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.

Adipocytokine and ghrelin levels in relation to cardiovascular disease risk factors in women at midlife: longitudinal associations.

BACKGROUND: There are limited data concerning the relationships between changes in adipocytokines and cardiovascular disease (CVD) risk factors. OBJECTIVE: To examine the longitudinal associations between leptin, adiponectin, resistin and ghrelin levels and CVD risk factor levels in women at midlife. DESIGN: Prospective, observational study. SUBJECTS AND MEASUREMENTS: Leptin, adiponectin, resistin, ghrelin levels and CVD risk factors were measured in specimens collected from 40 women at 3 points in time corresponding to the pre-, peri- and postmenopause stages of their natural menopause transition. RESULTS: In longitudinal analyses adjusted for CVD risk factors and leptin at the previous menopausal stage, aging, education, smoking and physical activity, greater increases in leptin over the menopause transition were associated with greater decreases in high-density lipoprotein cholesterol (HDL-c) and greater increases in diastolic blood pressure, glucose, insulin and insulin resistance (all P < 0.05). Larger decreases in adiponectin over the menopause transition were associated with greater increases in systolic blood pressure, insulin and insulin resistance and with greater decreases in HDL-c. Greater increases in ghrelin levels over the menopausal transition were associated with greater low-density lipoprotein cholesterol increases (P = 0.014). Resistin was not associated with CVD risk factor changes. CONCLUSION: There were significant adverse associations of adipocytokines and ghrelin with multiple CVD risk factor changes in women across midlife. Given that this time period is dynamic for CVD risk, these data underscore the need for additional prospective studies.

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.

Carbonated soft drinks and dental caries in the primary dentition.

We analyzed fluid intake data among children aged 2-10 years from a 24-hour dietary recall interview in the NHANES III (1988-94) to investigate the effect of high consumption of carbonated soft drinks on caries in the primary dentition. We used cluster analysis to determine fluid consumption patterns. Four distinct fluid consumption patterns were identified: high carbonated soft drinks, high juice, high milk, and high water. About 13% of children had a high carbonated soft drink consumption pattern; they also had a significantly higher dental caries experience in the primary dentition than did children with other fluid consumption patterns. A fluid intake pattern comprised mainly of milk, water, or juice was less likely to be associated with dental caries. Findings of this study suggest that high consumption of carbonated soft drinks by young children is a risk indicator for dental caries in the primary dentition and should be discouraged.

Weight, fat mass, and central distribution of fat increase when women use depot-medroxyprogesterone acetate for contraception.

OBJECTIVE: To compare longitudinal changes in weight, body fat, and ratio of central to peripheral fat mass among first-time depot-medroxyprogesterone acetate (DMPA) users to women using no hormonal contraception, and to evaluate user characteristics associated with that change. DESIGN: Prospective longitudinal study. SUBJECTS: Healthy women, aged 18-35 y, using DMPA for contraception (n=178) and women using no hormonal contraception (n=145). MEASUREMENTS: Weight, body fat, and the central distribution of fat, measured at 3-month intervals for 30 months, by electronic scale and dual-energy X-ray absorptiometry (DEXA). The ratio of central to peripheral distribution of body fat was computed by dividing the body fat in the conventional DEXA trunk region of interest (ROI) by the ROI's that encompass the arms, hips and legs. RESULTS: Women using DMPA had a significantly greater increase in all measures of fatness than women using no hormonal method of contraception (P<0.03). The observed weight of DMPA users increased from a mean of 69.4 kg (s.d.=16.9) at baseline to 75.5 kg (s.d.=25.0) at 30 months; an increase of 6.1 kg (8.8.%). Fat mass increased from a mean of 25.3 kg (s.d.=12.6 kg) at baseline to 31.4 kg (s.d.=17.8); an increase of 6.1 kg (23.6%) in DMPA users. The ratio of central to peripheral fat mass in DMPA users changed from 0.95 (s.d.=0.155) at baseline to 1.01(s.d.=0.198) at 30 months. In contrast, weight, fat mass and the ratio of central to peripheral fat mass of control participants remained virtually unchanged over the same time period. Women with higher baseline physical activity levels had a smaller increase in body fat (P=0.003) and the fat ratio (P=0.03), but not weight (P=0.48). No other user characteristics including, smoking, past oral contraceptive use or previous pregnancies predicted change in level of fatness. CONCLUSIONS: This study has demonstrated a change in body composition toward greater fatness and toward a central redistribution of fat among DMPA users as compared to controls and provides important information to be used when counseling women regarding contraceptive methods. Given the potential long-term implication of these changes, further study is recommended to determine whether the gains in fatness are reversed following DMPA discontinuation and to examine the role of progestins in the development and maintenance of obesity.

Age at natural menopause in a sample of Puerto Rican women

OBJECTIVES: To characterize the distribution of age at menopause in a sample of Puerto Rican women and to evaluate the differences in demographic, health and lifestyle factors associated with menopausal state. BACKGROUND: Age at natural menopause may be an important marker of a woman's long-term risk of chronic disease. Understanding which factors influence the timing of menopause remains limited and while ethnic differences in age at menopause have been reported, little data are available for Puerto Rican women. METHODS: In 2000, a self-administered questionnaire was completed by a sample of 300 women aged 30-59 attending health fairs in the cities of Carolina, Aguadilla and Yauco, Puerto Rico (PR). Data from this interview was used to determine age at menopause which was described with probit analysis. Women from different menopausal status groups were compared with respect to demographic, lifestyle and health characteristics by using contingency table analysis and chi-square statistics. RESULTS: In a sample where 53% of women were menopausal, the median age of natural menopause was 51.4 years (95% confidence intervals 50.3-52.5). Compared to premenopausal women, naturally and surgically postmenopausal women had lower educational attainment, increased parity and were more likely to be obese (p < 0.05). CONCLUSION: This analysis provides the first estimate of age at natural menopause among women living in PR and the age is similar to that reported in other populations. Determining whether this population tends to have an early or late menopause will facilitate a better understanding of the potential chronic disease profile of Puerto Rican women as they age.

Magnetic resonance-detected subchondral bone marrow and cartilage defect characteristics associated with pain and X-ray-defined knee osteoarthritis.

OBJECTIVE: To assess whether the presence of subchondral bone marrow abnormalities (bone marrow edema (BME)) and cartilage defects, determined by magnetic resonance imaging (MRI), would explain the difference between painful osteoarthritis of the knee (OAK) compared with painless OAK or pain without OAK. METHOD: Four groups of women (30 per group), aged 35-55 years, were recruited from the southeast Michigan Osteoarthritis cohort (group 1: painful OAK; group 2: painless OAK; group 3: knee pain without OAK; and group 4: no OAK or knee pain). OAK was defined by a Kellgren-Lawrence score of 2 or greater, while pain was based on self-report. BME and cartilage defects were identified from MRI. RESULTS: BME lesions were identified in 56% of all knees. BME lesions were four times (95% CI=1.7, 8.7) more likely to occur in the painless OAK group as compared with the group with pain, but no OAK. BME lesions >1cm were more frequent (OR=5.0; 95% CI=1.4, 10.5) in the painful OAK group than all other groups. While the frequency of BME lesions was similar in the painless OAK and painful OAK groups, there were more lesions, >1cm, in the painful OAK group. About 75% of all knees had evidence of some cartilage defect, of which 35% were full-thickness defects. Full-thickness cartilage defects occurred frequently in painful OAK. One-third of knees with full-thickness defects and 47% of knees with cartilage defects involving bone had BME >1cm. Women with radiographic OA, full-thickness articular cartilage defects, and adjacent subchondral cortical bone defects were significantly more likely to have painful OAK than other groups (OR=3.2; 95% CI=1.3, 7.6). CONCLUSION: The finding on MRI of subchondral BME cannot satisfactorily explain the presence or absence of knee pain. However, women with BME and full-thickness articular cartilage defects accompanied by adjacent subchondral cortical bone defects were significantly more likely to have painful OAK than painless OAK.

Endogenous hormones and bone turnover markers in pre- and perimenopausal women: SWAN.

We tested the hypothesis that higher serum osteocalcin and urinary N-telopeptide of type I collagen (NTx) concentrations would be found in women with increasing cycle irregularity or increased follicle stimulating hormone concentrations. We studied 2,375 pre- and early perimenopausal women from the Study of Women's Health Across the Nation (SWAN), aged 42-52 years, who self-identified their race/ethnic origin as African-American (28.3%), Caucasian (49.4%), Japanese (10.5%) or Chinese (11.8%). Outcome measures were serum osteocalcin, a measure of bone formation, and NTx, a measure of bone resorption. The explanatory variables were menopausal status, based on self-reported regularity of menstrual bleeding, and circulating endogenous hormone concentrations including estradiol (E(2)), testosterone (T), sex hormone binding globulin (SHBG) and follicle stimulating hormone (FSH) concentrations. Additionally, we evaluated the association of the bone turnover markers with the Free Androgen Index (FAI) and the Free Estradiol Index (FEI), ratios of total testosterone and estradiol concentrations to SHBG, respectively. Higher FSH concentrations were associated with higher NTx concentrations ( beta=0.003, partial r2=2.1%, p<0.0001), both before and after adjusting for other covariates (total explained variability of 9%). Higher FSH concentrations were also associated with higher osteocalcin concentrations ( beta=-0.216, partial r2=4.1%, p<0.0001, total explained variability of 15.4%). There were no significant associations of the bone turnover markers with other endogenous hormones, following adjustment for covariates. Mean osteocalcin and NTx values were not significantly different in premenopausal women compared to early perimenopausal women. In these pre- and early perimenopausal women, higher FSH concentrations, but not other serum reproductive hormone concentrations, are positively associated with greater bone turnover prior to the last menstrual period.

The association of endogenous hormone concentrations and bone mineral density measures in pre- and perimenopausal women of four ethnic groups: SWAN.

We evaluated bone mineral density (BMD), hormone concentrations and menstrual cycle status to test the hypothesis that greater variations in reproductive hormones and menstrual bleeding patterns in mid-aged women might engender an environment permissive for less bone. We studied 2336 women, aged 42-52 years, from the Study of Women's Health Across the Nation (SWAN) who self-identified as African-American (28.2%), Caucasian (49.9%), Japanese (10.5%) or Chinese (11.4%). Outcome measures were lumbar spine, femoral neck and total hip BMD by dual-energy X-ray densitometry (DXA). Explanatory variables were estradiol, testosterone, sex hormone binding globulin (SHBG) and follicle stimulating hormone (FSH) from serum collected in the early follicular phase of the menstrual cycle or menstrual status [premenopausal (menses in the 3 months prior to study entry without change in regularity) or early perimenopause (menstrual bleeding in the 3 months prior to study entry but some change in the regularity of cycles)]. Total testosterone and estradiol concentrations were indexed to SHBG for the Free Androgen Index (FAI) and the Free Estradiol Index (FEI). Serum logFSH concentrations were inversely correlated with BMD (r = -10 for lumbar spine [95% confidence interval (CI): -0.13, -0.06] and r = -0.08 for femoral neck (95% CI: -0.11, -0.05). Lumbar spine BMD values were approximately 0.5% lower for each successive FSH quartile. There were no significant associations of BMD with serum estradiol, total testosterone, FEI or FAI, respectively, after adjusting for covariates. BMD tended to be lower (p values = 0.009 to 0.06, depending upon the skeletal site) in women classified as perimenopausal versus premenopausal, after adjusting for covariates. Serum FSH but not serum estradiol, testosterone or SHBG were significantly associated with BMD in a multiethnic population of women classified as pre- versus perimenopausal, supporting the hypothesis that alterations in hormone environment are associated with BMD differences prior to the final menstrual period.

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.

Assessing menstrual cycles with urinary hormone assays.

The Study of Women's Health Across the Nation (SWAN) is a multiethnic cohort study of middle-aged women enrolled at seven US sites. A subset of 848 women completed a substudy in which their urinary gonadotropins and sex steroid metabolites were assessed during one complete menstrual cycle or up to 50 consecutive days. Urine was analyzed for LH, FSH, estrone conjugates (E1c), and pregnanediol glucuronide (Pdg). To prepare for serial analysis of this large, longitudinal database in a population of reproductively aging women, we examined the performance of algorithms designed to identify features of the normal menstrual cycle in midreproductive life. Algorithms were based on existing methods and were compared with a "gold standard" of ratings of trained observers on a subset of 396 cycles from the first collection of Daily Hormone Substudy samples. In evaluating luteal status, overall agreement between and within raters was high. Only 17 of the 396 cycles evaluated were considered indeterminate. Of the 328 cycles rated as containing evidence of luteal activity (ELA), 320 were considered ELA by use of a Pdg threshold detection algorithm. Of 51 cycles that were rated as no evidence of luteal activity, only 2 were identified by this algorithm as ELA. Evaluation of the day of the luteal transition with methods that detected a change in the ratio of E1c to Pdg provided 85-92% agreement for day of the luteal transition within 3 days of the raters. Adding further conditions to the algorithm increased agreement only slightly, by 1-8%. We conclude that reliable, robust, and relatively simple objective methods of evaluation of the probability and timing of ovulation can be used with urinary hormonal assays in early perimenopausal women.

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.

Natural history of bone loss over 6 years among premenopausal and early postmenopausal women.

The aims of this prospective cohort study were to determine rates of premenopausal and early postmenopausal bone loss, age at onset of bone loss, and whether rates of bone loss depend on baseline bone mineral density (BMD). The cohort of 614 women aged 24-44 years at baseline from the longitudinal Michigan Bone Health Study was followed for 6 years beginning in 1992-1993. Up to five BMD measurements of the lumbar spine (L(2-4)) and the femoral neck were obtained through 1998-1999 by using dual x-ray absorptiometry and were standardized (as z scores) relative to a young adult, female BMD distribution. Regression models were used to estimate rates of BMD change and to examine BMD as a function of age. At the lumbar spine, the rate of BMD change for premenopausal women varied with time. At the femoral neck, the rate of change was -1.6% (95% confidence interval: -0.9%, -2.3%) of a z score annually (annual loss of 0.3% of baseline BMD (g/cm(2))). Evidence for age at onset of bone loss at the lumbar spine was inconclusive. Bone loss began by the midtwenties at the femoral neck. Additional annual change of -0.7% (95% confidence interval: -0.2%, -1.2%) of a z score was observed at the femoral neck for each unit increase in BMD z score at baseline.

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.

IGF-I, osteocalcin, and bone change in pregnant normotensive and pre-eclamptic women.

Pre-eclampsia is a pregnancy disorder of uncertain etiology that affects 5-10% of all pregnancies, with symptoms typically presenting around or after 20 wk gestation. We hypothesized that IGF-I, osteocalcin, and bone loss would be different among women with pre-eclampsia compared with normotensive pregnant women. There were 962 pregnant healthy women, aged 12-35, who were assessed at entry to care, at 28 wk, and at delivery for osteocalcin and IGF-I concentrations. Bone ultrasound was measured at entry to care and at 6 wk postpartum, whereas bone mineral density was measured by dual x-ray densitometry at delivery. There were 64 women (6.7%) among the women being followed who developed pre-eclampsia. In women with pre-eclampsia, IGF-I concentrations were 74% greater in the third trimester compared with the first trimester, whereas there was little change in osteocalcin concentrations. In contrast, normotensive women had an average increase of 43% in IGF-I concentrations accompanied by a 63% decline in osteocalcin concentrations. In women with pre-eclampsia, IGF-I and osteocalcin concentrations were significantly correlated (r = 0.48 and 0.43) at both the first and third trimester time points, but only in the third trimester among normotensive women (r = 0.27). The bone change difference between the two groups was not statistically significant. Women with pre-eclampsia appear to have an exaggerated IGF-I responsiveness compared with women who are normotensive; however, the strong correlation between IGF-I and osteocalcin in women with pre-eclampsia suggests that the IGF-I is able to retain its role as a local regulator of bone remodeling, as indicated by the osteocalcin concentrations.