D. C. Bauer

Serum 25-Hydroxyvitamin D Concentrations and Risk for Hip Fractures

Context Vitamin D supplementation may help prevent fractures, but the relationship between blood vitamin D concentrations and fracture risk is unclear. Contribution These authors observed an increased risk for hip fracture among women with lower serum 25-hydroxyvitamin D [25(OH) vitamin D] concentrations that was independent of measures of frailty, body mass index, physical function, and falls. Caution The authors did not measure bone mineral density (BMD), so they could not determine whether 25(OH) vitamin D concentrations give different information about fracture risk than that offered by BMD. Implication Low serum 25(OH) vitamin D concentrations seem to be associated with a higher hip fracture risk. The Editors Vitamin D deficiency is common in older adults, especially during the winter (1) and in homebound populations (2), general medical inpatients (3), and community-dwelling women admitted to the hospital with acute hip fracture (4). A recently published evidence-based report on vitamin D and bone health (5) found the level of evidence for an association between serum 25-hydroxyvitamin D [25(OH) vitamin D] concentrations and fracture risk to be inconsistent (5). Since publication of that review, 1 prospective study (6) reported no relationship between serum 25(OH) vitamin D concentrations and fractures, whereas another (7) reported a significantly lower risk for hip fracture with 25(OH) vitamin D concentrations greater than 60 nmol/L. Vitamin D concentration could be associated with fractures in several ways. It could influence muscle strength and balance, both of which contribute to falls and disability (810). The association between 25(OH) vitamin D concentrations and fracture may also be influenced by renal function, because renal insufficiency has been linked to fracture (11) and to vitamin D deficiency (12). Several interactions between vitamin D and estrogen receptors have been described (13); hormone therapy has been shown to reverse abnormalities in vitamin D metabolism (14), and low vitamin D concentrations have also been linked to higher bone turnover (15, 16). Thus, sex-steroid hormones and bone turnover could contribute to the association between 25(OH) vitamin D concentration and fractures. We conducted a nested casecontrol study within the WHI-OS (Womens Health Initiative Observational Study) among 400 case-patients with adjudicated incident hip fracture and 400 control participants. We tested whether low serum 25(OH) vitamin D concentrations are associated with a higher risk for hip fractures in community-dwelling women and whether this relationship may be mediated by poor physical functioning, frailty, falls, sex-steroid hormones, renal function, or bone turnover. Methods Study Population Our study population came from the WHI-OS, a prospective cohort study that enrolled 93676 women between 1994 and 1998 at 40 U.S. clinical centers (age range, 50 to 79 years). Study methods are described in detail elsewhere (17). In brief, women were eligible if they were postmenopausal, were unlikely to move or die within 3 years, were not enrolled in the WHI clinical trials, and were not currently participating in any other clinical trial. The human subjects review committees from each participating institution approved the study. Follow-up and Outcome Ascertainment We sent women questionnaires annually to report any hospitalization and other outcomes, including fractures. As of August 2004, median follow-up duration was 7.1 years (range, 0.7 to 9.3 years). At that time, 3.7% of participants had withdrawn or were lost to follow-up and 5.3% had died. We reviewed medical records to verify cases of hip fracture, and blinded central adjudicators confirmed the cases (18). We excluded patients with pathologic hip fractures. Nested CaseControl Study Design The present study is a casecontrol study nested within the prospective design of WHI-OS. We excluded women who had a history of hip fracture; were receiving hormone therapy up to 1 year before enrollment; or were currently receiving androgens, selective estrogen receptor modulators, antiestrogens, or other osteoporosis treatments (bisphosphonates, calcitonin, or parathyroid hormone). We also excluded women with insufficient serum stored or of unknown ethnicity, leaving 39793 eligible participants. Of these, 404 women had a hip fracture. We randomly selected 400 of these women to form the incident hip fracture group. For each case-patient, we selected 1 control participant who was within 1 year of the case-patients age at screening, was of matching race or ethnicity, and had their blood drawn within 120 days of the case-patients blood draw date; 99% of case-patients and control participants were matched within 30 days. Baseline Clinical Variables We divided clinical centers into 3 geographic regions on the basis of latitude: northern (>40 N), middle (35 to 40 N), and southern (<35 N). We ascertained all covariates at baseline. Clinic interviewers recorded current use of prescription medications by direct inspection of medicine containers. We entered prescription names into the WHI database and assigned drug codes by using Medispan software (First DataBank, San Bruno, California). Average amounts of elemental calcium and vitamin D preparations were entered directly from supplement containers. Dietary intakes of calcium and vitamin D were assessed by using a semiquantitative food-frequency questionnaire (19). Total calcium and vitamin D intake was defined as the sum of diet and supplements. We used questionnaires to ascertain date of birth, race or ethnicity, age at menopause, history of any fracture after age 55 years, smoking, parental history of hip fracture, self-rated health status, and alcohol consumption. We classfied physical activity on the basis of frequency and duration of walking and mild, moderate, and strenuous activities in the previous week. We calculated kilocalories of energy expended in 1 week as the metabolic equivalent (kcal hours/week per kg) (20). We measured physical function by using the RAND Short Form-36 physical function scale, which comprises 10 items measuring whether health now limits physical function in moderate or vigorous activity (2 items); strength to lift, carry, stoop, bend, or stair climb (4 items); ability to walk various distances without difficulty (3 items); and self-care (1 item) (21). The scale is scored from 0 to 100, with higher scores indicating better physical function. We compared women with a score greater than 90 versus those with a score less than or equal to 90, a cutoff value corresponding to the median score. We computed a frailty score, which included self-reported muscle weakness and impaired walking speed (RAND Short Form-36 physical function scale score <75), exhaustion (RAND Short Form-36 vitality scale score <55), low physical activity (lowest quartile of physical activity), and unintended weight loss between baseline and 3 years of follow-up (22). A woman was considered frail if she reported 3 or more of these indicators. Weight was measured on a balance-beam scale with the participant dressed in indoor clothing without shoes. Height was measured by using a wall-mounted stadiometer. Body mass index was calculated as weight (in kg) divided by height (in m2). Laboratory Procedures Laboratory personnel blinded to casecontrol status obtained a 12-hour fasting blood sample at the baseline visit, which was processed and stored at 80C according to strict quality control procedures (23). Serum 25(OH) vitamin D concentrations and sex-steroid hormone levels were measured at the Reproductive Endocrine Research Laboratory at the University of Southern California. 25-Hydroxyvitamin vitamin D was measured by using a radioimmunoassay with DiaSorin reagents (DiaSorin, Stillwater, Minnesota). The sensitivity of the assay was 3.75 nmol/L. The interassay coefficients of variation were 11.7%, 10.5%, 8.6%, and 12.5% at 14.0, 56.8, 82.5, and 122.5 nmol/L, respectively. Estradiol and testosterone concentrations were quantified by using sensitive and specific radioimmunoassays after organic solvent extraction and celite column partition chromatography (2427). The intra- and interassay coefficients of variation were 7.9% and 8% to 12%, respectively, for estradiol and 6% and 10% to 12%, respectively, for testosterone. We calculated bioavailable hormone concentrations by using mass action equations (2830). We measured sex hormonebinding globulin by using a solid-phase, 2-site chemiluminescent immunoassay. The intra- and interassay coefficients of variation were 4.1% to 7.7% and 5.8% to 13%, respectively. Serum cystatin C, a marker of renal function that is independent of age and weight, was measured at Medical Research Laboratories International, Highland Heights, Kentucky, by using the Dade Behring BN-II nephelometer and Dade Behring reagents (Dade Behring, Ramsey, Minnesota) in a particle-enhanced immunonepholometric assay. Serum C-terminal telopeptide of type I collagen and aminoterminal procollagen extensions propeptide were measured by immunoassay (Synarc, Lyon, France). Statistical Analysis We used chi-square and t tests to compare baseline characteristics between case-patients with hip fracture and matched control participants. We assigned 25(OH) vitamin D concentrations to quartile categories defined on the basis of the distribution in the control participants. To further assess confounding, we compared baseline characteristics across quartiles of 25(OH) vitamin D concentrations in case-patients and control participants combined. We calculated the P values for trend by using logistic regression and coding the variable of interest as a continuous variable. We assessed the association between serum 25(OH) vitamin D concentrations and incident hip fracture in conditional logistic regression models that retained the matched casecontrol design. We first examined the unadjusted associations and then adjusted for age, b

Added Value of Physical Performance Measures in Predicting Adverse Health‐Related Events: Results from the Health, Aging and Body Composition Study

OBJECTIVES: To determine how three different physical performance measures (PPMs) combine for added utility in predicting adverse health events in elders.

Clinical Use of Biochemical Markers of Bone Remodeling: Current Status and Future Directions

Abstract: Biochemical markers of bone turnover provide a means of evaluating skeletal dynamics that complements static measurements of bone mineral density (BMD). This review evaluates the use of commercially available bone turnover markers as aids in diagnosis and monitoring response to treatment in patients with osteoporosis. High within-person variability complicates but does not preclude their use. Elevated bone resorption markers appear to be associated with increased fracture risk in elderly women, but there is less evidence of a relationship between bone formation markers and fracture risk. The critical question of predicting fracture efficacy with treatment has not been answered. Changes in bone markers as currently determined do not predict BMD response to either bisphosphonates or hormone replacement therapy. Single measurements of markers do not predict BMD cross-sectionally (except possibly in the very elderly), or change in BMD in individual patients, either treated or untreated. On the other hand, research applications of bone turnover markers are of value in investigating the pathogenesis and treatment of bone diseases. Markers have potential in the clinical management of osteoporosis, but their use in this regard is not established. Additional studies with fracture endpoints and information on negative and positive predictive value are needed to evaluate fully the utility of bone turnover markers in individual patients.

Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects

Background: Inflammatory markers are increased in chronic obstructive pulmonary disease (COPD) and are hypothesised to play an important part in muscle dysfunction and exercise intolerance. Methods: The Health Aging and Body Composition (Health ABC) study is a prospective observational cohort of well functioning individuals aged 70–79 years. A cross sectional analysis of the baseline data was conducted to examine the association between inflammatory markers and ventilatory limitation, muscle strength, and exercise capacity. These associations were compared in participants with and without obstructive lung disease (OLD). Results: Of the 3075 participants enrolled in the Health ABC cohort, OLD was identified by spirometric testing in 268 participants and 2005 participants had normal spirometric results. Of the participants with OLD, 35%, 38%, and 27% participants had mild, moderate, and severe OLD, respectively. Participants with OLD had lower quadriceps strength (102.5 Nm v 108.9 Nm, p = 0.02), lower maximum inspiratory pressure (64.7 cm H2O v 74.2 cm H2O, p<0.0001), higher systemic interleukin (IL)-6 levels (2.6 pg/ml v 2.2 pg/ml, p<0.0001), and higher C-reactive protein (CRP) levels (3.5 mg/l v 2.5 mg/l, p<0.0001) than those with normal spirometry. In participants with OLD and those with normal spirometry, forced expiratory volume in 1 second (FEV1) was associated with IL-6 (adjusted regression coefficients (β) = −5.3 (95% CI −9.1 to−1.5) and −3.1 (95% CI −4.3 to −1.9), respectively). IL-6 and TNF were also associated with quadriceps strength among participants with OLD and those with normal spirometry (β = −6.4 (95% CI −12.8 to −0.03) and −3.4 (95% CI −5.4 to −1.3), respectively, for IL-6 and β = −10.1 (95% CI −18.7 to −1.5) and −3.8 (95% CI −7 to −0.6), respectively, for TNF). IL-6, quadriceps strength, and maximum inspiratory pressures were independent predictors of reduced exercise capacity in both groups. Conclusions: In well functioning elderly subjects with or without OLD, IL-6 is associated with reduced FEV1, quadriceps strength, and exercise capacity.

Subclinical Thyroid Dysfunction and Incident Hip Fracture in Older Adults

BACKGROUND Subclinical thyroid dysfunction is common in older adults and affects bone metabolism, but its effects on fracture risk have not been reported. We sought to determine prospectively whether older men and women with subclinical hyperthyroidism or hypothyroidism have an increased risk of hip fracture. METHODS Prospective cohort of 3567 US community-dwelling adults, 65 years or older, with biochemically defined subclinical thyroid dysfunction or euthyroidism was enrolled from June 10, 1989, through May 30, 1990, and followed up through 2004. Main outcome measures included incidence and hazard ratios (HRs), with 95% confidence intervals (CIs), of confirmed incident hip fractures for groups with subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroidism as defined at baseline. RESULTS During 39 952 person-years (median follow-up, 13 years), hip fracture incidence (per 1000 men-years) was 13.65 in men with subclinical hyperthyroidism (n = 29) and 10.27 in men with subclinical hypothyroidism (n = 184), both greater than 5.0 in men with euthyroidism (n = 1159). Men with subclinical hypothyroidism had a multivariable-adjusted HR of 2.31 (95% CI, 1.25-4.27); those with subclinical hyperthyroidism, 3.27 (0.99-11.30). After excluding those with baseline use of thyroid-altering medications, men with endogenous subclinical hyperthyroidism had a higher HR of 4.91 (95% CI, 1.13-21.27), as did men with endogenous subclinical hypothyroidism (2.45, 1.27-4.73). Hip fracture incidence (per 1000 women-years) was 8.93 in women with subclinical hypothyroidism (n = 359) and 10.90 in women with subclinical hyperthyroidism (n = 142) compared with 10.18 in women with euthyroidism (n = 1694). No clear association between subclinical dysfunction and fracture was observed in women. CONCLUSIONS Older men with subclinical hyperthyroidism or hypothyroidism are at increased risk for hip fracture. Whether treatment of the subclinical syndrome reduces this risk is unknown.

Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study

We used data from a longitudinal observation study to determine whether markers of cartilage turnover could serve as predictors of cartilage loss on magnetic resonance imaging (MRI). We conducted a study of data from the Boston Osteoarthritis of the Knee Study (BOKS), a completed natural history study of knee osteoarthritis (OA). All subjects in the study met American College of Rheumatology criteria for knee OA. Baseline and follow-up knee magnetic resonance images were scored for cartilage loss by means of the WORMS (Whole Organ Magnetic Resonance Imaging Score) semiquantitative grading scheme. Within the BOKS population, 80 subjects who experienced cartilage loss and 80 subjects who did not were selected for the purposes of this nested case control study. We assessed the baseline levels of cartilage degradation and synthesis products by means of assays for type I and II cleavage by collagenases (Col2:3/4Cshort or C1,2C), type II cleavage only with Col2:3/4Clongmono (C2C), type II synthesis (C-propeptide), the C-telopeptide of type II (Col2CTx), aggrecan 846 epitope, and cartilage oligomeric matrix protein (COMP). We performed a logistic regression to examine the relation of levels of each biomarker to the risk of cartilage loss in any knee. All analyses were adjusted for gender, age, and body mass index (BMI); results stratified by gender gave similar results. One hundred thirty-seven patients with symptomatic knee OA were assessed. At baseline, the mean (standard deviation) age was 67 (9) years and 54% were male. Seventy-six percent of the subjects had radiographic tibiofemoral OA (Kellgren & Lawrence grade of greater than or equal to 2) and the remainder had patellofemoral OA. With the exception of COMP, none of the other biomarkers was a statistically significant predictor of cartilage loss. For a 1-unit increase in COMP, the odds of cartilage loss increased 6.09 times (95% confidence interval [CI] 1.34 to 27.67). After the analysis of COMP was adjusted for age, gender, and BMI, the risk for cartilage loss was 6.35 (95% CI 1.36 to 29.65). Among subjects with symptomatic knee OA, a single measurement of increased COMP predicted subsequent cartilage loss on MRI. The other biochemical markers of cartilage synthesis and degradation do not facilitate prediction of cartilage loss. With the exception of COMP, if changes in cartilage turnover in patients with symptomatic knee OA are associated with cartilage loss, they do not appear to affect systemic biomarker levels.

Volumetric and Areal Bone Mineral Density Measures Are Associated with Cardiovascular Disease in Older Men and Women: The Health, Aging, and Body Composition Study

The associations of volumetric (vBMD) and areal (aBMD) bone mineral density measures with prevalent cardiovascular disease (CVD) and subclinical peripheral arterial disease (PAD) were investigated in a cohort of older men and women enrolled in the Health, Aging, and Body Composition Study. Participants were 3,075 well-functioning white and black men and women (42% black, 51% women), aged 68–80 years. Total hip, femoral neck, and trochanter aBMD were measured using dual-energy X-ray absorptiometry. Quantitative computed tomography was used to evaluate spine trabecular, integral, and cortical vBMD measures in a subgroup (n = 1,489). Logistic regression was performed to examine associations of BMD measures with CVD and PAD. The prevalence of CVD (defined by coronary heart disease, PAD, cerebrovascular disease, or congestive heart failure) was 29.8%. Among participants without CVD, 10% had subclinical PAD (defined as ankle-arm index <0.9). Spine vBMD measures were inversely associated with CVD in men (odds ratio of integral [ORintegral] = 1.34, 95% confidence interval [CI] 1.10–1.63; ORtrabecular = 1.25, 95% CI 1.02–1.53; ORcortical = 1.36, 95% CI 1.11–1.65). In women, for each standard deviation decrease in integral vBMD, cortical vBMD, or trochanter aBMD, the odds of CVD were significantly increased by 28%, 27%, and 22%, respectively. Total hip aBMD was associated with subclinical PAD in men (OR = 1.39, 95% CI 1.03–1.84) but not in women. All associations were independent of age and shared risk factors between BMD and CVD and were not influenced by inflammatory cytokines (interleukin-6 and tumor necrosis factors-α). In conclusion, our results provide further evidence for an inverse association between BMD and CVD in men and women. Future research should investigate common pathophysiological links for osteoporosis and CVD.

The influence of pre-existing diabetes mellitus on the host immune response and outcome of pneumonia: Analysis of two multicentre cohort studies

Background Although diabetes mellitus is implicated in susceptibility to infection, the association of diabetes with the subsequent course and outcome is unclear. Methods A retrospective analysis of two multicentre cohorts was carried out. The effect of pre-existing diabetes on the host immune response, acute organ function and mortality in patients hospitalised with community-acquired pneumonia (CAP) in the GenIMS study (n=1895) and on mortality following either CAP or non-infectious hospitalisations in the population-based cohort study, Health ABC (n=1639) was determined. Measurements included the mortality rate within the first year, risk of organ dysfunction, and immune responses, including circulating inflammatory (tumour necrosis factor, interleukin 6, interleukin 10), coagulation (Factor IX, thrombin–antithrombin complexes, antithrombin), fibrinolysis (plasminogen-activator inhibitor-1 and D-dimer) and cell surface markers (CD120a, CD120b, human leucocyte antigen (HLA)-DR, Toll-like receptor-2 and Toll-like receptor-4). Results In GenIMS, diabetes increased the mortality rate within the first year after CAP (unadjusted HR 1.41, 95% CI 1.12 to 1.76, p=0.002), even after adjusting for pre-existing cardiovascular and renal disease (adjusted HR 1.3, 95% CI 1.03 to 1.65, p=0.02). In Health ABC, diabetes increased the mortality rate within the first year following CAP hospitalisation, but not after hospitalisation for non-infectious illnesses (significant interaction for diabetes and reason for hospitalisation (p=0.04); HR for diabetes on mortality over the first year after CAP 1.87, 95% CI 0.76 to 4.6, p=0.16, and after non-infectious hospitalisation 1.16, 95% CI 0.8 to 1.6, p=0.37). In GenIMS, immediate immune response was similar, as evidenced by similar circulating immune marker levels, in the emergency department and during the first week. Those with diabetes had a higher risk of acute kidney injury during hospitalisation (39.3% vs 31.7%, p=0.005) and they were more likely to die due to cardiovascular and kidney disease (34.4% vs 26.8% and 10.4% vs 4.5%, p=0.03). Conclusions Pre-existing diabetes was associated with a higher risk of death following CAP. The mechanism is not due to an altered immune response, at least as measured by a broad panel of circulating and cell surface markers, but may be due to worsening of pre-existing cardiovascular and kidney disease.

Nulliparity and fracture risk in older women: the study of osteoporotic fractures.

Whether nulliparity increases fracture risk is unclear from prior studies, which are limited by small samples or lack of measured bone mineral density. No study has evaluated whether the effect of parity differs by skeletal site. We prospectively analyzed the relationship of parity to the risk of incident nontraumatic hip, spine, and wrist fractures in 9704 women aged 65 years or older participating in the Study of Osteoporotic Fractures to determine if parity reduces postmenopausal fracture risk, and if so, if this risk reduction is (1) greater at weight‐bearing skeletal sites and (2) independent of bone mineral density. Parity was ascertained by self‐report. Incident hip and wrist fractures were determined by physician adjudication of radiology reports (mean follow‐up, 9.8 years) and spine fractures by morphometric criteria on serial radiographs. The relationship of parity to hip and wrist fracture was assessed by proportional hazards models. Spine fracture risk was evaluated by logistic regression. Compared with parous women, nulliparous women (n = 1835, 19%) had an increased risk of hip and spine, but not wrist, fractures. In multivariate models, parity remained a significant predictor only for hip fracture. Nulliparous women had a 44% increased risk of hip fractures independent of hip bone mineral density (hazards ratio, 1.44; 95% CI, 1.17‐1.78). Among parous women, each additional birth reduced hip fracture risk by 9% (p = 0.03). Additionally, there were no differences in mean total hip, spine, or radial bone mineral density values between nulliparous and parous women after multivariate adjustment. In conclusion, childbearing reduces hip fracture risk by means that may be independent of hip bone mineral density.

Is age-related decline in lean mass and physical function accelerated by obstructive lung disease or smoking?

Background and aims Cross-sectional studies suggest that obstructive lung disease (OLD) and smoking affect lean mass and mobility. A study was undertaken to investigate whether OLD and smoking accelerate the ageing-related decline in lean mass and physical functioning. Methods 260 patients with OLD (mean±SD forced expiratory volume in 1 s (FEV1) 63±18% predicted), 157 smoking controls (FEV1 95±16% predicted), 866 former-smoking controls (FEV1 100±16% predicted) and 891 never-smoking controls (FEV1 104±17% predicted) participating in the Health, Aging and Body Composition (ABC) Study were studied. At baseline the mean age was 74±3 years and participants reported no functional limitations. Baseline and 7-year longitudinal data of body composition (by dual-energy x-ray absorptiometry), muscle strength (by hand and leg dynamometry) and Short Physical Performance Battery (SPPB) were investigated. Results Compared with never-smoking controls, patients with OLD and smoking controls had a significantly lower weight, fat mass, lean mass and bone mineral content (BMC) at baseline (p<0.05). While the loss of weight, fat mass, lean mass and strength was comparable between patients with OLD and never-smoking controls, the SPPB declined 0.12 points/year faster in men with OLD (p=0.01) and BMC declined 4 g/year faster in women with OLD (p=0.02). In smoking controls only lean mass declined 0.1 kg/year faster in women (p=0.03) and BMC 8 g/year faster in men (p=0.02) compared with never-smoking controls. Conclusions Initially well-functioning older adults with mild-to-moderate OLD and smokers without OLD have a comparable compromised baseline profile of body composition and physical functioning, while 7-year longitudinal trajectories are to a large extent comparable to those observed in never-smokers without OLD. This suggests a common insult earlier in life related to smoking.