Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study.

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 > or = 74 yr and femoral neck bone mineral density T score < or = -3, corresponding to -2.4 according to NHANES reference) (n = 1977), the RR reduction for hip fracture was 36% (P = 0.046). RR of vertebral fractures was reduced by 39% (P < 0.001) in the 3640 patients with spinal x-rays and by 45% in the subgroup without prevalent vertebral fracture. Strontium ranelate increased bone mineral density throughout the study, reaching at 3 yr (P < 0.001): +8.2% (femoral neck) and +9.8% (total hip). Incidence of adverse events (AEs) was similar in both groups. CONCLUSION: This study shows that strontium ranelate significantly reduces the risk of all nonvertebral and in a high-risk subgroup, hip fractures over a 3-yr period, and is well tolerated. It confirms that strontium ranelate reduces vertebral fractures. Strontium ranelate offers a safe and effective means of reducing the risk of fracture associated with osteoporosis.

Seven years of treatment with risedronate in women with postmenopausal osteoporosis.

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.

Bone status in rheumatoid arthritis assessed at peripheral sites by three different quantitative ultrasound devices.

Rheumatoid arthritis (RA) is characterized by periarticular and generalized loss of bone mass. Quantitative ultrasound (QUS) has been introduced as a method for the assessment of bone status and fracture risk. In this cross-sectional study bone status was assessed by QUS at different peripheral sites in 27 women with RA (mean disease duration 15 years) and in 36 healthy women matched for age, height and weight. Speed of sound (SOS, m/s), broadband ultrasound attenuation (BUA, dB/MHz) and stiffness of the calcaneus were assessed by a Lunar Achilles device. Amplitude-dependent SOS (Ad-SOS, m/s) of the second to fifth phalanx was measured by a DBM Sonic 1200, and SOS of the distal forearm and third phalanx was measured by a Omnisense multisite scanner. Bone mass (g/cm2 or g) of the hip, spine, distal forearm and total body was measured by dual-energy X-ray absorptiometry. QUS values were significantly reduced in RA at most sites ( p<0.005-0.001), but between-group differences were small, and large overlaps between the groups were noticed. After correction for bone mass, the observed differences remained statistically significant for the calcaneus and distal radius ( p<0.05). Independent associations between ultrasound measures and markers of disease activity were not demonstrated. In conclusion, bone status as assessed by QUS was compromised in RA, but whether ultrasound transmission may serve as a marker of disease progression and fracture risk in the individual patient remains to be clarified in prospective studies.

Dexamethasone, BMP-2, and 1,25-dihydroxyvitamin D enhance a more differentiated osteoblast phenotype: validation of an in vitro model for human bone marrow-derived primary osteoblasts.

In vitro models of bone cells are important for the study of bone biology, including the regulation of bone formation and resorption. In this study, we have validated an in vitro model of human osteoblastic cells obtained from bone marrow biopsies from healthy, young volunteers, aged 20-31 years. Osteoblast phenotypes were induced by either dexamethasone (Dex) or bone morphogenetic protein-2 (BMP-2). Bone marrow was obtained from biopsies at the posterior iliac spine. Cells were isolated by gradient centrifugation and grown to confluence. Cells were treated with 1 nM 1,25-dihydroxyvitamin D (vitamin D), 100 nM Dex, and/or 100 ng/ml BMP-2. The osteoblast phenotype was assessed as alkaline phosphatase (AP) activity/staining, production of osteocalcin and procollagen type 1 (P1NP), parathyroid hormone (PTH)-induced cyclic adenosine mono-phosphate (cAMP) production, and in vitro mineralization. AP activity was increased by Dex, but not by BMP-2 treatment. P1NP production was decreased after Dex treatment, while BMP-2 had no effect on P1NP levels. Osteocalcin production was low in cultures not stimulated with vitamin D. Dex or BMP-2 treatment alone did not affect the basic osteocalcin levels, but in combination with vitamin D, BMP-2 increased the osteocalcin production, while Dex treatment completely suppressed osteocalcin production. Further, PTH-induced cAMP production was greatly enhanced by Dex treatment, whereas BMP-2 did not affect cAMP production. Finally, in vitro mineralization was greatly enhanced in cultures enriched with either BMP-2 or Dex. Cell proliferation was only increased significantly by Dex treatment. In conclusion, the model described produces cells with an osteoblastic phenotype, and both Dex and BMP-2 can be used as osteoblast inducers. However, the two treatments produce osteoblastic cells with different phenotypic characteristics, and a selective activation of some of the most important genes and functions of the mature osteoblast can thus be performed in vitro.

Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience.

Limited placebo-controlled data are available to assess the long-term fracture efficacy of bisphosphonates. In order to determine the effects of 5 years of risedronate treatment, we extended a 3-year, placebo-controlled vertebral fracture study in osteoporotic women for an additional 2 years; women who entered the extension study continued to receive 5 mg risedronate or placebo according to the original randomization, with maintenance of blinding. End points included vertebral and nonvertebral fracture assessments, bone mineral density measurements, and changes in biochemical markers of bone turnover. A total of 265 women (placebo, 130; 5 mg risedronate, 135) entered the study extension and 220 (83%) completed the additional 2 years. Fracture results observed in the study extension were consistent with those observed in the first 3 years. The risk of new vertebral fractures was significantly reduced with risedronate treatment in years 4 and 5 by 59% (95% confidence interval, 19 to 79%, P = 0.01) compared with a 49% reduction in the first 3 years. Rapid and significant decreases in markers of bone turnover observed in the first 3 years were similarly maintained in the next 2 years of treatment. Increases in spine and hip bone mineral density that occurred in the risedronate group during the first 3 years were maintained or increased with a further 2 years of treatment. The mean increase from baseline in lumbar spine BMD over 5 years was 9.3% (P < 0.001). This study demonstrates that the effects of risedronate over 3 years on vertebral fracture and BMD are maintained with a further 2 years of treatment.

Hormone replacement therapy dissociates fat mass and bone mass, and tends to reduce weight gain in early postmenopausal women: a randomized controlled 5-year clinical trial of the Danish Osteoporosis Prevention Study.

The aim of this study was to study the influence of hormone replacement therapy (HRT) on weight changes, body composition, and bone mass in early postmenopausal women in a partly randomized comprehensive cohort study design. A total of 2016 women ages 45-58 years from 3 months to 2 years past last menstrual bleeding were included. One thousand were randomly assigned to HRT or no HRT in an open trial, whereas the others were allocated according to their preferences. All were followed for 5 years for body weight, bone mass, and body composition measurements. Body weight increased less over the 5 years in women randomized to HRT (1.94 +/- 4.86 kg) than in women randomized to no HRT (2.57 +/- 4.63, p = 0.046). A similar pattern was seen in the group receiving HRT or not by their own choice. The smaller weight gain in women on HRT was almost entirely caused by a lesser gain in fat. The main determinant of the weight gain was a decline in physical fitness. Women opting for HRT had a significantly lower body weight at inclusion than the other participants, but the results in the self-selected part of the study followed the pattern found in the randomized part. The change in fat mass was the strongest predictor of bone changes in untreated women, whereas the change in lean body mass was the strongest predictor when HRT was given. Body weight increases after the menopause. The gain in weight is related to a decrease in working capacity. HRT is associated with a smaller increase in fat mass after menopause. Fat gain protects against bone loss in untreated women but not in HRT-treated women. The data suggest that women's attitudes to HRT are more positive if they have low body weight, but there is no evidence that the conclusions in this study are skewed by selection bias.

Bone quality and bone mass as assessed by quantitative ultrasound and dual energy x ray absorptiometry in women with rheumatoid arthritis: relationship with quadriceps strength.

OBJECTIVE: To examine relationships of bone quality as assessed by quantitative ultrasound (QUS) and bone mineral density (BMD, g/cm(2)) with quadriceps strength (QS) in women with rheumatoid arthritis (RA). METHODS: Sixty seven women with RA according to the 1987 American College of Rheumatology (ACR) criteria were examined. Mean (SD) age was 62 (13) years, mean disease duration 15 years. Most were or had been receiving glucocorticoid treatment. Calcaneal bone quality expressed as speed of sound (SOS, m/s), broadband ultrasound attenuation (BUA, dB/MHz), and stiffness was measured by QUS. BMD of the femoral neck, spine, and distal forearm was measured by dual energy x ray absorptiometry (DXA). Maximal voluntary isokinetic quadriceps strength (Nm) was assessed by isokinetic dynamometry. Pain was recorded on a visual analogue scale (VAS), disability was scored by the Stanford Health Assessment Questionnaire (HAQ), and the degree of physical impairment was expressed by the Steinbrocker index (SI). RESULTS: In multiple regression analyses, QS predicted SOS, BUA, and stiffness (r(partial) ranging from 0.36 to 0.45, p<0.005) and femoral neck BMD (r(partial)=0.30, p<0.05) independently of age, height, weight, disease duration, HAQ, VAS, SI, and cumulative steroid dose. BMD of the spine and distal forearm was not associated with QS. After adjustment for covariates, women with subnormal BMD of the femoral neck (T score <-1), had a 20% lower QS than those with normal BMD (p<0.0001). CONCLUSIONS: Calcaneal bone quality and femoral neck BMD were associated with QS in women with RA. This finding indicates that physical activity including muscle strengthening exercises may play a part in the prevention of bone loss in these patients.

Evaluation of methods for prediction of bone mineral density by clinical and biochemical variables in perimenopausal women.

OBJECTIVES: to predict spinal and femoral bone mineral density (BMD) in perimenopausal women from simple clinical and biochemical variables. METHODS: 2016 women 3-24 months past last menstrual bleeding. Mean age 50.1+/-2.8 years. Age, height, weight, number of full term pregnancies, weekly hours of physical activity, sunbathing habits, use of sun bed, daily intake of calcium and vitamin D, smoking habits, consumption of alcohol, coffee, and tea, history of forearm or femoral neck fractures among the parents, serum osteocalcin (S-OC), serum bone specific isoenzyme of alkaline phosphatase (BSAP), and urine hydroxyproline/creatinine ratio (U-OHP) were used as predictors in three different mathematical models. Lumbar spine (L2-L4) and femoral neck BMD were measured by DEXA. Three mathematical models (multiple regression, logistic regression, and discriminant analysis) were applied. RESULTS: the multiple regression explained 19-21% of the total variation, and the logistic regression and discriminant function had a sensitivity between 53 and 67% with specificity ranging from 67 to 80%. Age, S-OC, serum bone specific alkaline phosphatase, and a maternal history of forearm or femoral neck fractures seemed to be reproducible risk factors for low bone mineral density irrespective of the mathematical model applied. When applied to a separate population, the models performed poorly. CONCLUSIONS: Simple clinical and biochemical variables are not useful to predict spinal and femoral BMD in the individual perimenopausal woman.

Vitamin D status and its adequacy in healthy Danish perimenopausal women: relationships to dietary intake, sun exposure and serum parathyroid hormone.

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 ) 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.

Comparison of quantitative ultrasound and dual X-ray absorptiometry in estrogen-treated early postmenopausal women.

Identifying individuals at risk of developing osteoporosis is important in order to initiate early treatment. Many new techniques have been proposed as alternatives for DXA-scanning. Some of these alternatives certainly have advantages, but none have so far been demonstrated to predict fractures better, or even to identify individuals at risk of osteoporosis as well as with the standard method. In this study, comprising a group of women from the Danish Osteoporosis Prevention Study, we wished to investigate whether a technique based on quantitative ultrasound (QUS) could identify individuals with low BMC/BMD as measured by dual X-ray absorptiometry (DXA). Furthermore, we wished to test whether the method could detect differences between untreated individuals and those treated with hormone replacement therapy. We found that QUS could detect differences between the treated and untreated groups, but it was unable to identify women with low BMD, although it might be able to identify persons not at risk of osteoporosis. Low QUS values should be followed by a regular DXA measurement to confirm the presence of osteoporosis.

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.

[Hormone replacement therapy reduces the risk of forearm fracture in postmenopausal women. Results of the Danish Osteoporosis Prevention Study]. / Behandling med hormonsubstitutionsterapi nedsaetter risikoen for underarmsbrud hos postmenopausale kvinder. Resultater fra Danish Osteoporosis Prevention Study.

In a prospective, controlled, comprehensive cohort trial of 2,016 healthy early postmenopausal women aged 45-58 years we studied fracture prevention through the use of oestrogen. There were two main study arms: a randomised arm (randomised to HRT [n = 502] or not [n = 504]) and a non-randomised arm (on HRT [n = 221] or not [n = 789] by own choice). After five years, an intention-to-treat analysis (n = 2,016) showed a reduction in the overall fracture risk (RR = 0.73, 95% CI: 0.50-1.05) and in the forearm fracture risk (RR = 0.45, 95% CI: 0.22-0.90) with oestrogen. Restriction of the analysis to women who had adhered to their initial allocation of either oestrogen (n = 395) or no oestrogen (n = 977) showed a significant reduction in both the overall fracture risk (RR = 0.61, 95% CI: 0.39-0.97) and the risk of forearm fractures (RR = 0.24, 95% CI: 0.09-0.69). We conclude that it is possible to reduce the number of forearm fractures in early postmenopausal women by the use of oestrogen as primary prevention.

Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women - results of the Danish Osteoporosis Prevention Study.

OBJECTIVES: To study the fracture reducing potential of hormonal replacement therapy (HRT) in recent postmenopausal women in a primary preventive scenario. METHODS: Prospective controlled comprehensive cohort trial: 2016 healthy women aged 45-58 years, from three to 24 months past last menstrual bleeding were recruited from a random sample of the background population. Mean age was 50. 8+/-2.8 years, and the number of person years followed was 9335.3. There were two main study arms: a randomised arm (randomised to HRT; n=502, or not; n=504) and a non-randomised arm (on HRT; n=221, or not; n=789 by own choice). First line HRT was oral sequential oestradiol/norethisterone in women with intact uterus and oral continuous oestradiol in hysterectomised women. RESULTS: After five years, a total of 156 fractures were sustained by 140 women. There were 51 forearm fractures in 51 women. By intention-to-treat analysis (n=2016), overall fracture risk was borderline statistically significantly reduced (RR=0.73, 95% CI: 0.50-1.05), and forearm fracture risk was significantly reduced (RR=0.45, 95% CI: 0.22-0.90) with HRT. Restricting the analysis to women who had adhered to their initial allocation of either HRT (n=395) or no HRT (n=977) showed a significant reduction in both the overall fracture risk (RR=0.61, 95% CI: 0.39-0.97) and the risk of forearm fractures (RR=0.24, 95% CI: 0.09-0.69). Compliance with HRT was 65% after five years. CONCLUSIONS: It is possible to reduce the number of forearm fractures and possibly the total number of fractures in recent postmenopausal women by use of HRT as primary prevention.

Vitamin D: should the supply in the Danish population be increased?

A working group was established to evaluate the need for an increased vitamin D intake in the Danish population. Vitamin D is primarily important for calcium homeostasis, calcium absorption in the intestine and calcium content in bones, and thereby for the strength of the bones. Only a few foods provide vitamin D and the intake in the Danish population is low compared to the recommendation. However, vitamin D is also produced by the skin from solar exposure. How much vitamin D is provided this way is not known but it is said to be the most important source. Measures of vitamin D status and clinical signs of vitamin D status are therefore important when assessing the possible need for increased vitamin D intake. Measures of vitamin D status have shown a low status in the elderly but not in the young. More than 50% of nursing-home residents have low blood vitamin D levels and many have biochemical signs of osteomalacia. Vitamin D deficiency increases the risk of osteoporosis. In Denmark, for instance, 13,000 admissions each year are caused by hip fractures alone, almost all among elderly people. Dark-skinned women often constitute a problem with respect to vitamin D sufficiency because of reduced production from the skin secondary to extensive covering, skin pigmentation and many hours spent indoors. It is concluded that the elderly and dark-skinned (veiled) women will benefit from an increased vitamin D supply. Four strategies to increase vitamin D supply were considered: dietary changes, increased solar exposure, dietary supplements with vitamin D and food fortification with vitamin D. It is concluded that the best solution is to recommend dietary supplements with vitamin D to elderly over 65 years, dark-skinned and veiled women and people who, because of disease, are unable to spend time outdoors.

Effects of silicone breast prostheses on the assessment of body composition by dual-energy X-ray absorptiometry.

We examined the influence of silicone breast prostheses on body composition as assessed by dual-energy X-ray absorptiometry (DXA). Eighteen women were measured with and without a pair of silicone breast prostheses placed on the upper part of the trunk simulating endogenous implants. Bone area, bone mineral content (BMC), areal bone mineral density (BMD), lean tissue mass (LTM) and fat tissue mass (FTM) of the total body and of the subregions of the body, i.e. the head, trunk, arms and legs, were measured by a Norland XR-36 DXA scanner. After application of the silicone prostheses, bone area, BMC and BMD of the total body significantly increased by an average of 3.7, 6.6 and 3.4% (P<0.0001), respectively. Total body LTM and FTM were not affected. In the trunk region, changes were more pronounced. Trunk BMC, for example, was overestimated by 17.9% (P<0. 0001). The prostheses also influenced measurements of truncal soft tissue composition, with a small but statistically significant overestimation of both LTM (1.1%) and FTM (2.1%) (P<0.05). No changes in bone mass and soft tissue composition were seen in the head, arms and legs. Activation of a high-density detection software utility provided by the manufacturer had no influence on any of the measurements. We conclude that silicone breast prostheses affect the assessment of body composition by DXA.

Human osteoblastic cells propagate intercellular calcium signals by two different mechanisms.

Effective bone remodeling requires the coordination of bone matrix deposition by osteoblastic cells, which may occur via soluble mediators or via direct intercellular communication. We have previously identified two mechanisms by which rat osteoblastic cell lines coordinate calcium signaling among cells: autocrine activation of P2 (purinergic) receptors leading to release of intracellular calcium stores, and gap junction-mediated communication resulting in influx of extracellular calcium. In the current work we asked whether human osteoblastic cells (HOB) were capable of mechanically induced intercellular calcium signaling, and if so, by which mechanisms. Upon mechanical stimulation, human osteoblasts propagated fast intercellular calcium waves, which required activation of P2 receptors and release of intracellular calcium stores but did not require calcium influx or gap junctional communication. After the fast intercellular calcium waves were blocked, we observed slower calcium waves that were dependent on gap junctional communication and influx of extracellular calcium. These results show that human osteoblastic cells can propagate calcium signals from cell to cell by two markedly different mechanisms and suggest that these two pathways may serve different purposes in coordinating osteoblast functions.

Quadriceps strength in women with a previous hip fracture: relationships to physical ability and bone mass.

Associations between physical ability, level of current physical activity and bone mass were examined in 47 elderly women (mean age 80 years) who had suffered from a hip fracture 3-36 months (mean 17 months) previously. Measures of physical ability included isokinetic quadriceps strength of both the non-fractured and fractured leg, and walking and stair climbing speed. An estimate of current physical activity was made using the Northwick Park activity index questionnaire specifically designed for hip fracture patients. Bone mineral density of the spine and hip (Ward's triangle, femoral neck and trochanter) was assessed by dual energy X-ray absorptiometry. Relationships between the measured parameters were analysed using multiple regression analyses, taking into account the confounding effects of age, height, weight and months since fracture. Quadriceps strength of the fractured leg was on average 18% lower than that of the contralateral leg (p < 0.001). Quadriceps strength of the fractured leg proved to be the most robust predictor of walking speed (Rpartial = 0.69, p < 0.0001), stair climbing speed (Rpartial = 0.46, p < 0.001) and the activity index (Rpartial = 0.56, p < 0.0001). Bone mineral density was independently predicted only by body weight (Rpartial range: 0.45-0.72, p < 0.001), not by any of the parameters of physical ability or by the Northwick Park activity index. In conclusion, quadriceps strength is markedly affected in women with a previous hip fracture and is associated with walking ability and level of physical activity. This study showed that bone mass is linked to body weight, not to physical ability and activity. Thus, the main benefit of muscle strengthening exercises in these women may be to promote mobility.

Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group.

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.

The influence of smoking on vitamin D status and calcium metabolism.

OBJECTIVE: To assess the influence 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)2D), 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 significantly reduced levels of serum 25OHD (P=0.02), 1,25(OH)2D (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 findings. Smokers had small but significant reductions in bone mineral density. CONCLUSIONS: Smoking has a significant 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. SPONSORSHIP: Grants from the Karen Elise Jensens Foundation.