Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteoclasts were isolated from membranous bone from four children without metabolic bone disease who were undergoing craniotomy for either tumor or trauma. Both freshly isolated osteoclasts and those cultured for 4-7 days exhibited the following characteristics: production of tartrate-resistant acid phosphatase (9.5-14.8 units), contraction in response to application of 100 mg/ml of human calcitonin, and formation of resorption lacunae on devitalized bone wafers. Nuclear estrogen and progesterone receptors were demonstrated by immunohistochemical techniques and quantitated in two of the patients by radioimmunoassay (estrogen receptor RIA, 23.6 and 23.8 cpm/micrograms protein; progesterone receptor RIA, 36.7 and 74.2 cpm/micrograms protein). The demonstration of sex steroid hormone receptors in the nucleus of osteoclasts derived from children with normal membranous bone has established a potential mechanism whereby direct modulation of bone resorption by the sex steroid estrogen and progesterone may occur.
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PMID:Osteoclasts isolated from membranous bone in children exhibit nuclear estrogen and progesterone receptors. 223 65

Sequential hormone therapy for advanced breast cancer can offer significant and prolonged disease control with minimal morbidity. Predictors of response to sequential hormone therapy have not previously been identified. Sixty postmenopausal women with advanced or recurrent breast cancer treated with sequential megestrol acetate and tamoxifen were evaluated to identify factors which predict response to sequential therapy. The response rate to first-line therapy was 28% (17/60). Forty-seven percent of patients who responded to the first therapy responded to the second (8/17). Four of 16 patients (25%) who failed the first hormone therapy responded to the second. The response rate to a second hormone therapy was 25% (15/60). Chi-square tests were used to test the association between a response to sequential hormonal therapy and prior chemotherapy, age at first hormone trial, number of sites of disease, dominant site of disease, sequence of hormonal therapy, second response on the basis of first response, presence of soft tissue disease or bone disease alone, and receptor value. A one-tailed Fisher exact probability test revealed that a greater proportion of receptor-positive patients exhibited positive responses to sequential hormonal therapies than did receptor-negative patients. All of the patients who responded to a second hormonal therapy were estrogen receptor (ER)- and progestogen receptor (PgR)-positive. Fisher exact probability tests revealed a statistically significant association between response to initial hormone therapy and response to a subsequent hormone trial. This study suggests that patients who fail their initial hormone trial should be considered for a second hormonal trial if they are ER- and PR-positive.
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PMID:Sequential hormone therapy for advanced breast cancer. 336 99

The skeleton is the most common organ to be affected by metastatic cancer, and tumors arising from the breast, prostate, thyroid, lung, and kidney possess a special propensity to spread to bone. Breast carcinoma, the most prevalent malignancy, causes the greatest morbidity. Of great clinical importance is the observation that metastatic bone disease may remain confined to the skeleton. In these patients, the decline in quality of life and eventual death is due almost entirely to skeletal complications and their subsequent treatment. Bone pain is the most common complication of metastatic bone disease, resulting from structural damage, periosteal irritation, and nerve entrapment. Recent evidence suggests that pain caused by bone metastasis may also be related to the rate of bone resorption. Hypercalcemia occurs in 5-10% of all patients with advanced cancer but is most common in patients with breast carcinoma, multiple myeloma, and squamous carcinomas of the lung and other primary sites. Pathologic fractures are a relatively late complication of bone involvement. The clinical courses of breast and prostate carcinoma are relatively long, with a median survival of 2-3 years. For patients with breast carcinoma, good prognostic factors for survival after the development of bone metastases are good histologic grade, positive estrogen receptor status, bone disease at initial presentation, a long disease free interval, and increasing age. In addition, patients with disease that remains confined to the skeleton have a better prognosis than those with subsequent visceral involvement. For patients with prostate carcinoma, adverse prognostic features include poor performance status, involvement of the appendicular skeleton and visceral involvement, whereas for patients with multiple myeloma, the levels of serum beta2-microglobulin and lactate dehydrogenase and the immunologic phenotype are the most important factors. These prognostic factors may be useful in planning the rational use of bisphosphonates in the treatment of advanced cancer.
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PMID:Skeletal complications of malignancy. 936 26

Osteoporosis is increasingly recognised in men. Low bone mass, risk factors for falling and factors causing fractures in women are likely to cause fractures in men. Bone mass is largely genetically determined, but environmental factors also contribute. Greater muscle strength and physical activity are associated with higher bone mass, while radial bone loss is greater in cigarette smokers or those with a moderate alcohol intake. Sex hormones have important effects on bone physiology. In men, there is no abrupt cessation of testicular function or 'andropause' comparable with the menopause in women; however, both total and free testosterone levels decline with age. A common secondary cause of osteoporosis in men is hypogonadism. There is increasing evidence that estrogens are important in skeletal maintenance in men as well as women. Peripheral aromatisation of androgens to estrogens occurs and osteoblast-like cells can aromatise androgens into estrogens. Human models exist for the effects of estrogens on the male skeleton. In men aged > 65 years, there is a positive association between bone mineral density (BMD) and greater serum estradiol levels at all skeletal sites and a negative association between BMD and testosterone at some sites. It is crucial to exclude pathological causes of osteoporosis, because 30 to 60% of men with vertebral fractures have another illness contributing to bone disease. Glucocorticoid excess (predominantly exogenous) is common. Gastrointestinal disease predisposes patients to bone disease as a result of intestinal malabsorption of calcium and colecalciferol (vitamin D). Hypercalciuria and nephrolithiasis, anticonvulsant drug use, thyrotoxicosis, immobilisation, liver and renal disease, multiple myeloma and systemic mastocytosis have all been associated with osteoporosis in men. It is possible that low-dose estrogen therapy or specific estrogen receptor-modulating drugs might increase BMD in men as well as in women. In the future, parathyroid hormone peptides may be an effective treatment for osteoporosis, particularly in patients in whom other treatments, such as bisphosphonates, have failed. Men with idiopathic osteoporosis have low circulating insulin-like growth factor-1 (IGF-1; somatomedin-1) concentrations, and IGF-1 administration to these men increases bone formation markers more than resorption markers. Studies of changes in BMD with IGF-1 treatment in osteoporotic men and women are underway. Osteoporosis in men will become an increasing worldwide public health problem over the next 20 years, so it is vital that safe and effective therapies for this disabling condition become available. Effective public health measures also need to be established and targeted to men at risk of developing the disease.
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PMID:Osteoporosis in men. New insights into aetiology, pathogenesis, prevention and management. 988 98

As populations age in the world's 7 major pharmaceutical markets, an increasing number of men and women, but especially women during their first postmenopausal decade, are falling victim to a bone disease that can result in hospitalisation, disability and death. This disease is osteoporosis. Indeed, by the year 2007, as many as 153,000,000 people will have experienced at least some significant osteopenia, if not osteoporosis. Although there are many different drugs, such as calcitonin, the bisphosphonates, estrogen and selective estrogen receptor modulators, that can slow or even stop further bone loss, there are currently few that can replace already lost bone by directly stimulating bone growth. However, a family of potent bone-building (or bone-anabolic) peptides is currently undergoing clinical development. These are the first-generation 84-amino acid native parathyroid hormone (PTH) and its 34- to 38-amino acid N terminal fragments, and the potent second-generation mini-PTHs. In this article, we briefly summarise what has so far been learned about how these molecules stimulate the production of new biomechanically strong bone in animals and humans.
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PMID:The bone-building action of the parathyroid hormone: implications for the treatment of osteoporosis. 1049 71

The approach of gene-targeted animal models is likely the most important experimental tool contributing to recent advances in skeletal biology. Modifying the expression of a gene in vivo, and the analysis of the consequences of the mutation, are central to the understanding of gene function during development and physiology, and therefore to our understanding of the gene's role in disease states. Researchers had been limited to animal models primarily involving pharmaceutical manipulations and spontaneous mutations. With the advent of gene targeting, however, animal models that impact our understanding of metabolic bone disease have evolved dramatically. Interestingly, some genes that were expected to yield dramatic phenotypes in bone, such as estrogen receptor-alpha or osteopontin, proved to have subtle phenotypes, whereas other genes, such as interleukin-5 or osteoprotegerin, were initially identified as having a role in bone metabolism via the analysis of their phenotype after gene ablation or overexpression. Particularly important has been the advance in knowledge of osteoblast and osteoclast independent and dependent roles via the selective targeting of genes and the consequent disruption of bone formation, bone resorption, or both. Our understanding of interactions of the skeletal system with other systems, ie, the vascular system and homeostatic controls of adipogenesis, has evolved via animal models such as the matrix gla protein, knock-out, and the targeted overexpression of Delta FosB. Challenging transgenic models such as the osteopontin-deficient mice with mediators of bone remodeling like parathyroid hormone and mechanical stimuli and extending phenotype characterization to mechanistic in vitro studies of primary bone cells is providing additional insight into the mechanisms involved in pathologic states and their potentials for therapeutic strategies. This review segregates characterization of transgenic models based on the category of gene altered, eg, reproductive hormones, calcitropic hormones, growth factors and cytokines, signaling molecules, extracellular matrix molecules and "other" genes. Models are also segregated based on phenotypes that are primarily osteoclastic, osteoblastic or mixed. As the technical ability to alter gene expression negatively or positively and in a tissue-specific and temporal manner continues to evolve, there are endless possibilities for generating genetically altered animal models with which to gain insight into metabolic bone diseases.
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PMID:Transgenic mouse models of metabolic bone disease. 1155 36

Lipophilic hormones of steroidal origin such as the sex hormones and 1,25-dihydroxy vitamin D(3) (1,25[OH](2)D(3)) function by regulating patterns of gene expression in cells. The mediators of such actions are nuclear receptors that recognize these ligands with high affinity and selectivity and function through several mechanisms as gene specific transcription factors. As a result of the mechanistic complexity of nuclear receptor action, recent studies have revealed that both synthetic analogs as well as novel mimetics of a receptor's natural hormonal ligand are capable of modulating functional responses in both cell- and gene-selective manners. These findings have given rise to the term selective receptor modulators, typified by such synthetic estrogen receptor ligands as tamoxifen and raloxifene. A number of vitamin D analogs have been prepared that appear to exhibit tissue-selective activity--most notable through their inability to induce levels of hypercalcemia typical of the activity of the natural hormone 1,25(OH)(2)D(3). Because this debilitating yet normal feature of the natural ligand limits its usefulness in a variety of clinical indications, including its application to prevent bone disease caused by secondary hyperparathyroidism, this feature of many of the new analogs is especially welcome. This article discusses what constitutes a selective receptor modulator and whether the current vitamin D analogs represent such entities.
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PMID:Vitamin D receptor-mediated gene regulation mechanisms and current concepts of vitamin D analog selectivity. 1220 98

A variety of cancers are associated with bone. Primary tumors can arise in bone, common cancers, such as those of breast and prostate origin, metastasize to bone, and multiple myeloma neoplastic disease affects bone profoundly. The cellular and molecular mechanisms underlying these pathological processes are increasingly being understood. The interaction of tumor cells with bone cells, osteoblasts and osteoclasts, and with the bone local environment is a new promising direction in research, which should help to develop new therapies. In this article we will relate the newest developments in the molecular research to the pathology of the tumor bone disease. Potential new targets for drugs, aimed specifically at tumor bone diseases, will be highlighted. Furthermore, we will describe the existing compounds that are either used in treatment or have a potential as therapeutic agents, such as bisphosphonates, Src inhibitors, and selective estrogen receptor modulators.
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PMID:Tumor bone diseases: molecular mechanisms and opportunities for novel treatments. 1267 61

Inflammatory bowel diseases, most frequently Crohn's disease, are frequently accompanied by decreased bone mineral content (30-70%). The osteopenia is not explained by the side effects of treatment or the secondary malabsorption. There must be a common pathological pathway in the background. The mineral content of bones is most easily measured by dual-ray absorptiometry. The measurement should be performed at the time of the diagnosis of bowel disease. It is useful to perform some routine laboratory examinations (serum calcium and phosphate, urinary calcium excretion level, etc.) and some special tests (serum osteocalcin and crosslaps) to exclude some other pathological pathways as well as to plan the anti-osteoporotic therapy. Appropriate calcium and vitamin-D supplementation is essential in prevention and therapy as well. Several drug-classes have proven useful in the therapy of severe osteoporosis associated with inflammatory bowel diseases such as bisphosphonates, hormone replacement therapy, selective estrogen receptor modulators and calcitonin. The authors provide an algorithm for the therapy of metabolic bone disease in inflammatory bowel disease.
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PMID:[Osteoporosis associated with inflammatory bowel diseases]. 1520 26

Osteoporosis is the most common metabolic bone disorder and remains an increasingly significant problem, affecting 200 million individuals worldwide. Osteoporosis often is undertreated and underrecognized, in part because it is a clinically silent disease until it manifests in the form of fracture. Sufficient recognition of the disease and its appropriate medical and nonmedical treatment are essential. Treatments including calcium and vitamin D, the bisphosphonates, estrogen, selective estrogen receptor modulators, calcitonin, parathyroid hormone, balance and exercise training programs, and the minimally invasive spine procedures vertebroplasty and kyphoplasty comprise a comprehensive multidisciplinary approach in the treatment of osteoporosis. The data suggest that medical treatment of osteoporosis is increasing each year as physician awareness is heightened. Nonmedical treatment of osteoporosis complements the appropriate pharmacologic treatment, and these treatments should be used together to maximize outcomes for patients with osteoporosis. Fracture data for the intravenous biphosphonates and the long-term effects of the minimally-invasive spine procedures vertebroplasty and kyphoplasty have yet to be reported in the literature, but the effects on bone mineral density, and short-term results of these procedures, respectively, have been promising.
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PMID:Osteoporosis: a review. 1529 97


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