The purpose of this randomized, double-masked, placebo-controlled study was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. The study was conducted at 80 study centers in Europe and Australia. Postmenopausal women (n = 1226) with two or more prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day, and up to 500 IU/day vitamin D if baseline levels were low. The study duration was 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for assessment of vertebral fractures, and bone mineral density was measured by dual-energy X-ray absorptiometry at 6-month intervals. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was seen within the first year (p = 0.001). The fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group over 2 years. The risk of nonvertebral fractures was reduced by 33% compared with control over 3 years (p = 0.06). Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of control. Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease.

Background: Strontium ranelate, a new oral drug shown to reduce vertebral fracture risk in postmenopausal women with osteoporosis, was studied in the Treatment of Peripheral Osteoporosis (TROPOS) study to assess its efficacy and safety in preventing nonvertebral fractures also. Methods: Strontium ranelate (2 g/d) or placebo were randomly allocated to 5091 postmenopausal women with osteo-porosis in a double-blind placebo-controlled 5-yr study with a main statistical analysis over 3 yr of treatment. Findings: In the entire sample, relative risk (RR) was reduced by 16% for all nonvertebral fractures (P 0.04), and by 19% for major fragility fractures (hip, wrist, pelvis and sa-crum, ribs and sternum, clavicle, humerus) (P 0.031) in strontium ranelate-treated patients in comparison with the placebo group. Among women at high risk of hip fracture (age >74 yr and femoral neck bone mineral density T score <3, corresponding to 2.4 according to NHANES reference) (n

Background: Strontium ranelate, a new oral drug shown to reduce vertebral fracture risk in postmenopausal women with osteoporosis, was studied in the Treatment of Peripheral Osteoporosis (TROPOS) study to assess its efficacy and safety in preventing nonvertebral fractures also.Methods: Strontium ranelate (2 g/d) or placebo were randomly allocated to 5091 postmenopausal women with osteoporosis in a double-blind placebo-controlled 5-yr study with a main statistical analysis over 3 yr of treatment.Findings: In the entire sample, relative risk (RR) was reduced by 16% for all nonvertebral fractures (P ‫؍‬ 0.04), and by 19% for major fragility fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, humerus) (P ‫؍‬ 0.031) in strontium ranelate-treated patients in comparison with the placebo group. Among women at high risk of hip fracture (age >74 yr and femoral neck bone mineral density T score <؊3, corresponding to ؊2.4 according to NHANES reference) (n ‫؍‬

Objective: To assess the in¯uence of smoking on serum parathyroid hormone (PTH), serum vitamin D metabolites, serum ionized calcium, serum phosphate, and biochemical markers of bone turnover in a cohort of 510 healthy Danish perimenopausal women. Design: A cross-sectional study. Setting: Copenhagen, Denmark. Subjects: Five-hundred-and-ten healthy women aged 45 ± 58 y, included 3 ± 24 months after last menstrual bleeding. None were using hormone replacement therapy. Methods: The women were grouped according to their current smoking status. The two groups were compared with regard to serum levels of 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25-(OH) 2 D), intact PTH, ionized calcium and phosphate, osteocalcin, as well as urine pyridinolines. Bone mineral density (BMD) was measured with DEXA-scans. Multiple regression analyses were performed to detect the effect of potentially confounding lifestyle factors, such as calcium and vitamin D intakes, alcohol and coffee consumption, sunbathing, and physical exercise. Results: Fifty percent were current smokers. Smokers had signi®cantly reduced levels of serum 25OHD (P 0.02), 1,25(OH) 2 D (P 0.001), and PTH (P`0.001). There was no difference in serum ionized calcium between smokers and non-smokers. We found a negative effect of smoking on serum osteocalcin (P 0.01), while urinary pyridinolines were similar in the two groups. The small differences in lifestyle between the two groups could not explain these ®ndings. Smokers had small but signi®cant reductions in bone mineral density. Conclusions: Smoking has a signi®cant effect on calcium and vitamin D metabolism, which is not likely to be explained by other confounding lifestyle factors. The depression of the vitamin D-PTH system seen among smokers may represent another potential mechanism for the deleterious effects of smoking on the skeleton, and may contribute to the reported risk of osteoporosis among smokers.

1. Eleven patients with the bone loss of ageing were treated with the vitamin D analogue 1 alpha-hydroxycholecalciferol and calcium for 3--6 months. 2. Muscle biopsies were taken from the vastus lateralis before and after the treatment and the activity of several enzymes was measured. Succinate dehydrogenase and total phosphorylase activities, which are a measure of the oxidative capacity, were low and increased significantly with the treatment. The lactate dehydrogenase activity, which can be taken as a measure of the anaerobic metabolism, was normal and did not change with treatment. The phosphagen stores, ATP and creatine phosphate were low and increased to normal with treatment. 3. Histochemical classification of the fibre composition revealed that the treatment induced an increase in the relative number of fast-twitch a (FTa or type II A) fibres accompanied by a reduction of the fast-twitch b (FTb or type II B) fibres. The cross-sectional area of the FTa fibres also increased with the treatment. 4. The present findings indicate that treatment with the active vitamin D analogue, 1 alpha-hydroxycholecalciferol, and calcium improves the myopathy associated with the bone loss of ageing.

We conducted this study to assess the prevalence of vitamin D insufficiency in a population of normal perimenopausal women, to examine the influence of sun exposure and vitamin D intake on the concentration of 25-hydroxyvitamin D (25OHD) and to examine the association between parathyroid hormone (PTH) and 25OHD. A total of 2016 healthy women aged 45±58, who had recently undergone a natural menopause, were enrolled over a 2´5-year period in the Danish Osteoporosis Prevention Study. A marked seasonal fluctuation of 25OHD was seen, with an abrupt rise in June and high values until October. The fluctuation could be related to number of hours of sunshine per month with a two months time lag. Dietary vitamin D intake, vitamin supplementation, sunlight exposure, and use of sun-bed were all significantly related to 25OHD concentrations. Sun exposure seemed to contribute the most. The overall prevalence of vitamin D deficiency (defined as serum 25OHD , 25 nmolal) was 7 %. However, in the subgroup avoiding direct sunshine and abstaining from vitamin D supplementation 32´8 % were vitamin D deficient in the winter±spring period. Although mean PTH was increased in the group with low serum 25OHD, PTH was not a sensitive marker of hypovitaminosis D in the individual, as only 16 % of those with vitamin D deficiency had PTH levels above normal range. Thus, we have shown, that healthy middle-aged Danish women are prone to vitamin D insufficiency in the winter±spring period, if they avoid sun exposure in the summer period and abstain from vitamin D supplementation.

The effects of 7 years of risedronate treatment were evaluated in a second 2-year extension of a 3-year vertebral fracture study in women with osteoporosis. For the first 5 years of the study, women received risedronate 5 mg/day or placebo according to the original randomization, with maintenance of blinding. All the women who entered into the 6-7 years extension study received risedronate 5 mg/day. Endpoints included vertebral and nonvertebral fracture assessments, changes in biochemical markers of bone turnover, and bone mineral density (BMD) measurements. A total of 164 women (placebo/risedronate group, 81; risedronate group, 83) entered the 6-7 years extension study and 136 (83%) completed the study. Annualized incidence of new vertebral fractures during the 6-7 years was similar between the 2 treatment groups (3.8%). The incidence of vertebral fractures did not change in the 7-year risedronate group during the 6-7 years as compared to 4-5 years, while a significant reduction was observed in the placebo group that switched to risedronate treatment during years 6-7. The incidence of nonvertebral fractures was 7.4% and 6.0% in the placebo/risedronate and risedronate groups, respectively, during years 6-7. Urinary N-telopeptide decreased from baseline by 54% and 63% at 3 months and 7 years, respectively, in the risedronate group. The increases in BMD from baseline after 5 years of risedronate treatment were maintained or increased further during years 6-7; lumbar spine BMD after 5 and 7 years of risedronate treatment increased from baseline by 8.8% and 11.5%, respectively, for this extension study population. Risedronate was well tolerated and the occurrence of upper gastrointestinal adverse events was low. After 7 years of continuous risedronate treatment there were significant increases in BMD and decreases in bone turnover to within premenopausal levels and there was no indication of any loss of anti-fracture efficacy.

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 calciumregulating 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.