Methodologic issues in clinical trials for prevention or risk reduction in osteoarthritis.

The design and execution of prevention trials for OA have methodological issues that are distinct from trials designed to impact prevalent disease. Disease definitions and their precise and sensitive measurement, identification of high-risk populations, the nature of the intervention (pharmaceutical, nutraceutical, behavioral) and its potential pleiotropic impacts on other organ systems are critical to consider. Because prevention trials may be prolonged, close attention to concomitant life changes and co-morbidities, adherence and participant retention in the trial is of primary importance, as is recognition of the potential for "preventive misconception" and "behavioral disinhibition" to affect the ability of the trial to show an effect of the intervention under study. None of these potential pitfalls precludes a successful and scientifically rigorous process and outcome. As technology improves the means to measure and predict the OA process and its clinical consequences, it will be increasingly possible to screen individuals for high-risk phenotypes, combining clinical factors with information from imaging, genetic, metabolic and other biomarkers and to impact this high-risk condition to avoid or delay OA both structurally and symptomatically.

Longitudinal changes of serum COMP and urinary CTX-II predict X-ray defined knee osteoarthritis severity and stiffness in women.

OBJECTIVE: To ascertain the predictive role of longitudinally acquired biochemical measures of cartilage turnover in relation to X-ray defined knee osteoarthritis (OAK), knee pain and functioning. METHODS: This is a feasibility study based on 72 enrollees of the Michigan site of Study of Women's Health Across the Nation (SWAN), a longitudinal, population-based cohort study with 11 annual visits to characterize health at the mid-life. At visits in 1996, 1998 and 2007, radiographs were evaluated for the presence of OAK [>or=2 on the Kellgren and Lawrence (K-L) scale]. Knee pain and stiffness were assessed by interview. Functioning was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Cartilage oligomeric matrix protein (COMP) and Type II collagen telopeptides (CTX-II) were assayed in serum and urine samples collected on alternate years from 1997 to 2006. We related trajectories of the cartilage biochemical markers from these five time points to OAK severity (no OAK, K-L score<2; mild OAK, K-L score=2; moderate/severe OAK, K-L score=3 or 4), pain, stiffness, or functioning, using longitudinal non-linear mixed modeling. RESULTS: The 2007 prevalence of X-ray defined OAK was 50% in these 72 women. Upward trajectories of COMP (P=0.02) and CTX-II (P=0.006) were associated with increased OAK severity and body size. COMP trajectories were associated with pain and stiffness, but not functioning. CTX-II trajectories were associated with stiffness scores, but not knee pain or functioning scores. CONCLUSION: Multiple, biennial measures of COMP or CTX-II taken over a 10-year period were predictive of subsequent OAK and knee stiffness.

Testosterone, sex hormone-binding globulin and free androgen index among adult women: chronological and ovarian aging.

BACKGROUND: In this study, levels and rates of change in total testosterone (T), sex hormone-binding globulin (SHBG) and free androgen index (FAI) were related to chronological age and to the final menstrual period (FMP) as an indicator of ovarian aging. METHODS: Data were annually acquired over a 15-year period in 629 women of the Michigan Bone Health and Metabolism Study cohort. Data were censored for hormone therapy use. Endogenous androgen patterns over time were described with stochastic processes and bootstrapping. RESULTS: With ovarian aging, T levels rose from a mean of 18 ng/dl commencing 10 years prior to the FMP to 27 ng/dl at the FMP. Over the 20-year period encompassing the FMP, modeled mean SHBG levels changed from 58 to 34 nM and the FAI ratio increased from 1.6 to 2.9 in a non-linear manner. With chronological aging, total T levels increased (P < 0.0001) from 43 to 50 years, but not thereafter. SHBG declined steadily with age with a modestly greater rate of change between 49 and 54 years. The FAI increased from 1.3 to 2.5 from 34 to 58 years. CONCLUSIONS: T increased from approximately age 40 until the FMP whereas SHBG had rate of change patterns reflecting both chronological and ovarian aging components. These data provide new insight into the endogenous androgen patterns at mid-life.

Factors related to declining luteal function in women during the menopausal transition.

CONTEXT: Reproductive hormones are incompletely characterized during the menopause transition (MT). HYPOTHESIS: Increased anovulation and decreased progesterone accompany progress through the MT. DESIGN: The Daily Hormone Study (DHS) of the Study of Women's Health Across the Nation (SWAN) included 848 women aged 43-53 yr at baseline who collected daily urine for one cycle or up to 50 d annually for 3 yr. MAIN OUTCOME MEASURES: LH, FSH, estrone conjugates, and pregnanediol glucuronide levels were assessed. Cycles were classified by presumed luteal (ovulatory) status and bleeding. Hormones were related to time in study, age, menopausal status, and selected variables. RESULTS: Ovulatory-appearing cycles declined from 80.9% at baseline to 64.7% by the third assessment (H3). Cycles presumed anovulatory and not ending with bleeding by 50 d (anovulatory/nonbleeding) increased from 8.4 to 24% by H3 and were associated with progress to early perimenopause [odds ratio (OR) = 2.66; confidence interval (CI) = 1.17-6.04] or late perimenopause (OR = 56.21; CI = 18.79-168.12; P < 0.0001), African-American ethnicity (OR = 1.91; CI = 1.06-3.43), and less than high school education (OR = 3.51; CI = 1.62-7.62). Anovulatory cycles ending with bleeding remained at about 10% from baseline to H3; compared with ovulatory cycles, they were associated with obesity (OR = 4.68; CI = 1.33-16.52) and more than high school education (OR = 2.12; CI = 1.22-3.69; P = 0.02). Serum estradiol in both the highest and lowest categories was associated with anovulatory/nonbleeding collections. Pregnanediol glucuronide decreased 6.6% for each year on study. Insulin sensitivity measures did not relate strongly to menstrual cycle hormones. CONCLUSIONS: Anovulation without bleeding represents progression of the MT. A small but detectable decrease in luteal progesterone excretion occurs as women progress through the MT.

Effects of smoking on the development of female reproductive cancers.

The effect of smoking on the development of breast, endometrial, and ovarian cancers is evaluated among cases identified between November 1980 and July 1982 in the Iowa Surveillance, Epidemiology, and End Results Cancer Registry. Population-based, age-frequency matched controls were also evaluated, adjusting for potential confounders: Age, age of menarche, age of menopause, duration of menses, female family reproductive cancer history, obesity, parity, infertility, and lifetime steroid hormone use. Logistic regression analyses of total pack-years of cigarette exposure indicate that smoking is not significantly related to the development of breast cancer [relative risk (RR) = .99; confidence interval (CI) = .97, 1.02] or ovarian cancer (RR = 1.00; CI = 1.00, 1.00). Among women with endometrial cancer, the risk for those who smoke is increased among premenopausal women (RR = 1.27; CI = .65, 2.59) and decreased among postmenopausal women (RR = .41; CI = .16, 1.04).

Lactose intolerance among Mexican Americans.

Thirty-three Mexican Americans between the ages of 9 and 60 were interviewed and tested for lactose intolerance. The participants of the study included 16 children and 17 persons not related by birth, including the parents of the children. Determination of lactose intolerance was based on a rise of less than 25mg/100 ml of blood glucose as measured by an Ames Dextrostix/Reflectance Meter following consumption of a lactose load. Forty-seven percent of the 17 nonrelated Mexican Americans were lactose intolerant. There was a marked relationship between low rise in blood glucose and symptoms of diarrhea, flatulence, and distention. Sixteen children from four families had an incidence of 50 per cent intolerance. The findings of intolerance in two successive generations of three families and in both sexes of the families adds support to the contention that lactose intolerance has a genetic basis, without sex predilection.

Relationship between 1,25-dihydroxyvitamin D and blood pressure in a geographically defined population.

In a cross-sectional, population-based study we measured casual, seated blood pressure with a random-zero sphygmomanometer and 1,25-dihydroxyvitamin D (1,25-[OH]2D) with a protein-binding assay in 373 women aged 20-80 y. 1,25-(OH)2D, an active metabolite that regulates serum calcium, was associated significantly and positively with systolic blood pressure (p = 0.020) and diastolic blood pressure (p = 0.003) after adjustment for age, Quetelet's index (a measure of obesity), and current thiazide use. A model including age, Quetelet's index, current thiazide use, and 1,25-(OH)2D explained 37% of the variability in systolic blood pressure observations, of which 7% of variability was explained by 1,25-(OH)2D. In this geographically defined population of women, the variability of blood-pressure measurements attributable to 1,25-(OH)2D was of the same order of magnitude as that attributable to Quetelet's index.

Retinol, supplemental vitamin A and bone status.

Studies of hypervitaminosis A in animals and anecdotal reports of accidental vitamin A poisoning in humans suggest impairment of bone remodeling and increased numbers of fractures. Because of the widespread use of high-dose vitamin A supplements which may produce subclinical hypervitaminosis associated with decreased bone mass and increased risk of fracture, we studied the relationship between current vitamin A supplement use, serum retinol levels, radial bone mass and fracture history in a geographically-defined population of 246 postmenopausal women, 55-80 years of age. More than 36% of this population used a vitamin A supplement with 8% of these consuming an amount in excess of 2000 retinol equivalents (RE)/day. Serum retinol was measured using high-pressure liquid chromatography and radial bone mass was measured using single photon absorptiometry. After controlling for age, current estrogen replacement, and current thiazide antihypertensive use, we observed no statistically significant relationship between vitamin A supplement use or serum retinol with radial bone mass or fractures.

Bone loss in adolescent and adult pregnant women.

OBJECTIVE: To determine the amount of change in bone ultrasound measures among pregnant adolescent girls and women and whether that change was associated with adolescence, maternal growth during pregnancy, limited weight gain during pregnancy, hypertension in pregnancy, or poor diet. METHODS: We used bone ultrasound measurements of attenuation and sound velocity to assess changes in quantitative ultrasound indices of 252 pregnant adolescent girls and women age 12-34 years. Bone ultrasound measurement of the os calcis was performed at 16 +/- 7 weeks' gestation (mean +/- standard deviation and 6 +/- 1 weeks postpartum. RESULTS: On average, the bone quantitative ultrasound index was 3.6% lower 6 weeks postpartum than at entry into care (P <.001). Nulliparous patients had significantly greater bone loss than did parous subjects. Still-growing adolescents had greater quantitative ultrasound index decreases than did grown women (-5.5% versus -1.9%, P <.02). Patients in the upper tertile of baseline quantitative ultrasound index lost more bone than did patients in the lower tertile (-5% versus 0.5%, P <.02). Pregravid weight, weight change during pregnancy, gynecologic age, and age at menarche predicted bone change in subgroups defined by parity or age; however, none of the differences in those variables were statistically significant. Greater dietary calcium intake, less physical activity, and pregnancy hypertension and preeclampsia were not associated with bone change. CONCLUSION: There has been inconsistent evidence of maternal bone loss during pregnancy. The findings of this study challenge the assumption that because of increased calcium absorption from the maternal intestine, no transitory bone loss occurs in pregnancy. The amount of bone loss among growing adolescents and nulliparous patients was consistent with the demands of fetal mineralization and the continued demands of the maternal skeleton during growth.

Development and critical evaluation of the food nomogram.

The historical development and validation of the Food Nomogram is described to show the scientific basis of formulas to predict caloric need. Prediction of basal caloric need in nutritional assessment using formulas such as that represented by the Mayo Foundation Nomogram is based on surface area and standardized kilocalories per unit of surface area. Though these quantities do reflect error, major discrepancies evolve with prediction of total need, including kilocalories for activity. In spite of these limitations, predicting formulas have been valuable tools in predicting total caloric need. Three formulas are contrasted and found reliable.

Functional limitations in women at midlife: the role of health conditions, behavioral and environmental factors.

This study examined risk factors for functional limitations in a community-based sample of 16,065 women from 5 ethnic groups, aged 40-55 years, enrolled in the Study of Women's Health Across the Nation. Almost 20% of this sample reported physical-functioning limitations. Functional limitations were associated with numerous disease conditions, including high blood pressure, diabetes, heart attack or angina, arthritis, osteoporosis, and cancer, and with several behavioral and environmental risk factors, including body mass index, difficulty paying for basics, and high levels of perceived stress. Consistent with findings in older women, this study shows that in addition to health conditions, potentially modifiable risk factors including high body mass index, difficulty paying for basics, and high levels of stress are associated with physical-functioning limitations of women at midlife.

Improving the assessment of gestational age in a Zimbabwean population.

OBJECTIVES: To evaluate the performance and the utility of using birthweight-adjusted scores of Dubowitz and Ballard methods of estimating gestational age in a Zimbabwean population. METHOD: The Dubowitz and the Ballard methods of estimating gestational age were administered to 364 African newborn infants with a known last menstrual period (LMP) at Harare Maternity Hospital. RESULTS: Both methods were good predictors of gestational age useful in differentiating term from pre-term infants. Our regression line was Y((LMP gestational age))=23.814+0.301*score for the Dubowitz and Y((LMP gestational age))=24.493+0.420*score for the Ballard method. Addition of birthweight to the regression models improved prediction of gestational age; Y((LMP gestational age))=23.512+0.219*score+0.0015*grams for Dubowitz and Y((LMP gestational age))=24.002+0.292*score+0.0016*grams for Ballard method. CONCLUSIONS: We recommend the use of our birthweight-adjusted maturity scales; the Dubowitz for studies of prematurity, and the Ballard for routine clinical practice.

BMI vs. body composition and radiographically defined osteoarthritis of the knee in women: a 4-year follow-up study.

OBJECTIVE: To elucidate the role of body mass index (BMI) and knee osteoarthritis (OAK) by evaluating measures of body composition including fat mass and skeletal muscle mass (SMM). METHODS: Data are from 541 women enrolled in the Michigan Bone Health Study, a longitudinal, population-based study. At visits in 1998 and 2002, radiographs were taken of both knees and were evaluated for the presence of OAK (>or=2 on the Kellgren-Lawrence (K-L) scale). Joint space width (JSW) was measured with electronic calipers. Fat mass and SMM were determined using bioelectrical impedance analysis. RESULTS: In 2002, the prevalence of OAK was 11% in this population of women whose mean age was 47 years. Fat mass, lean mass, SMM, waist circumference and BMI were greater in women with OAK compared to those without OAK. In multiple variable analyses adjusted for age, fat mass and SMM explained OAK prevalence and increasing OAK severity better than models with BMI; further SMM explained more variation than did fat mass. SMM was positively associated with level of left and right medial JSW while there was no consistent association of JSW and BMI or fat mass. CONCLUSION: Fat mass and SMM were associated with K-L OAK score and the amount of joint space, with more variation explained by SMM. SMM was highly associated with JSW. Therefore, though obesity, frequently characterized by BMI, is a frequently reported risk factor for OAK, this mis-attribution may mean that interventions that focus on weight loss as treatment for osteoarthritis should be aware that this may negatively impact muscle mass.

Recommendations from a multi-study evaluation of proposed criteria for staging reproductive aging.

In 2001, the Stages of Reproductive Aging Workshop (STRAW) proposed bleeding and endocrine criteria for defining the early and late menopausal transition stages. Based on expert consensus, STRAW recommended a shorter interval of amenorrhea than the commonly used 90-day amenorrhea criteria for late transition and a >7-day change in cycle length for early transition. The ReSTAGE collaboration used prospective menstrual calendar data from four cohorts (TREMIN, Melbourne Women's Midlife Health Project, Seattle Midlife Women's Health Study, and Study of Women's Health Across the Nation) to quantitatively evaluate STRAW's recommendations. This empirical assessment supported the STRAW recommendations that (1) > or =60 days of amenorrhea be used to define the late menopausal transition and (2) that early transition is consistent with a persistent 7 or more day difference in length of consecutive cycles. Serum follicle stimulating hormone (FSH) values > or =40 IU/l was an independent marker of the transition and, when occurring together with a bleeding marker, increased prediction of final menstrual period. Such a FSH criterion could be incorporated into the STRAW paradigm to facilitate prediction of proximity of the final menstrual period.

Lower peak bone mass and its decline.

There is evidence that two-thirds of the risk of osteoporotic fracture can be predicted from the pre-menopausal bone mineral density. The frequency of osteoporosis in older women may be modifiable by implementing invention strategies in the pre- and peri-menopausal periods. Lower peak bone mineral density and bone loss can be identified in women with altered reproductive hormone or calciotrophic hormone concentrations, or selected lifestyle practices. Alterations in reproductive hormones may occur in adolescence (from an early age of pregnancy or the amenorrhoea of anorexia nervosa or exercise), in the pre-menopause (nulliparity, oophorectomy, early ovarian failure or marginal hormonal status) or in the peri-menopause. Alterations in calciotrophic hormone concentrations include corticosteroid therapy and breast cancer treatment. Lifestyle risk factors include the misuse of alcohol and possibly smoking, physical inactivity or an imbalance in dietary intake. Effective intervention currently consists of treating underlying conditions and monitoring high-risk groups.

The menopause transition and the aging process: a population perspective.

The menopause transition period, extending from active reproductive capacity with well-characterized hormone profiles through reproductive senescence, has been less well studied than any other period of the life span except extreme old age. Yet, for the gerontologist, this is an important period to understand for at least two reasons. First, during this period changes in the neuroendocrine system and ovary may provide a model for the study of other aging-related processes. Second, specific characteristics of this transitional period (including duration, intensity, and age at menopause) may be considered "aging", and influence short-term health and quality-of-life status, as well as life expectancy. In addition to discussing the menopause transition in terms of age and culture, we include some of the theories and conceptual models that can influence the nature and interpretation of information from this time period, and its ultimate impact on health and health practice.

The natural history of emergent osteoarthritis of the knee in women.

OBJECTIVE: We assessed the probability that mid-aged women with a Kellgren and Lawrence (K-L) score of 1 are likely to progress to a score of 2 or regress to a score of zero at a second time point, 2-3 years later. METHODS: Osteoarthritis (OA) of measurements (weight-bearing X-rays and interviews) were undertaken in women from the Southeast Michigan population who were > or =40 years of age, and who participated in both the 1995 and 1998 measurements (N=679). RESULTS: Of the 17.1 % of women with a 1995 K-L score of 1 in their right knee, 37.1% had a K-L score of 1 in 1998 while 32.8 % had a score of > or =2 and 30.2% had a score of zero. For 26.0% of women, the score progressed by at least one unit over the 2.5 year period whereas scores for only 7.0% of women regressed in the same time period. Women who had a K-L score of 1 in the right knee in 1995 were 2.5 times more likely to have a K-L score of 1 in 1998 (95% CI=1.6-3.8); and were 2.2 times more likely to have a K-L score of 2 or greater (95% CI=1.4-3.5) in 1998 compared with other scores. These women were 74% less likely to have a score of zero in 1998 (95% CI=0.2-0.4). Further, other risk factors, specifically age and BMI were predictors of increasing K-L grade in 1998. CONCLUSION: These findings suggest that a score of 1 is part of the advancement to emergent OAK; and suggest the following criteria to characterize individuals who are at an intervenable stage on the pathway toward OAK: age > or =40, BMI > or =30, and K-L score of > or =1. From the perspective of both the individual and the examiner, these assessment characteristics are relatively simple to assess clinically.

Relationship of body composition measures and menstrual cycle length.

Menstrual cycle disruption has been observed in women with low body weight due to anorexia nervosa, or to athletics. However, the association of the full range of body composition measures with cyclicity has not been determined. Therefore, the purpose of this study was to determine the strength and direction of association between body composition measures (Quetelet Index, body fat mass, and body lean mass) and menstrual cycle length. Menstrual cycle diaries were distributed to women aged 24-45 in the Michigan Bone Health Study beginning in 1992. A total of 4392 menstrual cycles from 436 women were analysed from the first year of this ongoing study. Body composition measures (Quetelet Index or body mass index (kg/m2), body fat mass and body lean mass (kg) were obtained at annual clinic visits by means of dual-energy X-ray absorptiometry (DEXA). Mixed-model analyses were used to determine the degree of association between menstrual cycle length and body composition measures, controlling for age. There was a significant positive association with cycle length for each body composition measure. The relationship between each body composition measure and cycle length was nonlinear with the longest mean cycle lengths occurring with greater BMI, body fat mass or body lean mass. Longer cycle length was also noted at the lowest levels of BMI and body fat mass. These results may account for the purported later age at menopause for obese women.

Premature menopause in a multi-ethnic population study of the menopause transition.

BACKGROUND: Premature menopause, also termed premature ovarian failure (POF), is characterized by cessation of menstruation before the age of 40 years. Little information is available on the general prevalence of POF or on the prevalence by ethnic group. There is also a lack of information on the association of POF with health indicators. METHODS: A cross-sectional survey of women aged 40-55 years was conducted at seven sites in the USA to determine eligibility for a community-based, multi-ethnic longitudinal study of the peri-menopause (The Study of Women Across the Nation, SWAN). Interview data were used to (i). determine the prevalence of self-reported POF overall and by ethnic group, and (ii). assess the association of POF with selected self-reported variables related to health. Cases of POF included only women with no discernible cause for POF. RESULTS: POF was reported by 1.1% (126/11 652) of women. By ethnicity, 1.0% (95% CI, 0.7-1.4) of Caucasian, 1.4% (95% CI, 1.0-2.1) of African American, 1.4% (95% CI, 0.8-2.5) of Hispanic, 0.5% (95% CI, 0.1-1.9) of Chinese and 0.1% (95% CI, 0.02-1.1) of Japanese women experienced POF. The differences in frequency across ethnic groups were statistically significant (P = 0.01). Only Caucasian, African American and Hispanic women were included in further analyses since too few Asian women had POF. In a multivariate model, POF was independently associated with osteoporosis, female hormone use (excluding oral contraceptives), higher body mass index (BMI) and current smoking after adjustment for education level, ability to pay for basics, site and age at interview. In Caucasian women, use of female hormones, osteoporosis, severe disability and smoking were significantly associated with POF. In contrast, POF in African American women was associated with higher BMI and female hormone use, but not osteoporosis. CONCLUSIONS: The prevalence of POF appears to vary by ethnicity. Health factors associated with POF also vary by ethnicity but because of the cross-sectional study design, it is not possible to determine cause and effect relationships. Health risks of POF would benefit from further study.

Joint influence of fat and lean body composition compartments on femoral bone mineral density in premenopausal women.

Body composition (fat and lean compartments) and bone mineral density were measured in 246 healthy premenopausal women, aged 20-40 years, residing in Tecumseh, Michigan. Body composition was measured using four-point bioelectrical impedance and values for fat and lean compartments categorized into tertiles. Additionally, each woman was classified into one of nine different cells based on her location within a 3 x 3 table which reflects the joint distribution of both fat and lean compartments. Bone mineral density of the proximal femur, including the femoral neck and trochanter, was measured using dual photon densitometry. The mean femoral neck bone mineral density values increased significantly and linearly for each tertile of muscle mass (0.90, 0.95, and 1.02 g/cm2, p less than 0.0002). Femoral bone mineral density increased significantly but not linearly as the fat compartment progressed from the lowest to the highest tertile (0.95, 0.93, and 0.99 g/cm2). Bone mineral density of the proximal femur was similar and significantly greater in the high muscle/low fat and high muscle/high fat body composition subgroups compared with bone mineral density in the seven other groups. However, women in the high muscle/low fat subgroup had substantially lower mean weight (67 vs. 91 kg, p less than 0.0001) and mean Quetelet index (22.1 vs. 33.7 kg/m2, p less than 0.0001) than women in the high muscle/high fat subgroup. Bone mineral density values were similar and significantly lower in the following body composition cells: low muscle/low fat, low muscle/medium fat, and low muscle/high fat. Similar findings were observed at the trochanteric site. Low muscle is a risk factor for low bone mineral density in young adult women while higher fat is protective only when associated with substantial muscle.