062) within 90 days of operation for low‐trauma hip fracture. The 1486 patients with a baseline and at least one post‐baseline BMD assessment at TH or FN (ZOL = 745, placebo = 741) were included in the analyses. Percentage change from baseline in TH and FN BMD was assessed at months 12 and 24 and compared across subgroups of hip fracture patients. Percentage change from baseline in TH and FN BMD at months 12 and 24 was greater (p < 0.05) in ZOL‐treated patients compared with placebo in most subgroups. Treatment‐by‐subgroup interactions (p < 0.05) indicated that a greater effect on BMD was observed for TH BMD at month 12 in females, in patients in the lower tertile body mass index at baseline (≤22.6 kg/m²), and in patients with baseline FN BMD T‐score of ≤ –2.5; for FN BMD in patients who received ZOL for >6 weeks post‐surgery; and for TH and FN BMD in patients with a history of one or more prior fractures. All interactions were limited to the first 12 months after treatment with none observed for the 24‐month comparisons. (Clinical trial registration number NCT00046254.) © 2014 American Society for Bone and Mineral Research.     

Dietary intake of polyunsaturated fatty acids and risk of hip fracture in men and women

Summary

Data on the impact of polyunsaturated fatty acid intake on hip fracture risk are inconsistent. We investigated this association in 75,878 women and 46,476 men and did not find a significant role for polyunsaturated fatty acid intake in the prevention of hip fractures.

Introduction

Polyunsaturated fatty acids (PUFA) are important in the prevention of chronic diseases, but studies of bone health report inconsistent results. Our aim was to investigate the association between dietary PUFA intake and risk of hip fracture in two large prospective cohorts of men and women with long follow-up times and frequently updated dietary data.

Methods

The study population included 75,878 women and 46,476 men free of osteoporosis at baseline. Dietary intakes were assessed by a food frequency questionnaire at baseline and several times during the follow-up. Multivariable-adjusted Cox proportional hazards models were used to estimate relative risks (RR).

Results

During 24?years of follow-up, we identified 1,051 hip fracture cases due to low or moderate trauma among the women and 529 cases among the men. In the pooled analyses, no statistically significant associations were found between intakes of total PUFA [RR in the highest vs. lowest quintile: 0.99, 95% confidence interval (CI) 0.69, 1.43; p value for trend is =0.83], total n-3 PUFA (RR 0.89, 95% CI 0.75, 1.06; p value for trend is =0.26), total n-6 PUFA (RR 0.99, 95% CI 0.71, 1.38; p value for trend is =0.82), n-6/n-3 PUFA ratio or individual PUFAs, and hip fracture risk. However, in women low intakes of total PUFA, total n-6 PUFA, and linoleic acid were associated with higher risk.

Conclusions

This study does not support a significant role for PUFA intake in the prevention of hip fractures, although low total PUFA, n-6 PUFA, or linoleic acid intakes may increase the risk in women.     

Dietary Acid Load Is Associated With Lower Bone Mineral Density in Men With Low Intake of Dietary Calcium

High dietary acid load (DAL) may be detrimental to bone mineral density (BMD). The objectives of the study were to: (1) evaluate the cross‐sectional relation between DAL and BMD; and (2) determine whether calcium intake modifies this association. Men (n = 1218) and women (n = 907) aged ≥60 years were included from the National Health and Nutrition Examination Survey 2005–2008. Nutrient intake from 2, 24‐hour recalls was used to calculate net endogenous acid production (NEAP) and potential renal acid load (PRAL) (mEq/d). PRAL was calculated from dietary calcium (PRAL_diet) and diet + supplemental calcium (PRAL_total). Tests for linear trend in adjusted mean BMD of the hip and lumbar spine were performed across energy‐adjusted NEAP and PRAL quartiles. Modification by calcium intake (dietary or total) above or below 800 mg/d was assessed by interaction terms. Overall, mean age was 69 ± 0.3 years. Among women, there was no association between NEAP and BMD. PRAL_diet was positively associated with proximal femur BMD (p trend = 0.04). No associations were observed with PRAL_total at any BMD site (p range, 0.38–0.82). Among men, no significant associations were observed between BMD and NEAP or PRAL. However, an interaction between PRAL_diet and calcium intake was observed with proximal femur BMD (p = 0.08). An inverse association between PRAL_diet and proximal femur BMD was detected among men with <800 mg/d dietary calcium (p = 0.02); no associations were found among men with ≥800 mg/d (p = 0.98). A significant interaction with PRAL_total was not observed. In conclusion, when supplemental calcium is considered, there is no association between DAL and BMD among adults. Men with low dietary calcium showed an inverse relation with PRAL at the proximal femur; in women no interaction was observed. This study highlights the importance of calcium intake in counteracting the adverse effect of DAL on bone health. Further research should determine the relation between DAL and change in BMD with very low calcium intake. © 2014 American Society for Bone and Mineral Research.     

Distribution of bone density in the proximal femur and its association with hip fracture risk in older men: The osteoporotic fractures in men (MrOS) study

This prospective case‐cohort study aimed to map the distribution of bone density in the proximal femur and examine its association with hip fracture. We analyzed baseline quantitative computed tomography (QCT) scans in 250 men aged 65 years or older, which comprised a randomly‐selected subcohort of 210 men and 40 cases of first hip fracture during a mean follow‐up period of 5.5 years. We quantified cortical, trabecular, and integral volumetric bone mineral density (vBMD), and cortical thickness (CtTh) in four quadrants of cross‐sections along the length of the femoral neck (FN), intertrochanter (IT), and trochanter (TR). In most quadrants, vBMDs and CtTh were significantly (p < 0.05) lower in cases compared to the subcohort and these deficits were present across the entire proximal femur. To examine the association of QCT measurements with hip fracture, we merged the two quadrants in the medial and lateral aspects of the FN, IT, and TR. At most sites, QCT measurements were associated significantly (p < 0.001) with hip fracture, the hazard ratio (HR) adjusted for age, body mass index (BMI), and clinical site for a 1‐SD decrease ranged between 2.28 (95% confidence interval [CI], 1.44–3.63) to 6.91 (95% CI, 3.11–15.53). After additional adjustment for total hip (TH) areal BMD (aBMD), trabecular vBMDs at the FN, TR, and TH were still associated with hip fracture significantly (p < 0.001), the HRs ranged from 3.21 (95% CI, 1.65–6.24) for the superolateral FN to 6.20 (95% CI, 2.71–14.18) for medial TR. QCT measurements alone or in combination did not predict fracture significantly (p > 0.05) better than TH aBMD. With an area under the receiver operating characteristic curve (AUC) of 0.901 (95% CI, 0.852–0.950), the regression model combining TH aBMD, age, and trabecular vBMD predicted hip fracture significantly (p < 0.05) better than TH aBMD alone or TH aBMD plus age. These findings confirm that both cortical and trabecular bone contribute to hip fracture risk and highlight trabecular vBMD at the FN and TR as an independent risk factor. © 2012 American Society for Bone and Mineral Research.     

Preferential low bone mineral density of the femoral neck in patients with a recent fracture of the proximal femur

Bone mass is an important determinant of resistance to fractures. Whether bone mineral density (BMD) in subjects with a fracture of the proximal femur (hip fracture) is different from that of age-matched controls is still debated. We measured BMD of the femoral neck (FN) on the opposite side to the fracture, as well as femoral shaft (FS) and lumbar spine (LS) BMD by dual-photon absorptiometry in 68 patients (57 women and 11 men, mean age 78.8±1.0) 12.4±0.8 days after hip fracture following a moderate trauma. These values were compared with BMD of 93 non-fractured elderly control subjects (82 women and 11 men), measured during the same period. As compared with the controls, FN BMD was significantly lower in fractured women (0.592±0.013 v. 0.728±0.014 g/cm²,P<0.001) and in fractured men (0.697±0.029 v. 0.840±0.052,P<0.05). Expressed as standard deviations above or below the mean BMD of age and sex-matched normal subjects (Z-score), the difference in FN BMD between fractured women and controls was highly significant (–0.6±0.1 v. +0.1±0.1,P<0.001). As compared with mean BMD of young normal subjects, BMD was decreased by 36.9±1.4 and 22.4±1.5% (P<0.001) in fractured and control women, respectively. There was no significant difference between FN BMD of 33 women with cervical and 24 with trochanteric hip fractures (0.603±0.017 v. 0.577±0.020). FN BMD was lower than 0.705 g/cm² in 90% of fractured women. The prevalence of fracture increased with decreasing FN BMD, reaching 100% with values below 0.500 g/cm². FS and LS BMD were significantly lower in women with hip fracture than in controls (1.388±0.036 v. 1.580±0.030,P<0.001, for FS, and 0.886±0.027 v. 0.985±0.023,P<0.01, for LS), but these differences were not significant when expressed as a Z-score. In men with a recent hip fracture, FS BMD was significantly lower than in controls (1.729±0.096 v. 2.069±0.062,P<0.01), but the difference at the LS level did not reach statistical significance. These results indicate that both women and men with a recent hip fracture had decreased bone mineral density of the femoral neck, femoral shaft and lumbar spine. However, the difference appeared to be of higher magnitude for the femoral neck suggesting a preferential bone loss at this site.     

FRAX and Risk of Vertebral Fractures: The Fracture Intervention Trial

The validity of the WHO 10‐yr probability of major osteoporotic fracture model (FRAX) for prediction of vertebral fracture has not been tested. We analyzed how well FRAX for major osteoporotic fractures, with and without femoral neck BMD (FN BMD), predicted the risk of vertebral fracture. We also compared the predictive validity of FRAX, FN BMD, and prevalent vertebral fracture detected by radiographs at baseline alone or in combination to predict future vertebral fracture. We analyzed data from the placebo groups of FIT (3.8‐yr follow‐up, n = 3221) with ORs and areas under receiver operating characteristics (ROC) curves (AUC). FRAX with and without FN BMD predicted incident radiographic vertebral fracture. The AUC was significantly greater for FRAX with FN BMD (AUC = 0.71) than FRAX without FN BMD (AUC = 0.68; p = 0.002). Prevalent vertebral fracture plus age and FN BMD (AUC = 0.76) predicted incident radiographic vertebral fracture as well as a combination of prevalent vertebral fracture and FRAX with FN BMD (AUC = 0.75; p = 0.76). However, baseline vertebral fracture status plus age and FN BMD (AUC = 0.76) predicted incident radiographic vertebral fracture significantly better than FRAX with FN BMD (AUC = 0.71; p = 0.0017). FRAX for major osteoporotic fractures (with and without FN BMD) predicts vertebral fracture. However, once FN BMD and age are known, the eight additional risk factors in FRAX do not significantly improve the prediction of vertebral fracture. A combination of baseline radiographic vertebral fracture, FN BMD, and age is the strongest predictor of future vertebral fracture.     

Fetuin‐A and BMD in Older Persons: The Health Aging and Body Composition (Health ABC) Study

Fetuin‐A is a hepatic secretory protein that promotes bone mineralization in vitro. Whether fetuin‐A levels are associated with BMD in humans is unknown. The Health Aging and Body Composition study enrolled 3075 well‐functioning black and white persons 70–79 yr of age and measured BMD. This cross‐sectional study measured serum fetuin‐A using ELISA among a random sample of 508 participants within sex and race strata. Multivariate linear regression analysis evaluated the associations of fetuin‐A with BMD. Among women (n = 257), higher fetuin‐A levels were significantly associated with higher total hip (p = 0.02), lumbar spine (p = 0.03), and whole body BMD (p = 0.01) in models adjusted for age, race, diabetes, alcohol and tobacco use, physical activity, body mass index, C‐reactive protein levels, calcium supplement, and estrogen use. For example, each SD (0.38 g/liter) higher level of fetuin‐A was associated with 0.016 g/cm² higher total hip areal BMD. The association was of similar magnitude and direction for femoral neck BMD but did not reach statistical significance (p = 0.11). In contrast, among men (n = 251), fetuin‐A had no significant associations with total hip (p = 0.79), lumbar spine (p = 0.35), whole body (p = 0.46), or femoral neck BMD (p = 0.54) in multivariable models. We conclude that higher fetuin‐A levels are independently associated with higher BMD among well‐functioning community‐dwelling older women but not older men. Future studies should evaluate whether fetuin‐A may refine fracture risk assessment in older women.     

Serum 25‐hydroxyvitamin D and the risk of hip and nonspine fractures in older men

The association between vitamin D levels and incident fractures in older men is uncertain. To test the hypothesis that low serum 25‐hydroxyvitamin D [(25(OH)D] levels are associated with an increased risk of fracture, we performed a case‐cohort study of 436 men with incident nonspine fractures, including 81 hip fractures, and a random subcohort of 1608 men; average follow‐up time 5.3 years. Serum vitamin D₂ and vitamin D₃ were measured on baseline sera using mass spectrometry and summed for total vitamin D. Modified Cox proportional hazards models were used to estimate the hazard ratio (HR) of fracture with 95% confidence intervals (CIs). Multivariable models included age, clinic, season, race, height, weight, and physical activity. The mean (SD) total 25(OH)D was 24.6 (7.8) ng/mL in nonspine fracture subjects, 21.5 (7.9) ng/mL in hip fracture subjects, and 25.2 (7.8) ng/mL in controls (nonspine fracture subjects versus nonpatients, p = .14; hip fracture subjects versus controls, p < .0001). 25(OH)D levels were unrelated to nonspine fractures. One SD decrease in total 25(OH)D was associated with an increased risk of hip fracture (multivariate HR = 1.60; 95% CI 1.18–2.17). Compared with men in the top quartile of total 25(OH)D (≥28), the HR of hip fracture was 2.36 (95% CI 1.08–5.15) for men in the lowest quartile (<20) (p = .009 for trend). Adjusting for hip bone mineral density attenuated the association by more than 50% (p = .065 for trend). Low serum 25(OH)D concentrations are associated with a higher risk of hip fracture in older men. Measurement of 25(OH)D may be useful in identifying men at high risk of hip fracture. © 2010 American Society for Bone and Mineral Research.     

Association of Increased Urinary Albumin With Risk of Incident Clinical Fracture and Rate of Hip Bone Loss: the Osteoporotic Fractures in Men Study

Prior studies suggest that increased urine albumin is associated with a heightened fracture risk in women, but results in men are unclear. We used data from Osteoporotic Fractures in Men (MrOS), a prospective cohort study of community‐dwelling men aged ≥65 years, to evaluate the association of increased urine albumin with subsequent fractures and annualized rate of hip bone loss. We calculated albumin/creatinine ratio (ACR) from urine collected at the 2003–2005 visit. Subsequent clinical fractures were ascertained from triannual questionnaires and centrally adjudicated by review of radiographic reports. Total hip BMD was measured by DXA at the 2003–2005 visit and again an average of 3.5 years later. We estimated risk of incident clinical fracture using Cox proportional hazards models, and annualized BMD change using ANCOVA. Of 2982 men with calculable ACR, 9.4% had ACR ≥30 mg/g (albuminuria) and 1.0% had ACR ≥300 mg/g (macroalbuminuria). During a mean of 8.7 years of follow‐up, 20.0% of men had an incident clinical fracture. In multivariate‐adjusted models, neither higher ACR quintile (p for trend 0.75) nor albuminuria (HR versus no albuminuria, 0.89; 95% CI, 0.65 to 1.20) was associated with increased risk of incident clinical fracture. Increased urine albumin had a borderline significant, multivariate‐adjusted, positive association with rate of total hip bone loss when modeled in ACR quintiles (p = 0.06), but not when modeled as albuminuria versus no albuminuria. Macroalbuminuria was associated with a higher rate of annualized hip bone loss compared to no albuminuria (–1.8% more annualized loss than in men with ACR <30 mg/g; p < 0.001), but the limited prevalence of macroalbuminuria precluded reliable estimates of its fracture associations. In these community‐dwelling older men, we found no association between urine albumin levels and risk of incident clinical fracture, but found a borderline significant, positive association with rate of hip bone loss. © 2016 American Society for Bone and Mineral Research.     

Underestimated Fracture Probability in Patients With Unilateral Hip Osteoarthritis as Calculated by FRAX

Osteoporosis (OP) and osteoarthritis (OA) are age-related diseases often considered to be mutually exclusive. We previously found that 25% of women with advanced OA had occult OP and that femoral neck (FN) bone mineral density (BMD) T-scores were significantly higher for osteoarthritic vs contralateral hips. The FRAX calculator incorporates clinical risk factors and FN BMD T-score to estimate 10-yr total fracture probability and hip fracture probability. In 35 women and men aged 41 yr or older with unilateral hip OA scheduled for hip replacement, we tested whether FRAX fracture probability is underestimated when using data for the OA rather than the contralateral hip. There were between-hip differences for FN BMD T-score (p < 0.0001), total fracture probability (p = 0.0004), and hip fracture probability (p = 0.0009). Use of FN BMD T-scores resulted in OP treatment recommendations for 0% and 11% of subjects compared with 11% and 17% for total fracture probability and hip fracture probability, respectively. In 6–11% of subjects in this series, the FRAX calculator underestimated fracture probability with data for the OA hip. With the increased use of FRAX in clinical use, these data suggest that measurement of BMD at the contralateral hip may yield higher calculated FRAX total and hip fracture probabilities.     

Distribution of cortical bone in the femoral neck and hip fracture: a prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study

In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men. There were significant gender differences in Est CTh measurements in the control group but not in the case group. In multivariable analysis for risk of femoral neck (FN) fracture, Est CTh in the supero-anterior (SA) quadrant was significant in both women and men, and remained a significant predictor after adjustment for FN areal BMD (aBMD, dimensions g/cm2, DXA-like), (p=0.05 and p<0.0001, respectively). In conclusion, Est CTh in the SA quadrant best discriminated cases (n=143) from controls (n=298), especially in men. Cortical thinning superiorly in the hip might be of importance in determining resistance to fracture.     

Calcaneal ultrasonic measurements discriminate hip fracture independently of bone mass

We studied 336 elderly white women, of whom 22 had previously suffered a hip fracture and 22 had previously suffered a vertebral fracture. All subjects were 60 years old or older with a mean age of 73.7 years. Measurements of ultrasonic transmission velocity (UTV), broad-band ultrasonic attenuation (BUA) and stiffness (STF) were made at the os calcis using a Lunar Achilles ultrasound device. Measurements of lumbar spine bone mineral density (L2–4 BMD) and femoral neck BMD were made using dual-energy X-ray absorptiometry. The fracture groups were significantly older and had more years since menopause than the control groups. Logistic regression showed that measurements of UTV, STF and BUA discriminated between fracture and non-fracture subjects for both the hip (p<0.001) and spine (p<0.05). Femoral neck BMD discriminated both hip and vertebral fractures from controls (p<0.001 andp<0.01, respectively). Spinal BMD discriminated between subjects with vertebral fractures and those without (p<0.01), but not hip fractures (p=0.64). For hip fracture, areas under receiver-operating characteristic (ROC) curves were 0.85 for UTV, 0.83 for STF, 0.79 for BUA, 0.78 for femoral neck BMD and 0.53 for spinal BMD. For vertebral fracture, areas under the ROC curve were 0.68 for UTV, 0.70 for STF, 0.66 for BUA, 0.66 for femoral neck BMD and 0.67 for spinal BMD. To determine whether calcaneal ultrasonic measurements discriminated, independently of BMD, fracture from control groups, UTV, BUA and STF were adjusted for BMD, age and years since menopause using multiple regression analysis and the residuals from the regressions were incorporated into a logistic regression analysis. Adjusted ultrasonic measurements discriminated hip fracture from control groups (p<0.005 for UTV;p<0.05 for BUA;p<0.01 for STF) but not vertebral fracture (p=0.37 for UTV;p=0.53 for BUA;p=0.25 for STF). These results show that, when ultrasonic measurements were adjusted for BMD and age, they still discriminated between hip fracture and control groups. This finding supports the hypothesis that ultrasonic measurements contain information about bone strength not contained in bone density measurements that may be useful in predicting hip fractures. Therefore, calcaneal ultrasound measurements may provide a safe, low-cost addition to bone densitometry.