Current guidelines recommend that serum C-terminal telopeptide of type I collagen (CTX) and serum procollagen type 1 aminoterminal propeptide (PINP), measured by standardized assays, be used as reference markers in observational and interventional studies. However, there are limited data to determine whether serum CTX and PINP are associated with hip fracture risk among postmenopausal women. We determined the associations of serum CTX and serum PINP with hip fracture risk among postmenopausal women aged 50 to 79 years at baseline. We performed a prospective case-control study (400 cases, 400 controls) nested in the Women's Health Initiative Observational Study, which enrolled participants at 40 US clinical centers. Cases were women with incident hip fracture not taking osteoporosis medication; hip fractures were confirmed using medical records. Untreated controls were matched by age, race/ethnicity, and date of blood sampling. Serum CTX and serum PINP were analyzed on 12-hour fasting blood samples. The main outcome measure was incident hip fracture risk (mean follow-up 7.13 years). After adjustment for body mass index, smoking, frequency of falls, history of fracture, calcium and vitamin D intake, and other relevant covariates, neither serum CTX level nor serum PINP level was statistically significantly associated with hip fracture risk (CTX p_trend  = 0.22, PINP p_trend  = 0.53). Our results do not support the utility of serum CTX level or PINP level to predict hip fracture risk in women in this age group. These results will inform future guidelines regarding the potential utility of these markers in fracture prediction. © 2018 American Society for Bone and Mineral Research.

Purpose

The osteoprotogerin/receptor activator of NF-kappa β/receptor activator of NF-kappa β ligand (OPG/RANK/RANKL) pathway plays a critical role in bone remodeling. This study investigated associations between serum levels of OPG, soluble RANKL (sRANKL), and the ratio of OPG/sRANKL to risk of incident hip fracture.

Methods

A nested case-control study was conducted among postmenopausal, Caucasian women aged 50-79 at baseline (1993-1998), followed for hip fracture through March 2005 in the Women's Health Initiative Observational Study. 400 incident hip fracture cases were selected and individually matched to 400 controls with no prior fracture or incident hip fracture. Matching factors were baseline age, enrollment date and hormone therapy (HT) exposure. Baseline serum OPG and sRANKL levels were measured using high sensitivity ELISA. Odds ratios were computed for quartiles of each biomarker adjusting for matching factors and hip fracture risk factors.

Results

Serum OPG was significantly associated with older age, low physical activity and poorer physical function in control women. sRANKL was inversely associated with total calcium intake in control women, but not associated with age or other fracture risk factors. The odds ratio for hip fracture comparing the highest to lowest quartiles of OPG was 2.28 (95% confidence interval (CI), 1.45-3.61) after adjusting for the matching variables (p-value for linear trend <0.001), and 1.87 (95% CI, 1.15-3.04; p for linear trend=0.02) after adjusting for self-rated health status, physical activity and physical functioning. No significant associations between sRANKL or the ratio of OPG/sRANKL and hip fracture risk were observed.

Conclusion

Serum OPG levels were independently associated with a nearly twofold increased risk of hip fracture in postmenopausal women.

Objective

The purpose of this study is to examine the validity of, and factors associated with, the accuracy of self-report (participant-report and proxy-report) for fractures.

Design

Study participants were from the Women's Health Initiative Clinical Trial and Observational Study cohorts. All women were postmenopausal; populations included American Indian, Asian/Pacific Islander, black, Hispanic, and non-Hispanic white. The average length of follow-up was 4.3 years. Self-reported fractures were adjudicated by reviewing medical records. The first adjudicated self-report of fractures for each participant was included in the analysis (n = 6,652).

Results

We found substantial variations in validity of self-report by the fracture site. Agreements between self-reports for single-site fractures and medical records were high for hip (78%) and forearm/wrist (81%) but relatively lower for clinical spine fractures (51%). The average confirmation rate for all single-site fractures was 71%. Misidentification of fracture sites by participants or proxy-reporters seemed to be a cause of unconfirmed self-reports. Higher confirmation rates were observed in participant-reports than in proxy-reports. Results of the multivariate analysis indicated that multiple factors, such as ethnicity, a history of osteoporosis or fractures, body mass index, years since menopause, smoking status, and number of falls in the past year were significantly (P < 0.05) related to the validity of self-report.

Conclusion

The validity of self-reports for fracture varies by fracture sites and many other factors. The assessed validity in this study is likely conservative because some of the unconfirmed self-reports may be due to poor medical record systems. The validity of self-reports for hip and forearm/wrist fractures is high in this study, supporting their use in epidemiological studies among postmenopausal women.

Background

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to stimulate bone formation in laboratory studies, both in vitro and in vivo. While early epidemiologic studies showed lower risk for hip fracture among statin users than nonusers, subsequent studies have produced mixed results.

Objective

To examine the association of statin use with incidence of hip, lower arm or wrist, and other clinical fractures and with baseline levels of bone density.

Design

Prospective study.

Setting

Women's Health Initiative Observational Study conducted in 40 clinical centers in the United States.

Participants

93 716 postmenopausal women ages 50 to 79 years.

Measurements

Rates of hip, lower arm or wrist, and other clinical fractures were compared among 7846 statin users and 85 870 nonusers over a median follow-up of 3.9 years. In 6442 women enrolled at three clinical centers, baseline levels of total hip, posterior-anterior spine, and total-body bone density measured by using dual-energy x-ray absorptiometry were compared according to statin use.

Results

Age-adjusted rates of hip, lower arm or wrist, and other clinical fractures were similar between statin users and nonusers regardless of duration of statin use. The multivariate-adjusted hazard ratios for current statin use were 1.22 (95% CI, 0.83 to 1.81) for hip fracture, 1.04 (CI, 0.85 to 1.27) for lower arm or wrist fracture, and 1.11 (CI, 1.00 to 1.22) for other clinical fracture. Bone density levels did not statistically differ between statin users and nonusers at any skeletal site after adjustment for age, ethnicity, body mass index, and other factors.

Conclusion

Statin use did not improve fracture risk or bone density in the Women's Health Initiative Observational Study. The cumulative evidence does not warrant use of statins to prevent or treat osteoporosis.

Calcium plus vitamin D (CaD) supplementation has a modest but significant effect on slowing loss of femoral bone mass and reducing risk of hip fractures in adherent postmenopausal women. The goal of this study was to determine if CaD supplementation influences hip structural parameters that are associated with fracture risk. We studied 1,970 postmenopausal women enrolled in the Women's Health Initiative randomized controlled trial of CaD at one of three bone mineral density (BMD) clinical centers. Hip structural analysis software measured BMD and strength parameters on DXA scans at three regions: femoral narrow neck, intertrochanter, and shaft. Random effects models were used to test the average differences in hip BMD and geometry between intervention and placebo. There was greater preservation of hip BMD at the narrow neck with CaD relative to placebo across 6 years of intervention. CaD also altered the underlying cross-sectional geometry at the narrow neck in the direction of greater strength, with small increases in cross-sectional area and section modulus and a decrease in buckling ratio with CaD relative to placebo. While trends at both the intertrochanter and shaft regions were similar to those noted at the narrow neck, no significant intervention effects were evident. There was no significant interaction of CaD and age or baseline calcium levels for hip structural properties. CaD supplementation is associated with modest beneficial effects on hip structural features at the narrow neck, which may explain some of the benefit of CaD in reducing hip fracture risk.

Background

It is unclear how well surrogate markers for vitamin D exposure (eg, oral intake of vitamin D and estimates of sunlight exposure), with and without consideration of other potential predictors of 25-hydroxyvitamin D [25(OH)D] concentrations, similarly rank individuals with respect to 25(OH)D blood concentrations.

Objective

The objective was to determine how much variation in serum 25(OH)D concentrations (nmol/L) could be explained by a predictive model with the use of different vitamin D surrogate markers (latitude of residence, mean annual regional solar irradiance estimates, and oral sources) and other individual characteristics that might influence vitamin D status.

Design

A random sample of 3055 postmenopausal women (aged 50-70 y) participating in 3 nested case-control studies of the Women's Health Initiative Calcium plus Vitamin D Clinical Trial was used. Serum 25(OH)D values, assessed at year 1 (1995-2000), and potential predictors of 25(OH)D concentrations, assessed at year 1 or Women's Health Initiative baseline (1993-1998), were used.

Results

More than half of the women (57.1%) had deficient (<50 nmol/L) concentrations of 25(OH)D. Distributions of 25(OH)D concentrations by level of latitude of residence, mean annual regional solar irradiance, and intake of vitamin D varied considerably. The predictive model for 25(OH)D explained 21% of the variation in 25(OH)D concentrations. After adjustment for month of blood draw, breast cancer status, colorectal cancer status, fracture status, participation in the hormone therapy trial, and randomization to the dietary modification trial, the predictive model included total vitamin D intake from foods and supplements, waist circumference, recreational physical activity, race-ethnicity, regional solar irradiance, and age.

Conclusions

Surrogate markers for 25(OH)D concentrations, although somewhat correlated, do not adequately reflect serum vitamin D measures. These markers and predictive models of blood 25(OH)D concentrations should not be given as much weight in epidemiologic studies of cancer risk.

With aging, renal function tends to decline, as evidenced by reduced glomerular filtration rate. High-protein intake may further stress the kidneys by causing sustained hyperfiltration. To investigate whether dietary protein is associated with impaired renal function, we used data from 2 nested case-control studies within the Women's Health Initiative Observational Study (n = 2419). We estimated protein intake using a FFQ and estimated glomerular filtration rate (eGFR) from cystatin C. To account for the original study designs, inverse probability weights were applied. Self-reported energy and protein were calibrated using biomarkers of energy and protein intake. Associations between protein intake and renal function were estimated by weighted linear and logistic regression models. Average calibrated protein intake (mean ± SD) was 1.1 ± 0.2 g/(kg body weight·d).Twelve percent (n = 292) of women had impaired renal function. The odds of impaired renal function, defined as eGFR <60 mL/(min·1.73m(2)), was not associated with calibrated protein intake. When eGFR was modeled continuously, there was no association with calibrated protein when protein was expressed in absolute (g/d) or relative to energy (protein % energy/d), but protein relative to body weight [g/(kg body weight·d)] was associated with higher eGFR. There was no evidence for effect modification by age, BMI, or general health status. These data suggest higher protein intake is not associated with impaired renal function among postmenopausal women without a diagnosis of chronic kidney disease.

Background

It has been suggested that hormone therapy may help counter undesirable changes in body composition in older women.

Objective

This study was designed to test whether estrogen plus progestin (E+P) therapy favorably affects age-related changes in body composition in postmenopausal women.

Design

The substudy was composed of 835 women from the estrogen plus progestin trial of the Women's Health Initiative who were randomly assigned to receive either E+P therapy (n = 437) or placebo (n = 398). The women had a mean age of 63.1 y and, on average, were 13.8 y past menopause. More than 17% of the participants were from an ethnic minority. No significant differences in baseline body composition (measured with dual-energy X-ray absorptiometry) by intervention assignment were observed.

Results

After 3 y of intervention, the women who received active E+P therapy lost less lean soft tissue mass (-0.04 kg) than did the women who received placebo (-0.44 kg; P = 0.001). Additionally, the women in the E+P group had less upper-body fat distribution than did the women in the placebo group (change in ratio of trunk to leg fat mass: -0.025 for the E+P group and 0.004 for the placebo group; P = 0.003). A sensitivity analysis, which was conducted on the women who took > or = 80% of the study medication during the intervention period, corroborated the findings from the intent-to-treat analysis.

Conclusions

A 3-y E+P intervention significantly reduced both the loss of lean soft tissue mass and the ratio of trunk to leg fat mass in postmenopausal women. However, the effect sizes were small, and whether these changes in body composition lead to significant health benefits remains to be confirmed.

Purpose

We conducted a secondary analysis of a randomized, placebo-controlled trial to test if hormone therapy (HT) altered the risk of open-angle glaucoma (OAG), and if the risk reduction varied by race.

Design

Secondary analysis of randomized controlled trial data.

Methods

We linked Medicare claims data to 25 535 women in the Women's Health Initiative. Women without a uterus were randomized to receive either oral conjugated equine estrogens (CEE 0.625 mg/day) or placebo, and women with a uterus received oral CEE and medroxyprogesterone acetate (CEE 0.625 mg/day + MPA 2.5 mg/day) or placebo. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence interval.

Results

After exclusion of women with prevalent glaucoma or without claims for eye care provider visits, the final analysis included 8102 women (mean age = 68.5 ± 4.8 years). The OAG incidence was 7.6% (mean follow-up = 11.5 ± 5.2 years; mean HT duration = 4.4 ± 2.3 years). Increased age (P trend = .01) and African-American race (HR = 2.69, 95% CI = 2.13-3.42; white as a reference) were significant risk factors for incident OAG. We found no overall benefit of HT in reducing incident OAG (HR = 1.01, 95% CI = 0.79-1.29 in the CEE trial, and HR = 1.05, 95% CI = 0.85-1.29 in the CEE + MPA trial). However, race modified the relationship between CEE use and OAG risk (P interaction = .01), and risk was reduced in African-American women treated with CEE (HR = 0.49, 95% CI = 0.27-0.88), compared to placebo. Race did not modify the relation between CEE + MPA use and OAG risk (P interaction = .68).

Conclusions

Analysis suggests that HT containing estrogen, but not a combination of estrogen and progesterone, reduces the risk of incident OAG among African-American women. Further investigation is needed.