Bone minerals changes in obese women during a moderate weight loss with and without calcium supplementation.

A significant relationship between body weight (BW) and bone mass (BM) has been established previously. A diet-induced weight loss is accompanied by a significant decrease in bone mineral density (BMD) and total body bone mineral (TBBM), but the underlying mechanisms are not clarified. Sixty-two obese women were included in the study. Dual-energy X-ray absorptiometry (DXA) and measurements of a series of calcium-regulating hormones and biochemical markers of bone turnover were performed at baseline and after 1 month and 3 months on a low calorie diet. Thirty of the women were randomized to a daily supplement of 1 g of calcium. After an additional 3 months without dietary prescriptions or calcium supplements, a subgroup of 48 subjects (24 from each group) were scanned again using DXA. There was a significant decrease in TBBM after 1 month and 3 months. A similar pattern was observed in the bone mineral content (BMC) of the lumbar spine in the patients who did not receive a calcium supplement, whereas no changes occurred in the supplemented group. The initial calcium supplementation seemed to protect against bone loss in the lumbar spine but not in the TBBM. In the nonsupplemented group, a statistically significant inverse correlation was found between the calcium/creatinine ratio in the morning urine and the changes in BMC of the lumbar spine. Such a relationship was not seen in the calcium-supplemented group. In the nonsupplemented group, no significant biochemical changes were observed, whereas a significant decrease in serum parathyroid hormone (PTH) was seen in the calcium-supplemented group. This might explain some of the protective effects of calcium supplementation on trabecular bone mass. We conclude that a diet-induced weight loss is accompanied by a generalized bone loss, which probably is explained mainly by a reduced mechanical strain on the skeleton. This loss can be partly inhibited by a high calcium intake. Therefore, a calcium supplementation should be recommended during weight loss, even if the diet contains the officially recommended amounts of calcium.

Orlistat (Ro 18-0647), a lipase inhibitor, in the treatment of human obesity: a multiple dose study.

OBJECTIVE: To evaluate efficacy and tolerability of the lipase inhibitor Orlistat (Ro 18-0647) in doses of 10, 60 and 120 mg three times a day in addition to a mild hypocaloric diet containing 30% of calories as fat. DESIGN: 4 week single-blind placebo run-in period of diet alone followed by a 12 week double-blind, placebo-controlled, randomized treatment period. SETTINGS: Five European outpatient clinics specializing in endocrinology and/or the treatment of obesity, one central laboratory. SUBJECTS: Of 237 healthy obese subjects meeting the inclusion criteria, 188 showed compliance to the diet during the run-in period and were randomized for the treatment period. MAIN OUTCOME MEASURES: Primary efficacy criterion was the difference in weight loss after 12 weeks of treatment between the Orlistat treated groups and the diet alone group. Secondary efficacy criteria were changes in serum total, HDL- and LDL-cholesterol. RESULTS: Compared to placebo a mean (+/- s.e.) additional weight loss of 0.63 +/- 0.54 kg with 30 mg a day (P = 0.246), 0.71 +/- 0.55 kg with 180 mg a day (P = 0.190) and 1.75 +/- 0.54 kg with 360 mg a day was seen (P = 0.001) or Orlistat was observed. Overall data indicated dose-dependency. Small decreases were seen in total and LDL-cholesterol (significant in the 180 and 360 mg a day groups) and LDL- to HDL-cholesterol ratio (significant in the 360 mg a day group only). Mild, mostly gastrointestinal side effects were observed more frequently in the Orlistat groups and caused premature withdrawal from the study in only four patients. No marked laboratory abnormalities were shown, including the lipid-soluble vitamins A, D and E. CONCLUSION: Orlistat, in an apparently dose-dependent manner, leads to additional weight loss compared to diet alone and overall, is well tolerated.

Bone loss accompanying voluntary weight loss in obese humans.

Dual-energy x-ray absorptiometry was performed in 51 obese patients before and after 15 weeks on a low-calorie diet. Of these patients 39 were scanned 6 months later. Total and regional body bone mineral, fat mass, and fat free mass were measured. In the control group, 9 normal volunteers were scanned with up to 23 kg lard distributed anteriorly, and 9 volunteers were scanned with 15 kg lard posteriorly. The lard was then gradually removed to simulate the fat loss found in the patient group. In the patient group the mean weight loss was 12,273 g, the mean fat loss was 11,014 g, and the mean bone mineral loss was 171.6 g after 15 weeks. Close correlation between the fat loss and the bone loss was found and calculated to be 16.5 g bone mineral per kg fat in the patient group, in contrast with 0.5 g bone mineral per kg fat in the control group. In the control group, 15 kg lard placed posteriorly had no statistically significant effect on the bone measurements. If weight and fat were regained at the scanning time 6 months later, the bone mineral was regained as well. Patients with further weight loss continued to lose bone mineral. One patient lost 754 g bone mineral in 9 months. Her weight loss was 45 kg in that period, and the bone mineral content remained within the range for normal women at her age. Methodologic and pathogenetic problems are discussed. It is concluded that the observed bone loss should be regarded as physiologic normalization accompanying a diet-induced weight loss in the obese.

24-hour energy expenditure and substrate oxidation rates are unaffected by body fat distribution in obese women.

Twenty-four-hour energy expenditure (EE) and nonprotein respiratory quotient (RQnp) were measured by indirect calorimetry in 19 upper-body-obese (UBO) and 15 lower-body-obese (LBO) women with similar body mass index (BMI) and body fat percent. The measurements were performed in a respiration chamber on a predetermined physical activity program and a controlled diet. No differences between the UBO and LBO groups were found in 24-hour, daytime, and sleeping EE after adjustment for differences in fat-free mass (FFM). Furthermore, no group effect was observed in RQnp, but a positive correlation was found between RQnp and age. Despite the fact that an increased free fatty acid (FFA) turnover has been found in UBO subjects, the present study does not support the contention that upper-body obesity is accompanied by an increased lipid oxidation.

The acute and chronic effects of ephedrine/caffeine mixtures on energy expenditure and glucose metabolism in humans.

This paper describes a 24-week open follow-up trial with reduced obese patients all receiving an ephedrine/caffeine combination (20 mg/200 mg) three times a day. The study was a continuation of a previous 24-week double-blind placebo-controlled study where the ephedrine/caffeine mixture had shown superior weight-reducing properties when compared with either ephedrine alone (20 mg) or caffeine alone (200 mg) three times a day. The medication was stopped between weeks 24-26 in order to evaluate withdrawal symptoms. The follow-up period was from weeks 26 to 50. Of 127 patients included, 99 completed the follow-up treatment, which resulted in an additional weight loss of 1.1 kg (P = 0.02). Adverse drug reactions were all minor and temporary. We conclude that the ephedrine/caffeine combination is safe and effective in long-term treatment in improving and maintaining weight loss. The side-effects are minor and transient and no clinically relevant withdrawal symptoms have been observed.

Safety and efficacy of long-term treatment with ephedrine, caffeine and an ephedrine/caffeine mixture.

In a randomized, placebo-controlled, double blind study, 180 obese patients were treated by diet (4.2 MJ/day) and either an ephedrine/caffeine combination (20mg/200mg), ephedrine (20mg), caffeine (200mg) or placebo 3 times a day for 24 weeks. 141 patients completed this part of the study. All medication was stopped between week 24-26 in order to catch any withdrawal symptoms. From week 26 to 50, 99 patients completed treatment with the ephedrine/caffeine compound in an open trial design, resulting in a statistically significant (p = 0.02) weight loss of 1.1kg. In another randomized, double-blind, placebo-controlled 8 week study on obese subjects we found the mentioned compound showed lean body mass conserving properties. We conclude that the ephedrine/caffeine combination is effective in improving and maintaining weight loss, further it has lean body mass saving properties. The side effects are minor and transient and no withdrawal symptoms have been found.

The effect of ephedrine/caffeine mixture on energy expenditure and body composition in obese women.

Treatment with beta 2-agonists promotes fat loss and muscle growth in numerous species, but human studies are lacking. We studied the effect of a compound with beta 2-agonistic properties (ephedrine 20 mg/caffeine 200 mg [E + C]). Fourteen obese women were treated with a 4.2-MJ/d diet and either E + C or placebo (P) three times per day for 8 weeks in a double-blind study. Weight-loss was not different in the groups, but the E + C group lost 4.5 kg more body fat and 2.8 kg less fat-free mass (FFM). The decrease in 24-hour energy expenditure (EE) seen in the P group was 10% at day 1 and 13% at day 56, but was only 7% and 8% in the treated group (P = .044). The higher EE in the E +C group was entirely covered by fat oxidation. These findings provide evidence that promotion of fat loss and preservation of FFM during weight reduction may also be achieved pharmacologically in humans.

The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. A double blind trial.

The sympathomimetic agent ephedrine has potent thermogenic and anti-obesity properties in rodents. The effect is markedly enhanced by caffeine, while caffeine given alone has no effect. This study was undertaken to find out if a similar weight reducing synergism between ephedrine and caffeine is present in obese patients. In a randomized, placebo-controlled, double blind study, 180 obese patients were treated by diet (4.2 MJ/day) and either an ephedrine/caffeine combination (20mg/200mg), ephedrine (20 mg), caffeine (200 mg) or placebo three times a day for 24 weeks. Withdrawals were distributed equally in the four groups, and 141 patients completed the trial. Mean weight losses was significantly greater with the combination than with placebo from week 8 to week 24 (ephedrine/caffeine, 16.6 +/- 6.8 kg vs. placebo, 13.2 +/- 6.6 kg (mean +/- s.d.), P = 0.0015). Weight loss in both the ephedrine and the caffeine groups was similar to that of the placebo group. Side effects (tremor, insomnia and dizziness) were transient and after eight weeks of treatment they had reached placebo levels. Systolic and diastolic blood pressure fell similarly in all four groups. We conclude, that in analogy with animal studies, the ephedrine/caffeine combination is effective, while caffeine and ephedrine separately are ineffective for the treatment of human obesity.

Pharmacology of thermogenic drugs.

Thermogenic combinations of ephedrine with caffeine and newer selective beta 3-agonists are being assessed for the treatment of obesity. The actions of beta-agonists may be multifaceted, with acute stimulation of thermogenic mechanisms in various tissues. During chronic treatment recruitment of brown fat may occur and hypertrophy of skeletal muscle may occur and simultaneously increase lean body tissue and reduce fat mass by stimulation of lipolysis and energy expenditure. The weight-reducing effect of an ephedrine-caffeine combination was superior to placebo treatment during 24 wk of energy restriction in obese women, whereas caffeine and ephedrine separately had no effect. In a second study it was found that ephedrine-caffeine compared with placebo preserved fat-free mass and enhanced fat loss, which could be accounted for both by anorexia (75%) and by increased thermogenesis (25%). The ephedrine-caffeine compound seems useful for the treatment of obesity and may serve as reference in the clinical assessment of new beta-agonists.

Dexfenfluramine as adjuvant to a low-calorie formula diet in the treatment of obesity: a randomized clinical trial.

Dexfenfluramine (dF) was compared to placebo as adjuvant to a very energy-restricted diet (1.6-4.2 MJ/24 h). The diet was continued as long as possible or until a satisfactory weight loss had been achieved, and dietary efforts were continued throughout the study. Of the 37 females and five males included, 71 per cent could be followed up for 12 months. Initial BMI ranged from 28 to 54 kg/m2. The lowest body weight was reached 1 month earlier in the dF group (P = 0.037). Throughout the study, the reduction of excess weight (REW) was greater in dF patients (P less than 0.05 only at 4 and 6 months). At 6 months, excess weight had declined by 15 per cent more in the dF group than in the placebo group (95 per cent confidence limits of the median being 1-31 per cent). Between 6 and 12 months, both groups regained weight significantly, the rates of regain differing only insignificantly. At 12 months, excess weight showed a net decrease of only 8 per cent more in the dF group than in the placebo group (95 per cent confidence limits being -7 to +24 per cent). Therefore, REW showed no significant group difference after 12 months. Type of obesity (android or gynoid) as determined by waist to hip ratio had no significant impact on either weight loss, REW, reductions of waist and hip circumferences, or on waist to hip ratio changes. S-alkaline phosphatases and s-uric acid declined significantly in the dF group only. Side-effects were all mild and their prevalence showed no group difference.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of long-term dexfenfluramine treatment on 24-hour energy expenditure in man. A double-blind placebo controlled study.

In order to investigate the effect of long-term treatment with dexfenfluramine (dF) on 24-hour energy expenditure (EE), 10 obese females were studied in a double-blind design. Shortly before and 4 weeks after cessation of a 13 months treatment period with either dF (30 mg/day) or placebo (PL) the 24-hour EE was measured. The measurements were performed using a 24 m3 direct heat sink calorimeter with continuous real time measurements of evaporative and sensible heat losses. The patients performed a standardized program of exercise, rest and meals. The measurements were performed at 24 degrees C and at a humidity between 3 and 11 g/m3. Discontinuation of dF treatment did not change energy expenditure significantly from placebo, neither when expressed in kJ/kg lean body mass nor in kJ/kg body weight. After cessation of treatment total 24-hour EE decreased likewise nonsignificantly by 2.9 percent in the dF group and by 4.0 percent in the PL group. EE measured over 24 hours was subdivided into day and night periods and into resting energy expenditure as well as a measurement of the heat losses over a period of 3 hours after a meal. This subdivision of the EE showed similar nonsignificant differences. The conclusion is therefore that dF possesses no significant thermogenic effect during long-term administration in human obese subjects.

Impaired glucose-induced thermogenesis and arterial norepinephrine response persist after weight reduction in obese humans.

A reduced thermic response and an impaired activation of the sympathetic nervous system (SNS) has been reported after oral glucose in human obesity. It is, however, not known whether the reduced SNS activity returns to normal along with weight reduction. The thermic effect of glucose was lower in eight obese patients than in matched control subjects (1.7% vs 9.2%, p less than 0.002). The increase in arterial norepinephrine after glucose was also blunted in the obese patients. After a 30-kg weight loss their glucose and lipid profiles were markedly improved but the thermic effect of glucose was still lower than that of the control subjects (4.2%, p less than 0.001). The glucose-induced arterial norepinephrine response remained diminished in the reduced obese patients whereas the changes in plasma epinephrine were similar in all three groups. The results suggest that a defective SNS may be a cause in the development of obesity.

Dietary fibre added to very low calorie diet reduces hunger and alleviates constipation.

To examine whether supplement of dietary fibre may improve compliance to a very low calorie diet (VLCD) a nutrition powder providing 388 kcal/day (men: 466 kcal/day) was compared with a similar version containing plant fibre 30 g/day. Twenty-two obese patients entered the study. After a baseline habitual diet, they were randomized to two weeks of treatment in a single blind design to either VLCD with or without dietary fibre. Subsequently, they were crossed over for further 2 weeks of treatment. All patients completed the study. The two groups had similar weight losses (about 10 kg/4 weeks), and dietary fibre did not improve this result. During VLCD with fibre hunger ratings were significantly lower than during VLCD without fibre (fibre effect, ANOVA; P less than 0.01). Bowel movements decreased from 1.9/day on habitual diet to 0.7/day on VLCD without fibre, but increased to 1.0/day by fibre supplement (fibre effect, P less than 0.01). No effect of fibre supplementation to VLCD was found on satiety, consistency of faeces and flatulence. The supplement of dietary fibre did not influence plasma concentrations of divalent cations as calcium, iron or magnesium, nor did it add any lowering effect on plasma glucose, cholesterol or triglyceride to that of VLCD. In conclusion, the supplement of dietary fibre to VLCD may improve compliance by reducing hunger and increasing the number of bowel movements, without impairment of absorption of divalent cations.