Meryl S. LeBoff

Comparison of Weight-Loss Diets with Different Compositions of Fat, Protein, and Carbohydrates

BACKGROUND The possible advantage for weight loss of a diet that emphasizes protein, fat, or carbohydrates has not been established, and there are few studies that extend beyond 1 year. METHODS We randomly assigned 811 overweight adults to one of four diets; the targeted percentages of energy derived from fat, protein, and carbohydrates in the four diets were 20, 15, and 65%; 20, 25, and 55%; 40, 15, and 45%; and 40, 25, and 35%. The diets consisted of similar foods and met guidelines for cardiovascular health. The participants were offered group and individual instructional sessions for 2 years. The primary outcome was the change in body weight after 2 years in two-by-two factorial comparisons of low fat versus high fat and average protein versus high protein and in the comparison of highest and lowest carbohydrate content. RESULTS At 6 months, participants assigned to each diet had lost an average of 6 kg, which represented 7% of their initial weight; they began to regain weight after 12 months. By 2 years, weight loss remained similar in those who were assigned to a diet with 15% protein and those assigned to a diet with 25% protein (3.0 and 3.6 kg, respectively); in those assigned to a diet with 20% fat and those assigned to a diet with 40% fat (3.3 kg for both groups); and in those assigned to a diet with 65% carbohydrates and those assigned to a diet with 35% carbohydrates (2.9 and 3.4 kg, respectively) (P>0.20 for all comparisons). Among the 80% of participants who completed the trial, the average weight loss was 4 kg; 14 to 15% of the participants had a reduction of at least 10% of their initial body weight. Satiety, hunger, satisfaction with the diet, and attendance at group sessions were similar for all diets; attendance was strongly associated with weight loss (0.2 kg per session attended). The diets improved lipid-related risk factors and fasting insulin levels. CONCLUSIONS Reduced-calorie diets result in clinically meaningful weight loss regardless of which macronutrients they emphasize. (ClinicalTrials.gov number, NCT00072995.)

Clinician’s Guide to Prevention and Treatment of Osteoporosis

The Clinician’s Guide to Prevention and Treatment of Osteoporosis was developed by an expert committee of the National Osteoporosis Foundation (NOF) in collaboration with a multispecialty council of medical experts in the field of bone health convened by NOF. Readers are urged to consult current prescribing information on any drug, device, or procedure discussed in this publication.The Clinician’s Guide to Prevention and Treatment of Osteoporosis was developed by an expert committee of the National Osteoporosis Foundation (NOF) in collaboration with a multispecialty council of medical experts in the field of bone health convened by NOF. Readers are urged to consult current prescribing information on any drug, device, or procedure discussed in this publication.

A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study

PURPOSE We conducted a 5-year, double-blind, randomized, placebo-controlled study to determine whether salmon calcitonin nasal spray reduced the risk of new vertebral fractures in postmenopausal women with osteoporosis. SUBJECTS AND METHODS A total of 1,255 postmenopausal women with established osteoporosis were randomly assigned to receive salmon calcitonin nasal spray (100, 200, or 400 IU) or placebo daily. All participants received elemental calcium (1,000 mg) and vitamin D (400 IU) daily. Vertebral fractures were assessed with lateral radiographs of the spine. The primary efficacy endpoint was the risk of new vertebral fractures in the salmon calcitonin nasal spray 200-IU group compared with the placebo group. RESULTS During 5 years, 1,108 participants had at least one follow-up radiograph. A total of 783 women completed 3 years of treatment, and 511 completed 5 years. The 200-IU dose of salmon calcitonin nasal spray significantly reduced the risk of new vertebral fractures by 33% compared with placebo [200 IU: 51 of 287, placebo: 70 of 270, relative risk (RR) = 0.67, 95% confidence interval (CI): 0.47- to 0.97, P = 0.03]. In the 817 women with one to five prevalent vertebral fractures at enrollment, the risk was reduced by 36% (RR = 0.64, 95% CI: 0.43- to 0.96, P = 0.03). The reductions in vertebral fractures in the 100-IU (RR = 0.85, 95% CI: 0.60- to 1.21) and the 400-IU (RR = 0.84, 95% CI: 0.59- to 1.18) groups were not significantly different from placebo. Lumbar spine bone mineral density increased significantly from baseline (1% to 1. 5%, P<0.01) in all active treatment groups. Bone turnover was inhibited, as shown by suppression of serum type-I collagen cross-linked telopeptide (C-telopeptide) by 12% in the 200-IU group (P <0.01) and by 14% in the 400-IU group (P<0.01) as compared with placebo. CONCLUSION Salmon calcitonin nasal spray at a dose of 200 IU daily significantly reduces the risk of new vertebral fractures in postmenopausal women with osteoporosis.

Age‐related intrinsic changes in human bone‐marrow‐derived mesenchymal stem cells and their differentiation to osteoblasts

In vivo and in vitro studies indicate that a subpopulation of human marrow‐derived stromal cells (MSCs, also known as mesenchymal stem cells) has potential to differentiate into multiple cell types, including osteoblasts. In this study, we tested the hypothesis that there are intrinsic effects of age in human MSCs (17–90 years). We tested the effect of age on senescence‐associated β‐galactosidase, proliferation, apoptosis, p53 pathway genes, and osteoblast differentiation in confluent monolayers by alkaline phosphatase activity and osteoblast gene expression analysis. There were fourfold more human bone MSCs (hMSCs) positive for senescence‐associated β‐galactosidase in samples from older than younger subjects (P < 0.001; n = 17). Doubling time of hMSCs was 1.7‐fold longer in cells from the older than the younger subjects, and was positively correlated with age (P = 0.002; n = 19). Novel age‐related changes were identified. With age, more cells were apoptotic (P = 0.016; n = 10). Further, there were age‐related increases in expression of p53 and its pathway genes, p21 and BAX. Consistent with other experiments, there was a significant age‐related decrease in generation of osteoblasts both in the STRO‐1+ cells (P = 0.047; n = 8) and in adherent MSCs (P < 0.001; n = 10). In sum, there is an age‐dependent decrease in proliferation and osteoblast differentiation, and an increase in senescence‐associated β‐galactosidase‐positive cells and apoptosis in hMSCs. Up‐regulation of the p53 pathway with age may have a critical role in mediating the reduction in both proliferation and osteoblastogenesis of hMSCs. These findings support the view that there are intrinsic alterations in human MSCs with aging that may contribute to the process of skeletal aging in humans.

Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer

PURPOSE We sought to evaluate the effects of chemotherapy-induced ovarian failure on bone loss and markers of skeletal turnover in a prospective longitudinal study of young women with breast cancer receiving adjuvant chemotherapy. PATIENTS AND METHODS Forty-nine premenopausal women with stage I/II breast cancers receiving adjuvant chemotherapy were evaluated within 4 weeks of starting chemotherapy (baseline), and 6 and 12 months after starting chemotherapy with dual-energy absorptiometry and markers of skeletal turnover osteocalcin and bone-specific alkaline phosphatase. Chemotherapy-induced ovarian failure was defined as a negative pregnancy test, greater than 3 months of amenorrhea, and a follicle-stimulating hormone > or = 30 MIU/mL at the 12-month evaluation. RESULTS Among the 35 women who were defined as having ovarian failure, highly significant bone loss was observed in the lumbar spine by 6 months and increased further at 12 months. The median percentage decrease of bone mineral density in the spine from 0 to 6 months and 6 to 12 months was -4.0 (range, -10.4 to +1.0; P =.0001) and -3.7 (range, -10.1 to 9.2; P =.0001), respectively. In contrast, there were no significant decreases in bone mineral density in the 14 patients who retained ovarian function. Serum osteocalcin and bone specific alkaline phosphatase, markers of skeletal turnover, increased significantly in the women who developed ovarian failure. CONCLUSION Chemotherapy-induced ovarian failure causes rapid and highly significant bone loss in the spine. This may have implications for long-term breast cancer survivors who may be at higher risk for osteopenia, and subsequently osteoporosis. Women with breast cancer who develop chemotherapy-induced ovarian failure should have their bone density monitored and treatments to attenuate bone loss should be evaluated.

Serum 25-Hydroxyvitamin D Concentrations and Risk for Hip Fractures

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

Does Obesity Really Make the Femur Stronger? BMD, Geometry, and Fracture Incidence in the Women's Health Initiative-Observational Study

Heavier individuals have higher hip BMD and more robust femur geometry, but it is unclear whether values vary in proportion with body weight in obesity. We studied the variation of hip BMD and geometry across categories of body mass index (BMI) in a subset of postmenopausal non‐Hispanic whites (NHWs) from the Womens Health Initiative Observational Cohort (WHI‐OS). The implications on fracture incidence were studied among NHWs in the entire WHI‐OS. Baseline DXA scans of hip and total body from 4642 NHW women were divided into BMI (kg/m2) categories: underweight (<18.5), healthy weight (18.5–24.9), overweight (25–29.9), and mild (30–34.9), moderate (35–39.9), and extreme obesity (>40). Femur BMD and indices of bone axial (cross‐sectional area [CSA]) and bending strength (section modulus [SM]) were extracted from DXA scans using the hip structure analysis (HSA) method and compared among BMI categories after adjustment for height, age, hormone use, diabetes, activity level, femur neck‐shaft angle, and neck length. The association between BMI and incident fracture was studied in 78,013 NHWs from the entire WHI‐OS over 8.5 ± 2.6 (SD) yr of follow‐up. Fracture incidence (cases/1000 person‐years) was compared among BMI categories for hip alone, central body (hip, pelvis, spine, ribs, and shoulder girdle), upper extremity (humerus and distal), and lower extremity (femur shaft and distal but not hip). Femur BMD, CSA, and SM were larger in women with higher BMI, but values scaled in proportion to lean and not to fat or total body mass. Women with highest BMI reported more falls in the 12 mo before enrollment, more prevalent fractures, and had lower measures of physical activity and function. Incidence of hip fractures and all central body fractures declined with BMI. Lower extremity fractures distal to the hip trended upward, and upper extremity incidence was independent of BMI. BMD, CSA, and SM vary in proportion to total body lean mass, supporting the view that bones adapt to prevalent muscle loads. Because lean mass is a progressively smaller fraction of total mass in obesity, femur BMD, CSA, and SM decline relative to body weight in higher BMI categories. Traumatic forces increase with body weight, but fracture rates at the hip and central body were less frequent with increasing BMI, possibly because of greater soft tissue padding. There was no evident protective effect in fracture rates at less padded distal extremity sites. Upper extremity fractures showed no variation with BMI, and lower extremity fracture rates were higher only in the overweight (BMI = 25–29.9 kg/m2).

Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension.

SUMMARY To determine whether prostaglandins contribute to the depressor response to the converting enzyme inhibitor, captopril, we measured the plasma prostaglandln levels by radioimmunoassay before and after captopril administration, and then examined the effect of prostaglandin synthetase inhibition on captoprils antihypertensive effect. When a single oral captopril dose (25-100 mg) was given to 31 sodium-restricted patients with essential hypertension, the levels of the stable transformation product of prostacyclin remained immeasurable and that of thromboxane A, did not change, while the metabolite of PGE, (PGE-M) increased by 53% (34 ± 4 pg/ml pre-captopril, 52 ± 5 pg/ral after; p < 0.001). As expected, blood pressure (BP) and angiotensin II (AH) levels fell, and kinin levels rose (all changesp < 0.001). We then blocked prostaglandin synthesis in 18 of these subjects for 24 hours with either indomethacin (n = 10) or aspirin (n = 8) before repeating the captopril dose, to assess the importance of these PGE-M increments. The PGE-M responses to captopril were effectively blocked in nine of 10 subjects receiving indomethacin and four of eight receiving aspirin. In these 13 patients, the depressor response to captopril was significantly blunted (− 20 ± 3 mm Hg pre-synthetase inhibition vs − 13 ± 2 mm Hg post; p < 0.05). When these agents did not block the PGE-M response to captopril, the BP response was also unchanged (-15 ± 4 mm Hg pre, −18 ± 5 mm Hg post). Neither indomethacin nor aspirin changed the AH or kinin responses to captopril. We conclude that the prostaglandins may be important mediators of captoprils antihypertensive effect in the sodium-restricted state.

AGA technical review on osteoporosis in hepatic disorders

B one disease is a major complication of chronic liver disease (CLD) and liver transplantation and can result in spontaneous or low-trauma fracturing that significantly impacts on morbidity, quality of life, and even survival. The etiology of these disorders is complex and multifactorial. The general biology and pathogenesis of osteoporosis, including its relationship with inflamma-tory states, diagnostic tools, and clinical utility of bone densitometry, has been reviewed elsewhere in the AGA Technical Review on Osteoporosis in Gastrointestinal Diseases. 1 In this review, issues specific to osteoporosis and hepatic disease will be discussed. Methods routinely used in skeletal assessment and relevant terminology will be briefly summarized. The development of bone densitometry has made it possible to measure bone mass and assess its contribution to fracture risk. It is generally accepted that bone mass is the single best predictor of in vitro skeletal strength 2– 4 and fracture risk. 5 The most widely available bone density technology is dual-energy x-ray absorptiometry (DXA), which is currently the gold standard for measurement of bone mass. Conventional DXA (also known as central DXA) is able to measure all skeletal structures, including those in the thicker body regions such as the lumbar spine and hip. The related isotopic method, dual-photon absorptiometry (DPA), is now rarely used. Other methods are available for measuring bone in the extremities using radionuclide sources, x-ray, or ultra-sonography. Quantitative computed tomography can be used to measure bone density but is infrequently used outside of research settings. Conventional diagnostic ra-diographs are still an important component in the assessment of osteoporosis because the presence of fragility fractures (such as vertebral compression fractures) indicates osteoporosis and high fracture risk independent of bone mineral density (BMD). Bone density measurements follow a bell-shaped (Gaussian) distribution. Therefore, they are described as the number of standard deviations (SD) that the value deviates from the mean for normal controls. Age-related changes in bone density must be taken into account. The Z-score refers to the number of SD above or below the mean for an age-matched population. The T-score refers to the number of SD above or below the mean for a young adult population (corresponding to peak bone mass). A World Health Organization report formulated diagnostic ranges for osteoporosis based on T-score 6 : normal is a T-score greater than Ϫ1.0 (i.e., the patients BMD is no more than 1 deviation below the young adult mean), osteopenia (low bone mass) …

Expression of an Extracellular Calcium‐Sensing Receptor in Human and Mouse Bone Marrow Cells

The cloning of a G protein–coupled, extracellular calcium (Ca2+e)‐sensing receptor (CaR) from bovine parathyroid provided direct evidence that Ca2+e‐sensing can occur through receptor‐mediated activation of G proteins and their associated downstream regulators of cellular function. CaR transcripts and protein are present in various tissues of humans and other mammals that are involved in Ca2+e homeostasis, including parathyroid, kidney, and thyroidal C‐cells. The present study was performed to determine whether bone marrow cells express the CaR, since cells within the marrow space could be exposed to substantial changes in Ca2+e related to bone turnover. Using DNA and RNA probes from the human parathyroid CaR cDNA, we identified CaR transcripts of 5.2 and ∼4.0 kilobases by Northern analysis of poly(A+) RNA from low‐density mononuclear cells isolated from whole human bone marrow that are putatively enriched in marrow progenitor cells, including bone cell precursors. In situ hybridization also identified CaR transcripts in the same cell preparations. Reverse transcription‐polymerase chain reaction demonstrated >99% nucleotide identity between transcripts from human bone marrow cells and the corresponding regions of the human CaR cDNA. Antisera specific for several different regions within the extracellular domain of the CaR were reactive with low‐density human marrow cells that were either adherent or nonadherent to plastic. About one‐third of the adherent, CaR‐immunoreactive cells were also positive for alkaline phosphatase, a nonspecific marker of preosteoblasts, osteoblasts, and assorted cells of the colony‐forming unit‐fibroblast lineage. In addition, a substantial fraction (∼60%) of low density murine marrow cells cultured for 1 week at 4.8 mM Ca2+e expressed both CaR immunoreactivity and nonspecific esterase, an enzyme expressed by monocyte/macrophages and fibroblasts. Finally, erythroid precursors and megakaryocytes from murine marrow as well as blood platelets expressed abundant CaR immunoreactivity, while peripheral blood erythrocytes and most polymorphonuclear leukocytes did not. These studies indicate that the CaR is present in low‐density mononuclear bone marrow cells as well as in cells of several hematopoietic lineages and could potentially play a role in controlling the function of various cell types within the marrow space.