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.

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.

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.

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.

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.

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.

Testosterone concentrations in women aged 25-50 years: associations with lifestyle, body composition, and ovarian status.

While there is substantial evidence of the importance of endogenous and exogenous estrogen in reproductive health and chronic disease, there is little consideration of androgens in women's health. In the Michigan Bone Health Study (1992-1995), the authors examined the correlates of testosterone concentrations in pre- and perimenopausal women (i.e., age, menopausal status, body composition, and lifestyle behaviors) in a population-based longitudinal study including three annual examinations among 611 women aged 25-50 years identified through a census in a midwestern community. Current smokers had the highest testosterone concentrations with decreasing values in former and nonsmokers (p = 0.0001). Body composition measures (body mass index, body fat (%), weight (kg), lean body mass (kg), and fat mass (kg)) were significantly and positively associated with total testosterone concentrations in a dose-response manner. Hysterectomy with oophorectomy was associated with significantly lower testosterone concentrations. Alcohol consumption, physical activity, and dietary macronutrient intake were not associated with testosterone concentrations. This is one of the first studies to examine correlates of serum testosterone concentrations in anticipation of the growing interest in the role of androgens in women's health. The greater circulating levels of testosterone in obese women and smokers suggest that testosterone concentrations should be considered in the natural history of disease conditions where obesity and smoking are risk factors, including cardiovascular disease.

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.

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.

The effect of weight cycling on blood lipids and blood pressure in the Multiple Risk Factor Intervention Trial Special Intervention Group.

OBJECTIVE: To assess whether weight cycling has adverse effects on blood lipids or blood pressure. DESIGN: Cohort study, six years of follow-up, comparing net change in blood lipids and blood pressure among weight cyclers and non-cyclers. SUBJECTS: Men (n = 4353), age 35-57 y, at high risk for heart disease because of smoking, high blood pressure, and elevated cholesterol concentration in the Multiple Risk Factor Intervention Trial (MRFIT)--a 22-site, multi-center collaborative primary prevention trial conducted in the US, 1973-1983. MEASUREMENTS: A weight cycle was defined as loss and regain of at least 5% of mean weight. Outcome measures were changes from baseline to year six in total serum cholesterol, high density lipoprotein cholesterol (HDL), the ratio of total cholesterol to HDL, and diastolic blood pressure. ANALYSIS: Analysis of covariance models were developed, with number of weight cycles as the predictor variable. The hypothesis was that men who weight cycled would experience less improvement in blood lipids and blood pressure than those who did not cycle. Adjustments were made for net weight change and other factors affecting each outcome. RESULTS: Men who weight cycled did not have the predicted smaller improvements in total cholesterol, HDL, the ratio of total cholesterol to HDL, or diastolic blood pressure, compared with noncyclers. CONCLUSION: An adverse effect of weight cycling on blood pressure or blood lipids was not found. The excess mortality previously reported among weight cyclers in this population can probably not be attributed to effects on these CVD risk factors.

Worksite cancer screening and nutrition intervention for high-risk auto workers: design and baseline findings of the Next Step Trial.

BACKGROUND: This article describes the design and baseline findings of The Next Step Trial, a health promotion intervention targeting automobile industry employees at increased colorectal cancer risk. The intervention encouraged colorectal cancer screening participation and adoption of low-fat, high-fiber diets. METHODS: Twenty-eight worksites (n = 5,042) were randomized to control (a company-sponsored screening program) or intervention (an enhanced screening program including a personalized educational booklet and motivational telephone call and diet-change program including nutrition classes, self-help materials, and computer-generated personalized feedback). Outcomes included screening compliance and fat and fiber intake. RESULTS: Pretrial data indicated targeted employees were predominantly older, well educated, married, Caucasian men. Sixty-one percent (SE = 2) participated in the screening program in the preceding 2 years, and 24% (SE = 1) reported a history of colorectal polyps or cancer. Fifty-eight percent of the cohort responded to the baseline questionnaire; respondents were older and more educated; more were married, retired, and Caucasian than nonrespondents. Mean dietary intakes were 36.9% energy from fat (SE = 0.21), 8.8 g fiber/1000 kcal (SE = 0.07), and 3.4 servings of fruits and vegetables per day (SE = 0.04). CONCLUSIONS: Baseline data show moderate screening participation and dietary intakes that did not meet guidelines; hence intervention efforts were warranted. Data from this trial will support a rigorous test of whether this high-risk employee population is responsive to targeted health promotion, early cancer detection, and prevention interventions.

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.

Elevated parathyroid hormone-related peptide associated with lactation and bone density loss.

OBJECTIVE: To investigate the hypothesis that parathyroid hormone-related peptide (PRHrP) may be involved with bone loss and recovery as a means of providing adequate calcium and phosphate to infants. DESIGN: An 18-month prospective cohort study. SETTING: General community setting with recruitment occurring at birthing education classes. PARTICIPANTS: Volunteer sample of 115 postpartum healthy women aged 20 to 40 years, and 0 or 1 parity prior to parturition with no intent to breast-feed or intent to breast-feed at least 6 months. MAIN OUTCOME MEASURES: Parathyroid hormone-related peptide, prolactin, estradiol, 1,25-dihydroxyvitamin D, 24-hydroxyvitamin D, femoral bone mineral density, and bone turnover markers were measured in 115 postpartum women at 2 weeks, 2 months, 4 months, 6 months, 12 months, and 18 months postpartum. Lumbar bone mineral density was measured at 2 weeks, 6 months, 12 months, and 18 months postpartum. RESULTS: Elevated PTHrP values were significantly associated (P<.001) with breast-feeding status, elevated prolactin levels, and lower serum estradiol levels, conditions occurring during lactation. Furthermore, elevated PTHrP levels were negatively and significantly associated (P<.01) over time with bone mineral density change at both the spine and the femoral neck, even after accounting for prolactin levels, breast-feeding status, return of menstruation, estradiol levels, PTH levels, 1,25-dihydroxyvitamin D levels, dietary calcium intake, physical activity, and body size. CONCLUSION: These data clearly support the hypothesis that PTHrP is an alternative mechanism associated with bone loss and recovery during and subsequent to lactation.