Effect of Lifestyle Intervention on the Hormonal Profile of Frail, Obese Older Men.

OBJECTIVE: Obesity-associated hypogonadism is hypothesized to be due to the suppressive effect of high estradiol (from an increase in aromatase activity present in the abundant adipose tissue) on the hypothalamic-pituitary-gonadal unit resulting in low testosterone production. Although weight loss has been found to be effective in reducing estradiol and raising testosterone levels in studies of younger men, its effect in frail, obese older men is understudied. Thus, the objective of this study was to determine the effect of lifestyle intervention on hormone levels in frail, obese older men. DESIGN: Randomized controlled trial of lifestyle intervention in frail, obese older men (≥65 yo) for 1 year. SETTING: University hospital. METHODS: Forty frail, obese elderly men were randomized, for a 52-week study, to any of the following treatment groups: (1) control group, (2) diet-induced weight loss group (diet group), (3) exercise training group (exercise group), and (4) diet-induced weight loss and exercise training group (diet-exercise group). The objective was to achieve a ~10 % weight loss at 6 months and maintain this weight for an additional 6 months. Physical function was assessed by the modified physical performance testing (modified PPT). Estradiol was measured by radioimmunoassay, testosterone by automated immunoassay, and sex hormone-binding globulin by enzyme-linked immunoassay. RESULTS: After 12 months of intervention, diet alone resulted in a weight loss of -10.1 ± 1.9 kg in the diet group and -9.1 ± 0.9 kg in the diet-exercise group. This resulted in a significant decrease (both p<0.05) in total estradiol compared to baseline among subjects in the diet (-2.5 ± 1.3 pg/ml) and diet-exercise group (-2.2 ± 4.0 pg/ml). Free estradiol index also significantly decreased (both p <0.05) in both the diet (-0.39 ± 0.14 pmol/nmol) and diet-exercise (-0.52 ± 0.12 pmol/nmol) group. Total testosterone significantly increased (p<0.05) in response to diet (71.0 ± 21.0 ng/dl) and diet-exercise (49.9 ± 15.5 pg/ml) resulting in values of 287.0 ± 28.1 ng/dl in the diet and 317.6 ± 33.1 ng/dl in the diet-exercise group. However, because there was a significant increase in sex hormone-binding globulin levels in both the diet and diet-exercise groups, free testosterone index and the changes in free testosterone index were not significant compared to baseline. Regardless of changes in hormonal levels, patients in the diet, exercise, and diet-exercise groups experienced significant improvements in the modified PPT from baseline. CONCLUSION: Weight loss from lifestyle intervention resulted in significant decreases in total and free estradiol levels in frail, obese older men, but this did not result in a clinically important increase in total testosterone nor a significant increase in free testosterone. Thus, alternative forms of treatment in addition to lifestyle intervention may be necessary to improve the hormonal profile among these patients. Nevertheless, whether further improvement in hormonal profile would result in better physical performance than what can be achieved by lifestyle alone in these subjects remains uncertain.

Changes in thigh muscle volume predict bone mineral density response to lifestyle therapy in frail, obese older adults.

UNLABELLED: We studied the relationships among strength, muscle mass, and bone mineral density (BMD) with lifestyle change. Lifestyle therapy consisted of exercise, diet, and diet plus exercise. Diet was by caloric restriction to induce and maintain a weight loss of 10 % from baseline body weight. Exercise attenuated weight loss-induced muscle and bone losses. Exercise improved strength despite muscle loss in patients on diet and exercise. Changes in strength did not correlate with changes in BMD. However, changes in thigh muscle volume correlated with, and predicted changes in hip BMD. INTRODUCTION: Losses of hip BMD and lean body mass are major complications of lifestyle therapy in frail, obese older adults; however, the contribution of mechanical strain loss from muscle loss is poorly defined. We determined the effect of changes in thigh muscle volume and muscle strength on BMD in frail, obese older adults undergoing lifestyle therapy aimed at intentional weight loss with or without exercise. METHODS: One hundred seven obese older adults were randomized to control, diet, exercise, and diet-exercise groups for 1 year. Thigh muscle volume was measured by magnetic resonance imaging, BMD by DXA, knee strength by dynamometry, total strength by one-repetition maximum (1-RM), and bone markers by immunoassay. RESULTS: Thigh muscle volume decreased in the diet group (-6.2 ± 4.8 %) and increased in the exercise group (2.7 ± 3.1 %), while it was not significantly different from the control in the diet-exercise group. Changes in hip BMD followed similar pattern as those in thigh muscle volume. Knee extension and flexion increased in the exercise group (23 ± 20 %; 25 ± 19 %) and diet-exercise group (20 ± 19 %; 20.6 ± 27 %) but were unchanged in the control and diet groups. Changes in thigh muscle volume correlated with changes in hip BMD (r = 0.55, P = <0.001) and were an independent predictor of changes in hip BMD (ß = 0.12, P = 0.03) in the multiple regression analyses after accounting for demographic factors and changes in weight and physical activity. There were no correlations between BMD changes and knee strength, 1-RM, and sclerostin changes. CONCLUSIONS: Changes in thigh muscle volume predict hip BMD changes in obese older patients undergoing lifestyle therapy. The effect of exercise in attenuating thigh muscle loss when added to diet may in part account for the reduction in weight loss-induced bone loss in the diet-exercise group.

Weight loss, exercise or both and cardiometabolic risk factors in obese older adults: results of a randomized controlled trial.

BACKGROUND: Obesity exacerbates the age-related decline in insulin sensitivity and is associated with risk for cardiometabolic syndrome in older adults; however, the appropriate treatment for obese older adults is controversial. OBJECTIVE: To determine the independent and combined effects of weight loss and exercise on cardiometabolic risk factors in obese older adults. DESIGN: One-hundred and seven obese (body mass index (BMI)≥30 kg m(-2)) older (≥65 years) adults with physical frailty were randomized to control group, diet group, exercise group and diet-exercise group for 1 year. Outcomes for this study included changes in insulin sensitivity index (ISI), glucose tolerance, central obesity, adipocytokines and cardiometabolic syndrome. RESULTS: Although similar increases in ISI occurred in the diet-exercise and diet groups at 6 months, the ISI improved more in the diet-exercise than in the diet group at 12 months (2.4 vs 1.2; between-group difference, 1.2; 95% confidence interval, 0.2-2.1); no changes in ISI occurred in both exercise and control groups. The diet-exercise and diet groups had similar improvements in insulin area under the curve (AUC) (-2.9 and -2.9 × 10(3) mg min dl(-1)), glucose AUC (-1.4 and -2.2 × 10(3)mg min dl(-1)), visceral fat (-787 and -561 cm(3)), tumor necrosis factor (-17.0 and -12.8 pg ml(-1)), adiponectin (5.0 and 4.0 ng ml(-1)), waist circumference (-8.2 and -8.4 cm), triglyceride (-30.7 and -24.3 g dl(-1)) and systolic/diastolic blood pressure (-15.9 and -13.1/-4.9 and -6.7 mm Hg), while no changes in these parameters occurred in both exercise and control groups. The cardiometabolic syndrome prevalence decreased by 40% in the diet-exercise and by 15% in the diet group. Body weight decreased similarly in the diet-exercise and diet groups (-8.6 and -9.7 kg) but not in the exercise and control groups. CONCLUSIONS: In frail, obese older adults, lifestyle interventions associated with weight loss improve insulin sensitivity and other cardiometabolic risk factors, but continued improvement in insulin sensitivity is only achieved when exercise training is added to weight loss.

Long-term maintenance of weight loss after lifestyle intervention in frail, obese older adults.

OBJECTIVES: To determine if long-term weight loss with associated improvement in physical and metabolic health can be maintained after lifestyle intervention in frail, obese older adults. DESIGN: Thirty-month follow-up pilot study of a 1-year lifestyle intervention trial. SETTING: Community. PARTICIPANTS: Sixteen frail, obese (body mass index=36±2 kg/m2) older (71±1 yr.) adults. MEASUREMENTS: Body weight and composition, physical function, markers of the metabolic syndrome, glucose and insulin response to an oral glucose tolerance test, bone mineral density (BMD), liver and renal function tests, and food diaries. RESULTS: At 30-month follow-up, weight (101.5±3.8 vs. 94.5±3.9 kg) and BMI (36.0 ±1.7 vs. 33.5±1.7 kg/m2) remained significantly below baseline (all p<0.05). No significant change in fat-free mass (56.7±2.1 vs. 56.9±2.2 kg) or appendicular lean mass (24.1±1.0 vs. 24.1±1.1kg, all p>0.05) occurred between 12 months (end of trial) and 30 months. Improvements in the physical performance test (PPT 27±0.7 vs. 30.2±0.6), insulin sensitivity (4.1±0.8 vs. 3.0±0.6), and insulin area under the curve (12484±2042 vs. 9270±1139 min.mg/dl) remained at 30 months compared to baseline (all p<0.05). Waist circumference (116±3 vs. 109±3 cm) and systolic blood pressure (134±6 vs. 123±5 mm HG) remained decreased at 30 months compared to baseline (all p<0.05). Whole body and lumbar spine BMD did not change; however, total hip BMD progressively decreased at 30 months compared to baseline (0.985±.026 vs. 0.941±.024 g/cm2; p<0.05). There were no adverse effects on liver or renal function. Food frequency questionnaire data showed lower overall caloric intake (-619±157 kcal/day) at 30 months compared to baseline (p<0.05). CONCLUSION: These findings suggest that long-term maintenance of clinically important weight loss is possible in frail, obese older adults. Weight maintenance appears to be achieved through continued caloric restriction. Larger, long-term studies are needed to follow up on these findings and investigate mechanisms and behaviors underlying maintenance of weight loss and physical function.

Bisphosphonate-associated femoral fracture: implications for management in patients with malignancies.

Reports of femoral shaft fractures in patients on long-term bisphosphonates (BPs) have raised important concerns on the safety for this class of drugs. Patients with malignancies are potentially at a higher risk for this complication considering the dose and the duration of treatment with BPs. In this report we describe the case of 56-year-old woman with multiple myeloma who developed a non-traumatic left femoral shaft fracture after treatment with high dose BPs for 6 years, following a bone marrow transplant. Intramedullary rod fixation of the fractured femur resulted in "splitting" of the fractured bone followed by poor healing and nonunion of the fractured bone. This case illustrates a potential problem in the management of patients with femoral shaft fractures from prolonged BPs, most especially those who are on high doses for malignant conditions. However, considering the number of patients who benefit from BPs, this complication should not discourage clinicians from using these agents in patients where treatment is indicated.

Bone turnover markers: understanding their value in clinical trials and clinical practice.

While bone mineral density (BMD) by dual-energy X-ray absorptiometry is the primary method of determining fracture risk, assessing bone turnover may add valuable information for the management of patients with low bone mass. Bone turnover markers (BTMs) are used in clinical trials where they can provide essential information on the biological efficacy of osteoporosis treatments. In such population-based studies, BTMs can predict fracture risk independent of BMD. When combined with BMD, they improve the fracture risk estimate above and beyond BMD alone in postmenopausal osteoporotic women. Since changes in bone turnover after the initiation of therapy with bone resorption inhibitors occur much more rapidly than changes in BMD, treatment efficacy could, in theory, be determined within weeks of using BTMs. However, such predictive value is limited by the large biological variability of these biochemical markers, even though newer automated methods have reduced their analytical variability. Consequently, widespread adoption as a means of predicting treatment efficacy in fracture prevention for individual patients cannot yet be recommended. BTMs may be useful for monitoring adherence to antiresorptive therapy and may aid in identifying patients for whom antiresorptive therapy is most appropriate. Thus, although BTMs are currently confined to clinical research applications, further improvement in assay precision may extend their diagnostic value in clinical settings.

Estrogen metabolism modulates bone density in men.

Estrogen is a critical hormone for bone homeostasis in men, but no information is available on the role of estrogen metabolism among men. The aim of this study was to evaluate the effect of estrogen hydroxylation on male bone mineral density (BMD). Participants consisted of 61 healthy Caucasian males (mean age 66.6 +/- 1.0 years). Urinary estrogen metabolites were measured by enzyme-linked immunosorbent assay, serum estradiol by ultrasensitive radioimmunoassay, sex hormone binding globulin by radioimmunoassay, and BMD of the lumbar spine and the proximal femur by dual-energy X-ray absorptiometry. Active estrogen metabolites, 16alpha-hydroxyestrone (16alphaOHE(1)) and estriol (E(3)), positively correlated with adjusted BMD in all regions of the proximal femur (all P < 0.05) but not at the lumbar spine, and those in the highest tertile of urinary 16alphaOHE(1 )had the highest BMD. Free estradiol index (FEI) also positively correlated with BMD of the total hip, femoral neck, and intertrochanter (all P < 0.05), while there was no correlation between BMD with inactive metabolites (2-hydroxyestrone and 2-methoxyestrone) and serum testosterone. Multiple regression analysis showed 16alphaOHE(1), FEI, and body mass index are important independent predictors of BMD in all regions of the proximal femur. Estrogen metabolism may modulate BMD in men. Increased urinary 16alphaOHE(1) and E(3) levels are associated with high BMD at the proximal femur, and 16alphaOHE(1) appears to be a major determinant of BMD among the metabolites evaluated.

The oxidative metabolism of estradiol conditions postmenopausal bone density and bone loss.

Because lifelong exposure to estrogen is a strong determinant of bone mass, we asked whether metabolic conversion of estrogen to either inactive or active metabolites would reflect postmenopausal bone mineral density (BMD) and rate of bone loss. Biochemical markers of inactive estrogen metabolites, urinary 2-hydroxyestrogen (2OHE1) and 2-methoxyestrogen (2MeOE1), and active metabolites, urinary 16alpha-hydroxyestrone (16alphaOHE1), estradiol (E2), and estriol (E3), were determined in 71 untreated, healthy postmenopausal women (age, 47-59 years) followed prospectively for 1 year. Urinary 2MeOE1 was correlated negatively with baseline vertebral (anteroposterior [AP] projection, r = -0.23 andp < 0.05; lateral view, r = -0.27 and p < 0.05) and proximal femur bone density measured by dual-energy X-ray absorptiometry (DXA; total, r = -0.38 and p < 0.01; neck, r = -0.28 and p = 0.02; trochanter, r = -0.44 and p < 0.01). BMDs of women in the lowest quartile of urinary 2MeOE1 (< 15 ng/g) were significantly higher than those in the highest quartile at all skeletal sites (p < 0.05). Likewise, women in the lowest quartile of urinary 2OHE1/16alphaOHE1 ratio (< 1.6) did not experience bone loss after 1 year, in contrast to women in the higher quartiles. We propose that the rate of inactivation of estrogens through 2-hydroxylation may contribute to postmenopausal osteoporosis.

An intact N terminus is required for the anabolic action of parathyroid hormone on adult female rats.

Intermittent administration of parathyroid hormone (PTH) peptides increases bone density in animal and human models of osteoporosis. In vitro studies have demonstrated that PTH analogs lacking the first two amino acids can stimulate cell proliferation in certain cell systems, whereas fragments with an intact N terminus can be antimitogenic. We have tested whether the truncated PTH(3-38) fragment may be a better "anabolic analog" than PTH(1-38) by monitoring bone density and biomechanical properties of the femur in 6-month-old ovariectomized (OVX) rats. Either PTH fragment was administered subcutaneously (8 micrograms/100 g of body weight) 5 days/week, for 4 weeks, starting 1 week after surgery. During the entire study, untreated OVX rats lost 12.1 +/- 4.4% of their initial bone density. PTH(1-38) reversed the initial bone loss, leading to complete restoration of presurgery values after 4 weeks of treatment. Conversely, administration of PTH(3-38) resulted in 13.2 +/- 5.8% bone loss, while continuous estrogen infusion (10 micrograms/kg/day) prevented bone loss but did not reverse it. Sham-operated animals also experienced significant bone loss in the vehicle and PTH(3-38)-treated groups (-4.5 +/- 6.7%, and -7.6 +/- 2.8%, respectively), whereas a significant gain in bone density (+4.4 +/- 5.6%) was observed in the rats treated with PTH(1-38). A bone quality factor (index of strain energy loss) and the impact strength (resistance to fracture) were 25% and 44% lower in femurs explanted from OVX animals treated with either vehicle or PTH(3-38), compared with sham-operated animals. On the contrary, no difference was observed between OVX and control animals after treatment with PTH(1-38), indicating a preservation of the capacity to withstand mechanical stress. Thus, PTH(1-38) counteracts estrogen-dependent loss of mineral density and bone biomechanical properties and increases bone density in estrogen-replete animals. An intact N terminus sequence is necessary for this anabolic action of PTH.

X-linked hypophosphatemia: a search for gender, race, anticipation, or parent of origin effects on disease expression in children.

X-Linked hypophosphatemia (XLH) is a sex-linked dominant disorder. It is possible that females are more mildly affected than males. No information is available regarding other potential genetic influences on XLH expression in patients, such as race, anticipation, parent of origin, or molecular heterogeneity. We investigated the above potential genetic influences on XLH expressivity using data from 116 pediatric patients. To compare biochemical parameters, we used data from the 30 prepubertal children (23 girls and 7 boys) selected because they had been without medical therapy for at least 3 months (25 of 30 never treated). To compare height z-scores, we used data from the 27 patients (pre- or postpubertal) selected because they had never received medical or surgical treatment. Ascertainment bias (i.e. referral of girls who were severely affected) was not apparent (observed female/male ratio, 1.64; expected, 2.00; P = 0.29). Parameters of mineral homeostasis did not show statistically significant differences between girls vs. boys, sporadic vs. multigenerational cases (except lower fasting serum phosphate levels in sporadic cases; mean +/- SEM, 2.68 +/- 0.10 vs. 3.02 +/- 0.04 mg/dL; P = 0.049), blacks vs. whites, or for the girls for whom affected fathers vs. mothers transmitted the disorder. Height z-scores correlated with renal phosphate reclamation (i.e. tubular maximum of phosphorus/glomerular filtration rate; r = 0.68; P = 0.014), but were not different for the groupings above. Furthermore, we found no evidence for meiotic drive or for a parental age effect to explain the 18.3% of patients that were new mutations for XLH. Our data fail to show any evidence for genetic heterogeneity or for gender, race, anticipation, or parent of origin effects on XLH expression in children. Despite the recent discovery of a gene (PEX) that is mutated in XLH, the sex-linked dominant phenotype and apparent absence of a gene dose effect in XLH expression in children require explanation.

Estrogen action on the bone mass of postmenopausal women is dependent on body mass and initial bone density.

Recent evidence suggests that estrogen replacement therapy (ERT) may be effective in preventing bone loss even in late postmenopausal women. We analyzed the role of age and other factors as determinants of ERT action on vertebral bone density (VBD) in 73 consecutive Caucasian postmenopausal women treated for 1 yr or longer. A group of 44 women who received calcium supplements only were analyzed as controls. VBD was measured every 6 months by dual energy x-ray absorptiometry, and yearly rates of change were calculated by linear regression for each subject. VBD increased in the estrogen-treated group (+17.32 +/- 2.84 mg/cm2.yr; 2.42 +/- 0.37%/yr) and did not significantly change in untreated subjects (-4.08 +/- 3.68 mg/cm2/yr; -0.60 +/- 0.58%/yr). Women older than 60 yr experienced greater, although not significant, increments compared to younger subjects (+3.23 +/- 4.03% vs. +1.42 +/- 3.00%/yr), as did women more than 10 yr postmenopausal compared to patients within 10 yr after the menopause (+3.38 +/- 4.11% vs. +1.19 +/- 2.70%/yr). Rates of VBD change were positively correlated with age (r = 0.29; P = 0.014), years since menopause (r = 0.33; P = 0.005), and body mass index (BMI; r = 0.35; P = 0.003) and negatively with estimated initial VBD (r = -0.23; P = 0.05). However, only the relationships between bone density changes and BMI (r = 0.33; P < 0.01) and estimated initial VBD (r = -0.26; P < 0.05) held in a partial correlation analysis. BMI and estimated initial VBD were the only significant predictive factors for response to ERT (r2 = 21%) in a multivariate regression model. Therefore, the response to ERT depends mostly on BMI and initial VBD. Women with large body frames and those with lower initial VBD respond better to estrogen than slender women with higher bone mass.

Estrogen status and heredity are major determinants of premenopausal bone mass.

To analyze their relative effects on premenopausal bone mass, we have studied the impact of lifelong estrogen exposure, assessed by an estrogen score (ES; computed on age at menarche, average length of menstrual cycles since menarche, and use of birth control pills), heredity, and some environmental factors on vertebral bone density (VBD), of 63 premenopausal women (age, 19-40 yr). Compared with women with normal bone density (Z score > -1), subjects with low VBD (Z score < -1) had significantly lower ES (15.1 +/- 3.9 vs. 18.7 +/- 2.4, P = 0.001), higher age at menarche (13.8 +/- 1.7 vs. 12.6 +/- 1.4 yr, P = 0.005), and lower serum estradiol (46.9 +/- 37 vs. 86.6 +/- 57 pg/ml, P = 0.023) and estrone levels (107.4 +/- 60 vs. 178.8 +/- 9.0 pg/ml, P = 0.05). Likewise, women in the lowest quartile for VBD had significantly lower ES (15.3 +/- 4.5 vs. 18.1 +/- 2.7, P = 0.006) and higher age at menarche (13.9 +/- 1.9 vs. 12.8 +/- .4, P = 0.02) than those in the upper three quartiles. A higher proportion of subjects with irregular menses (52 vs. 23%, P = 0.03) and a positive family history of osteoporosis (86 vs. 61%, P = 0.04) was found in the low VBD group compared with subjects with normal VBD. VBD correlated positively with ES (r = 0.44, P = < 0.001) and negatively with age at menarche (r = -0.30, P = 0.03) by simple linear regression, whereas no correlation was found between VBD and age, body mass index, parity, lactation, physical activity, sunlight exposure, and dietary calcium and vitamin D intakes. The correlation between VBD and ES improved after correcting for the effect of all the other variables by partial correlation analysis (Pearson partial r = 0.57, P = < 0.01), which also disclosed a significant contribution of dietary calcium to VBD. However, ES was the only significant independent determinant of VBD, by stepwise multiple regression analysis (R2 = 0.24). Therefore, premenopausal estrogen exposure, and possibly genetic predisposition, rather than environmental factors, are the major determinants for the development of peak bone mass before menopause.

Successful treatment of low turnover osteoporosis resulting from prolonged reserpine therapy with intermittent calcitonin and phosphate therapy.

Coherence therapy, popularly known by the acronym ADFR (Activate, Depress, Free, Repeat), was designed to increase bone mass in osteopenic patients. Accordingly, we report a case of a hypogonadal male with histologically proven low bone turnover osteoporosis and a progressive vertebral fracture syndrome, who responded favorably to ADFR treatment with the use of salmon calcitonin and inorganic phosphate. Dramatic increments in bone mass were observed during a 68-month period of therapy. Serial quantitative computerized tomography demonstrated a 146% increase from baseline in bone mineral density for the first 30 months of treatment, and dual energy radiography yielded a 36.5% increase for the subsequent 31-68 months. Furthermore, no episode of fracture occurred since coherence therapy was initiated.