Osteoprotegerin and its ligand: A new paradigm for regulation of osteoclastogenesis and bone resorption.
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In just 3 years, striking new advances have been made in understanding the molecular mechanisms that govern the crosstalk between osteoblasts/stromal cells and hemopoietic osteoclast precursor cells that leads to osteoclastogenesis. Led first by the discovery of osteoprotegerin (OPG), a naturally occurring protein with potent osteoclastogenesis inhibitory activity, rapid progress was made to the isolation of RANKL, a transmembrane ligand expressed on osteoblasts/stromal cells, that binds to RANK, a transmembrane receptor on hemopoietic osteoclast precursor cells. The interaction of RANK and RANKL initiates a signaling and gene expression cascade that results in differentiation and maturation of osteoclast precursor cells to active osteoclasts capable of resorbing bone. Osteoprotegerin acts as a decoy receptor; it binds to RANKL and blocks its interaction with RANK, thus inhibiting osteoclast development. Many of the calciotropic hormones and cytokines, including vitamin D3, parathyroid hormone, prostaglandin E2 and interleukin-11, appear to stimulate osteoclastogenesis through the dual action of inhibiting production of OPG and stimulating production of RANKL. Estrogen, on the other hand, appears to inhibit production of RANKL and RANKL-stimulated osteoclastogenesis. Recently, the results of the first clinical trial with OPG supported its potential as a therapeutic agent for osteoporosis. The new understanding provided by the RANK/RANKL/OPG paradigm for both differentiation and activation of osteoclasts has had tremendous impact on the field of bone biology and has opened new avenues for development of possible treatments of diseases characterized by excessive bone resorption. (+info)
Serum 25-hydroxyvitamin D concentrations and related dietary factors in peri- and postmenopausal Japanese women.
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BACKGROUND: Few studies of vitamin D nutrition in Asian populations have been conducted. OBJECTIVE: The objective was to assess 25-hydroxyvitamin D [25(OH)D] concentrations in healthy elderly Japanese women during the winter and to determine whether 25(OH)D concentrations are associated with lifestyle. DESIGN: We investigated 151 women aged 66.5 +/- 6.7 y (f1.gif" BORDER="0"> +/- SD) living in a rural community in February 1999. Serum 25(OH)D and intact parathyroid hormone were measured by using HPLC and an immunoradiometric assay, respectively. Information on lifestyle factors, including sunshine exposure and the consumption of vitamin D-rich foods, was also obtained through an interview. RESULTS: The mean (+/-SD) 25(OH)D concentration was 59.9 +/- 17.0 nmol/L. Vitamin D insufficiencies (<30 nmol/L) were found in 4.6% of the women, a value lower than that found in white populations. No correlation was found between age and 25(OH)D concentrations (r = 0.004, P = 0.957). The 25(OH)D concentration of subjects who consumed fish frequently (>/=4 times/wk) was 10.1 nmol/L higher (P < 0.001) than that of subjects with a moderate consumption of fish (1-3 times/wk). Additionally, those who did not consume eggs had significantly lower 25(OH)D concentrations than did those who consumed eggs >/=1 time/wk (P < 0.05). CONCLUSIONS: : The nutritional status of vitamin D in Japanese populations seems to be better than that in most Western populations. Frequent fish consumption is believed to help maintain adequate concentrations of serum 25(OH)D in elderly Japanese women during the winter. (+info)
Development and validation of the Osteoporosis Risk Assessment Instrument to facilitate selection of women for bone densitometry.
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BACKGROUND: Although mass screening for osteoporosis is not recommended among postmenopausal women, there is no consensus on which women should undergo testing for low bone mineral density. The objective of this study was to develop and validate a clinical tool to help clinicians identify which women are at increased risk for osteoporosis and should therefore undergo further testing with bone densitometry. METHODS: Using Ontario baseline data from the Canadian Multicentre Osteoporosis Study, we identified all cognitively normal women aged 45 years or more who had undergone testing with dual-energy x-ray absorptiometry (DXA) at both the femoral neck and the lumbar spine (L1-L4). Participants who had a previous diagnosis of osteoporosis or were taking bone active medication other than ovarian hormones were excluded. The main outcome measure was low bone mineral density (T score of 2 or more standard deviations below the mean for young Canadian women) at either the femoral neck or the lumbar spine. Logistic regression analysis and receiver operating characteristic (ROC) analysis were used to identify the simplest algorithm that would identify women at increased risk for low bone mineral density. RESULTS: The study population comprised 1376 women, of whom 926 were allocated to the development of the tool and 450 to its validation. A simple algorithm based on age, weight and current estrogen use (yes or no) was developed. Validation of this 3-item Osteoporosis Risk Assessment Instrument (ORAI) showed that the tool had a sensitivity of 93.3% (95% confidence interval [CI] 86.3%-97.0%) and a specificity of 46.4% (95% CI 41.0%-51.8%) for selecting women with low bone mineral density. The sensitivity of the instrument for selecting women with osteoporosis was 94.4% (95% CI 83.7%-98.6%). Use of the ORAI represented a 38.7% reduction in DXA testing compared with screening all women in our study. INTERPRETATION: The ORAI accurately identifies the vast majority of women likely to have low bone mineral density and is effective in substantially decreasing the need for all women to undergo DXA testing. (+info)
Bisphosphonates: safety and efficacy in the treatment and prevention of osteoporosis.
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Osteoporosis affects more than 28 million Americans. With the advent of accessible and affordable diagnostic studies, awareness and recognition of this disease by patients and clinicians are growing. Osteoporotic fractures of the spine and hip are costly and associated with significant morbidity and mortality. Over the past decade, a surge of new antiosteoporotic drugs have been labeled or are awaiting labeling by the U.S. Food and Drug Administration. One class of agents used to treat osteoporosis is the bisphosphonates, which inhibit bone resorption, cause an increase in bone mineral density and reduce the risk of future fractures caused by aging, estrogen deficiency and corticosteroid use. Overall, bisphosphonates have been shown to have a strong safety and tolerability profile. (+info)
Amylin inhibits ovariectomy-induced bone loss in rats.
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Amylin (AMY), a peptide co-secreted with insulin by pancreatic beta-cells, inhibits bone resorption and stimulates osteoblastic activity. The ovariectomized (OVX) rat is an established animal model for human osteoporosis. Thus, the present experiment was performed to study the effects of AMY on estrogen deficiency-induced bone loss in rats. Thirty-one 6-month-old Wistar rats were randomized by body weight (BW) into two groups. The first underwent surgical OVX (n=21). The second was sham-operated (SH; n=10). Sixty days after surgery, 11 OVX rats were s.c. injected with rat AMY (3 microg/100 g BW/day, for 30 days; OVX+AMY), and 10 with solvent alone in the same way (0.15 ml/100 g BW; OVX). Each rat, housed in an individual cage, was fed daily the mean quantity of diet consumed the day before by SH rats. This diet contained 0.24% calcium and 0. 16% phosphorus. The 31 animals were killed on day 90. No difference in daily weight gain and BW was observed between groups. Neither AMY treatment nor OVX had any significant effect upon femoral morphology, femoral failure load, diaphyseal femoral density (representative of cortical bone) and total femoral calcium content. Nevertheless, both distal metaphyseal (representative of cancellous bone) and total femoral bone densities were higher in SH and OVX+AMY than in OVX rats. The highest plasma osteocalcin concentration was measured in OVX+AMY rats. Simultaneously, urinary deoxypyridinoline excretion was lower in OVX+AMY than in OVX rats. These results indicate that in OVX rats, AMY treatment inhibited trabecular bone loss both by inhibiting resorption and by stimulating osteoblastic activity. (+info)
Osteoporosis: the increasing role of the orthopaedist.
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Osteoporosis is an ever-increasing problem as our population ages. However, it is also to a large extent a preventable problem. The orthopaedist now has the ability to determine bone mass, the rate of turnover, and the fracture risk. Skeletal bone mass can be evaluated with DXA; the rate of bone resorption can be determined by assessment of collagen-degradation urinary products; and the weight status, fracture history, and history of smoking can be used to predict the fracture risk in individual patients. The orthopaedic physician also needs to take an active role in advising their younger patients about achieving peak bone mass. All individuals should follow a program that includes adequate calcium replacement, 400 to 800 units of vitamin D, appropriate exercise, avoidance of significant weight loss, and cessation of smoking. At menopause, women should evaluate their risk factors and consider the use of estrogen not only for its skeletal benefits but also for its nonosseous effects. In patients with contraindications or an aversion to hormone therapy, bone densitometry should be performed to determine risks before expensive nonhormonal treatment is initiated. Additional studies such as measurement of collagen degradation products will help establish whether the patient's resorptive rate is high or stable. If the bone mass is 2.5 SDs below normal peak or if there is an increase in resorption, use of either estrogen, bisphosphontes, or calcitonin may be appropriate. If there is evidence of low-turnover osteoporosis with decreased osteoblast formation, sodium fluoride should be considered. Two thirds of the cost of osteoporosis in the United States is due to hip fractures. The orthopaedist is the primary physician who comes in contact with these fracture patients. It is therefore his or her responsibility to become knowledgeable about the treatment and prevention of osteoporosis. The bisphosphonates, hormones, and calcitonin provide predictable restoration of bone mass and significantly decrease the rate of osteoporotic fractures. (+info)
Acute effects of etidronate on glucocorticoid-induced bone degradation.
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OBJECTIVES: To study the acute short-term effects on the biochemical parameters of calcium and bone homeostasis in post-menopausal women treated with a high dose of prednisone alone or with additional etidronate, before and during 5 days of treatment. METHODS: Serum calcium, phosphorus, creatinine, alkaline phosphatase activity, osteocalcin, carboxy-terminal propeptide of type I procollagen (PICP), cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), parathyroid hormone (PTH), 25-hydroxyvitamin D and urinary excretion of calcium over 24 h were measured before and during 5 days of treatment in 14 post-menopausal women treated with a high dose of prednisone (60 mg/day) alone (group A) or combined with cyclical etidronate (group B). RESULTS: Significant differences from baseline were found in osteocalcin and urinary excretion of calcium in both groups and for ICTP in group B. Significant differences between groups were calculated at day 5 of the study for osteocalcin, ICTP and 24 h urine calcium excretion (P < 0.01). Urinary excretion of calcium over 24 h increased in group A (+14.7%; P < 0.05) and decreased in group B (-22.1%; P < 0.01). Osteocalcin levels decreased in group A (- 38.1%) and increased in group B (+27.4%; both P < 0.01). ICTP decreased only in group B (-19.4%; P < 0.01). CONCLUSIONS: The results are consistent with the fact that etidronate is acutely able to prevent bone resorption due to corticosteroids. The increase in osteocalcin in the etidronate-treated group is a new feature. A direct or indirect (PTH, 1,25 vitamin D?) stimulatory effect of etidronate on the osteoblast cannot be excluded. (+info)
Daidzein is more efficient than genistein in preventing ovariectomy-induced bone loss in rats.
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We investigated the ability of genistein and daidzein, two soybean isoflavones, compared with that of 17 alpha-ethinylestradiol, to prevent bone loss in ovariectomized rats, a model for postmenopausal osteoporosis. Female Wistar rats (n = 65; 12 mo old) were either sham-operated (SH; n = 13) or ovariectomized (OVX; n = 52). On d 0, OVX rats were randomly assigned to groups as follows: 13 received genistein [G; 10 mcg/(g body weight. d)], 13 were treated with daidzein [D; 10 mcg/(g body weight. d)], 13 received 17 alpha-ethinylestradiol [E(2); 30 mcg/kg body weight. d)] and 13 were untreated (OVX). Compounds were mixed with a soy protein-free powdered semipurified diet and given orally for 3 mo. On d 90, the bone mineral density (BMD) in lumbar vertebrae, femur and its metaphyseal and diaphyseal zones (rich in cancellous and cortical bone, respectively) was lower in OVX than in SH (P < 0.01). In D or E(2), the four BMD were not different from SH, whereas in G, only the diaphyseal BMD was not different from SH. Image analysis performed in the distal femur metaphysis revealed that the cancellous bone area was lower in OVX than in SH (P < 0.01). Only the area in D was not different from that in SH. Finally, the bone turnover, which was higher in OVX than in SH (P < 0.005 and P < 0.05 for plasma osteocalcin concentration and urinary deoxypyridinoline excretion, respectively), was not different in G, D or E(2) compared with SH. Therefore, consumption of 17 alpha-ethinylestradiol or daidzein was more efficient than genistein in preventing ovariectomy-induced bone loss in rats. (+info)