Molecular epidemiology of rabies epizootics in Texas

Glucocorticoids are potent osteopenic agents, producing negative calcium and bone balance via actions at many sites. The most significant adverse effects of glucocorticoid drugs on the skeleton are probably a direct inhibition of matrix synthesis by the osteoblast, reductions in calcium absorption in both the gut and the renal tubule, and the production of hypogonadism, particularly in men. Reductions in bone density of 10-40% result, the loss being more marked in trabecular bone and in patients receiving a high cumulative dose of the steroid. Fractures occur in about 30% of individuals who take these drugs for an average of 5 years. Bone loss is reversible when glucocorticoid treatment is withdrawn. Bone density can also be increased by sex hormone replacement in those with demonstrable deficiency, by bisphosphonates, and possibly by vitamin D metabolites. All patients treated with glucocorticoids for more than 6 months should be considered for bone densitometry and be offered appropriate drug treatment if values are towards the lower end of the young normal range or if there is already evidence of fractures occurring after minimal trauma. With this approach, the significant morbidity associated with steroid osteoporosis might be substantially avoided.     

Glucocorticoid-induced osteoporosis--mechanisms and preventions

It has been well known that patients with Cushing's syndrome have frequently osteoporosis or bone loss due to excess endogenous glucocorticoids and also osteopenia or osteoporosis is commonly observed in patients with long-term glucocorticoid therapy. In this paper, the mechanisms involved in bone loss in Cushing's syndrome and glucocorticoid-induced osteoporosis were demonstrated. In the patients with Cushing's syndrome, excess endogenous glucocorticoids increase bone resorption and decrease bone formation and also act to depress intestinal calcium absorption and increase urinary calcium excretion, leading to compensatory stimulation of parathyroid hormone secretion. Then, parathyroid hormone stimulates bone resorption. Thus, secondary osteoporosis is commonly observed due to excess glucocorticoid. Finally, preventions and managements for glucocorticoid-induced osteoporosis were discussed.     

Osteoporosis: pathogenesis, diagnosis, and treatment in older adults

Prevention of osteoporosis is a major health concern. Bone loss occurs throughout life in both women and men due to calcium deficiency, hormonal deficiency, and changes in bone formation. The diagnosis of osteoporosis can now be made prior to fragility fracture, allowing for prevention as well as treatment. Criteria for diagnosis of osteoporosis are reviewed, and a plan for the evaluation of secondary causes of osteoporosis is discussed. Also reviewed are prevention and treatment options such as exercise, calcium supplementation, hormone replacement, and new and investigational drugs.     

Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado-Joseph disease

Glucocorticoids (GC) are widely used for anti-inflammatory and immunosuppressive therapy. Thirty to 50% of GC-treated patients develop osteoporosis. Potential mechanisms of GC-induced osteoporosis (GC-OP) include abnormalities in calcium balance, vitamin D metabolism, parathyroid hormone release and activity, prostaglandin E2 and cytokine synthesis, interference with c-fos and p-53 expression in osteoblasts, and hypogonadism. Early diagnosis and detection of patients at risk are accomplished with rapid, safe and non-invasive bone density measurements. Preventive measures include maintaining a positive calcium balance, vitamin D supplementation (if indicated) and treatment of hypogonadism. The shortest duration and the smallest doses possible of GC for a particular condition are advisable. For high-risk patients and those with established GC-OP calcitonin or bisphosphonate therapy is recommended.     

Requirement for multiple lymphocyte subsets in protection by a live attenuated vaccine against retroviral infection

STUDY DESIGN: A case report and literature review of thoracic hyperkyphosis deformity secondary to glucocorticoid-induced osteoporosis in Cushing's disease. OBJECTIVES: To identify the pathophysiology of glucocorticoid-induced osteoporosis and to outline the diagnosis and treatment options for a patient with severe spinal deformity secondary to unrecognized excess glucocorticoid activity. SUMMARY OF BACKGROUND DATA: Glucocorticoid-induced osteoporosis is seen in patients exposed to supraphysiologic levels of endogenous or exogenously administered glucocorticoids. In these patients, glucocorticoids act to suppress bone formation and increase bone resorption by indirect and direct effects. These patients have a high prevalence of trabecular bone loss, resulting in much higher rates of vertebral body collapse and pathologic fracture and thus causing an increased propensity toward kyphotic spinal malalignment. METHODS: The literature was reviewed and case reports studied. This case report highlights the pathophysiology of the disease process that caused the spinal deformity and the surgical intervention used to correct the kyphotic deformity after the metabolic problem was resolved. RESULTS: This patient has responded well to treatment and surgical intervention to correct a thoracic hyperkyphotic deformity without complication. CONCLUSIONS: Unrecognized endogenous production of glucocorticoids in Cushing's disease should be considered in young adult patients with progressive osteoporotic spinal deformities.     

Inflammation and bone metabolism in rheumatoid arthritis. Pathogenetic viewpoints and therapeutic possibilities

BACKGROUND: Systemic osteoporosis is a common and pathogenetically heterogenous complication in rheumatoid arthritis. Various factors such as disease activity, dosage and duration of glucocorticoid treatment and immobilization are involved in pathogenesis of osteoporosis in rheumatoid arthritis. INFLAMMATION AND BONE METABOLISM: Proinflammatory cytokines secreted by immunocompetent cells have a role in the regulation of the activity of osteoblasts and osteoclasts. The effects of these proinflammatory cytokines include the inhibition of bone formation and an increase in bone resorption. Interleukin-6 and nitric oxide induced in osteoblasts by proinflammatory cytokines are likely to be important mediators between these cytokines and the function of osteoblasts and osteoclasts. Furthermore, disease activity dependent changes in the secretion of glucocorticoids and in vitamin D metabolism may be involved in the pathogenesis of osteoporosis in this disease. Alteration of bone remodeling associated with immobilization is an important factor of systemic bone loss in rheumatoid arthritis. CONCLUSION: The inflammatory process in rheumatoid arthritis may cause penarticular and systemic bone loss by various cytokine and hormone mediated mechanisms. Concluding from these pathogenetic mechanisms, bisphosphonates and active vitamin D metabolites are likely to be effective therapeutic options in osteoporosis associated with rheumatoid arthritis.     

Relation to osteoporosis of age- and hormone-induced changes in the metabolism of collagen and bone

Experimental evidence is presented which suggests that age-induced changes in the collagenous matrix, the main constituent of the organic portion of bones, are at least partially responsible for age-induced physiological osteoporotic changes in the skeleton. In particular, there seems to be a labile fraction of recently synthesized collagen in bones, which loses its metabolic activity rapidly with advancing age. Experimental and clinical hormonal disorders and disturbances in calcium metabolism also cause changes in skeletal metabolism; these changes seem to be largely mediated through changes in the collagenous matrix. In experimental hyperthyroidism and hyperparathyroidism, the rate of degradation of the collagenous matrix appears to act as a moderator or "final messenger" in hormone-induced bone resorption. In conditions with altered calcium metabolism, such as malabsorption associated with hypocalcemia, altered bone metabolism may be due to osteomalacia or hypocalcemia-induced hyperparathyroidism. An increase in the rate of bone destruction in relation to the rate of bone formation is probably also the cause of postmenopausal osteoporosis. At present there is no optimal form of hormonal treatment for age-induced or post menopausal osteoporosis. Estrogen replacement therapy may be the best available treatment for postmenopausal osteoporosis, but slowing down the already low rate of bone catabolism in elderly subjects by estrogen or other therapeutic means requires long periods of treatment before pronounced increases in the total mass of bones take place and prophylactic administration of estrogen may produce better results.     

Prevention of osteoporosis

The European Parliament presented June 10th in Brussels the 'Osteoporosis Report in EU--Means for Prevention'. It was emphasized that in the EU more than 3500 million Ecu have to be spent for hospitalization and that more than 500,000 hospitals beds are being used by osteoporotic patients. According to some calculations this number will double within the next 50 years. The EU has set up eight steps to be considered, e.g. have densitometric measurements available for persons with high risk and have these measurement paid by the insurances to further finance and support research for the very important areas of prevention and treatment. One distinguishes between primary, secondary and tertiary prevention of osteoporosis. Primary prevention aims at reaching at adolescent age a peak bone mass as high as possible. Secondary prevention aims at reducing bone loss peri- and postmenopausal. The tertiary prevention with manifest osteoporosis aims at preventing fractures. Emphasis of the primary prevention is, besides a sufficient calcium intake, to omit risk factors; with secondary prevention the use of medical treatments such as estrogens/gestagens, bisphosphonates, and recently also SERMs is applied. The tertiary prevention tries mostly to reduce the femur fractures. In addition to drugs such as vitamin D/calcium, vitamin D metabolites and bisphosphonates it is very important to create 'a fall-proof home'. Also very useful are hip protectors.     

Osteoporosis in men. New insights into aetiology, pathogenesis, prevention and management

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.     

Ultrastructural evaluation of the interaction of glucocorticoids and vitamin D on bone cells in thyroparathyroidectomized rats

To determine the direct effects of cortisol on bone, rats were thyroparathyroidectomized (T(X)PT(X)), fed a low-calcium diet, and given high (50 mg/kg) or low (8 mg/kg) pharmacologic levels of cortisol with or without excess vitamin D3 (15,000 IU). Rats given vitamin D had osteoblasts and osteocytes interpreted ultrastructurally to be actively engaged in matrix synthesis, mineralization of matrix, and in calcium mobilization. Osteoclasts were numerous on metaphyseal trabeculae and in vascular channels of cortical bone. In T(X)PT(X) rats not given vitamin D, osteoblasts and osteocytes were interpreted to have reduced metabolic activity with minimal evidence of participation in bone formation or resorption. Cortisol at both dose levels failed to alter the electron microscopic appearance of osteoblasts, osteocytes, and osteoclasts with or without vitamin D. Bone turnover indicated by urinary hydroxyproline excretion was unaffected by cortisol treatment. These findings suggest that glucocorticoids have little direct action on bone cells and that their effects on calcium metabolism are probably mediated by an interference in intestinal calcium transport and by secondary hyperparathyroidism.     

Calcium metabolism, osteoporosis and essential fatty acids: a review

Essential fatty acid (EFA)-deficient animals develop severe osteoporosis coupled with increased renal and arterial calcification. This picture is similar to that seen in osteoporosis in the elderly, where the loss of bone calcium is associated with ectopic calcification of other tissues, particularly the arteries and the kidneys. Recent mortality studies indicate that the ectopic calcification may be considerably more dangerous than the osteoporosis itself, since the great majority of excess deaths in women with osteoporosis are vascular and unrelated to fractures or other bone abnormalities. EFAs have now been shown to increase calcium absorption from the gut, in part by enhancing the effects of vitamin D, to reduce urinary excretion of calcium, to increase calcium deposition in bone and improve bone strength and to enhance the synthesis of bone collagen. These desirable actions are associated with reduced ectopic calcification. The interaction between EFA and calcium metabolism deserves further investigation since it may offer novel approaches to osteoporosis and also to the ectopic calcification associated with osteoporosis which seems to be responsible for so many deaths.     

Emergency management of a monstrous inguinal hernia

The risk of osteoporosis is increased in patients with inflammatory bowel disease: particularly in those with additional strong risk factors such as glucocorticoid therapy, hypogonadism, past history of fragility fracture or malnutrition. Where possible, bone densitometry should be performed to identify those in need of treatment, to avoid unnecessary treatment if bone density is normal and to monitor the effects of treatment designed to prevent bone loss. If bone densitometry is not available, treatment should be advised on the basis of strong risk factors. Hormone replacement therapy should be given to patients with hypogonadism and bisphosphonate therapy to those receiving long-term glucocorticoid treatment. The dose of glucocorticoids should be kept to a minimum and, where present, vitamin D deficiency should be corrected.     

Estrogens and bone metabolism

The authors present a review referring to cellular and biochemical control systems of bone remodeling as well as the effect of estrogens on modulation of bone metabolism. Systemic and local control factors such as PTH, calcitonin, vitamin D, prostaglandins, insulin-like growth factor-1, transforming growth factor-beta are analyzed as possible indirect targets for the estrogen induced inhibition of bone resorption. A direct receptor-linked action of estrogens on the osteoblast-lining cell unit, the most important modulator or bone metabolism, is furtherwise examined. The precise mechanism of the beneficial effect of estrogens for the prevention of postmenopausal bone loss and the treatment of established osteoporosis has not yet been clearly identified, but it seems likely that multiple mechanisms may be involved since postmenopausal osteoporosis itself appears as a heterogenic clinical condition related to multiple pathogenetic factors.     

Inflammatory bowel disease and osteoporosis

The relation between inflammatory bowel disease (IBD) and osteoporosis has received increasing attention during the past decade. The prevalence of low bone mass in patients with IBD has been reported to be more than 50%. The development of a quick non-invasive method to diagnose osteoporosis (dual-energy X-ray absorptiometry) provides a practical tool to identify the patient who needs special attention. The aetiology of the bone disease in patients with IBD has still not been elucidated, but corticosteroids may play a major role. Studies on the prevention/treatment of IBD-related osteoporosis are scarce. In a single uncontrolled study hormone replacement therapy proved effective in preventing bone loss in peri- and post-menopausal women with IBD. A placebo-controlled study showed that supplementation with calcium and vitamin D prevents bone loss in patients with Crohn's disease. The present paper reviews our current knowledge on the mechanisms and epidemiology of IBD-related bone disease.     

Osteoporosis in rheumatoid arthritis

Patients with rheumatoid arthritis (RA) develop both periarticular and generalized osteoporosis. Periarticular osteopenia in appendicular bones occurs early in the course of RA and is one of the earliest radiological signs of RA. An uncoupled state in bone resorption-formation linkage, contributes to the development of periarticular osteopenia and it might be mediated through an increased productions of cytokines and prostaglandins by synovium and bone marrow. Accordingly, early suppression of rheumatoid synovitis is necessary for the prevention of periarticular osteopenia. Generalized osteoporosis is also common in RA and leads to increased risk of fractures. Generalized osteoporosis considered to be multifactorial and factors contributing to lumbar osteoporosis might be different from those to loss of appendicular bones, such as femur and radius. Corticosteroids and menopausal state are important risk factors for lumbar osteoporosis. Rheumatoid activity and reduced physical activity are also important determinants. According to the previous studies, however, the influence of functional impairment is more prominent in the femoral BMD compared to spinal BMD. In addition to control of RA and maintenance of physical activity, hormone replacement therapy (HRT) and bisphosphonate are possible agents for the treatment of osteoporosis in RA patients, especially postmenopausal women.     

Detecting osteoporosis. Beyond the history and physical examination

A number of developments are contributing to clinicians' understanding of osteoporosis as a clinical continuum characterized by low bone mass and increased risk of fractures rather than as a disease characterized by fragility fractures. With improved capability for accurate measurement of bone mass, the prevalence of this disease has increased to include at least 25 million Americans. The responsibility of primary care physicians to detect and treat osteoporosis has increased accordingly. Parents should be counseled regarding their children's diet and lifestyle to optimize peak adult bone mass and ensure adequate dietary calcium intake. Adults should be counseled to minimize behaviors that result in accelerated bone loss (e.g., smoking, alcohol use, anorexia, bulimia). Physicians need to be aware of the serious potential complications of osteoporosis and offer counseling to menopausal women about the disease and the benefits and risks of hormone replacement and estrogen replacement therapy. Physicians should be familiar with technologies available in their community for measuring bone mass and recognize the need to consider prescribing pharmacologic and nonpharmacologic therapies for patients with low bone mass or osteoporosis. Physicians also can educate caregivers about prevention of falls and fractures in elderly patients who are unsteady on their feet. Improved technologies for bone mass measurement and fracture risk assessment, as well as expanded options for treatment and prevention of osteoporosis, are likely to become available within the next 5 to 10 years, thereby increasing the wisdom of early detection and treatment of osteoporosis.     

Pure red cell aplasia and myasthenia gravis with thymoma: a case report and review of the literature

In women, osteoporosis with fractures can happen between 50 years, the age of the menopause, and 80 years. Over these three decades, the condition of bone metabolism is not the same. The years after menopause present with high bone turnover. During these years, the administration of antiresorptive drugs is promising: Estrogens (plus progestagens), calcitonins, bisphosphonates. About 10 years after the menopause bone turnover slows down to low turnover. Now the administration of bone-formation stimulating agents is to be preferred: fluorides in the first line, perhaps anabolics in single cases. The prominent fracture of women older than 75 years is the hip fracture (type II osteoporosis). Bone turnover mostly is accelerated again, now due to secondary hyperparathyroidism as a consequence of long-lasting calcium and vitamin D deficiency. For treatment, calcium plus vitamin D is recommended. The exact diagnosis of the metabolic status of the skeleton is a prerequisite for the choice of the optimal therapeutic principle.     

Corticosteroid osteoporosis in the adult]

EARLY BONE LOSS: Bone loss is greatest in patients given supra-physiological doses of corticosteroids during the first months of treatment. The rate of loss then tapers off but persists throughout the duration of the treatment because of depressed osteoblast activity. EVALUATE THE RISK: Corticosteroid-induced osteoporosis is a multifactorial phenomenon depending in part on the duration and the dose of the treatment and in part on prior bone status and the causal disease. Young subjects can expect to recover bone mass partially or completely after withdrawal. Menopaused women not taking hormone replacement therapy have a low bone mass and are high risk patients. PREVENTION: Preventive measures against corticosteroid-induced osteoporosis should begin with treatment onset. Patients should be given calcium and vitamin D supplements, hormone replacement therapy (menopaused women) or androgens (hypogonadic men), and biphosphonates (for young patients at risk or in case of bone mass despite the preceding measures).     

Odontogenic focus as the etiology of cerebral ischemia]

Several authors have established a relationship between osteoporosis and periodontal disease. The ageing process is associated with a loss of both oral and total bone mass. It has been shown that a reduction of bone mineralization aggravates pathological periodontal changes, resulting in less support for the teeth. The present study investigates the nutritional influences that may condition the appearance of both pathological process. Insufficient dietary calcium and a reduction in the calcium: phosphorous ratio may favour the appearance of both these conditions by promoting bone reabsorption. Bone loss affects the following in descending order: jaw bones (especially alveolar bone), cranial bones, ribs, vertebrae and long bones. Alveolar bone which has the highest rate of renewal, is affected first and consequently is the most severely affected in the long term. The role of calcium in the etiology of osteoporosis is a controversial issue. Nevertheless, its implication has been proven in numerous investigations. The effect of adequate calcium intake on dental health has formed the basis of several recent studies. These investigations have demonstrated that increased calcium intake improves the suffering of inflammatory processes and tooth mobility in patients suffering from gingivitis with haemorrhaging. Based on the results of studies which link dietary calcium and phosphorous to the risk of osteoporosis and periodontal disease, and bearing in mind that in a large proportion of the Spanish population calcium intake is below that recommended, there is a need for a general improvement of the diet. It may be of special interest to increase the calcium intake of patients suffering periodontal disease. It may also help in the prevention of osteoporosis.     

Treatment of osteoporosis with bisphosphonates

Several bisphosphonates are effective for preventing bone loss associated with estrogen deficiency, glucocorticoid treatment, and immobilization, and for at least partially reversing bone loss in patients with postmenopausal osteoporosis and steroid-induced osteoporosis. The most promising of these agents are etidronate, alendronate, risedronate, and ibandronate. These drugs should have an important role in the prevention and treatment of osteoporosis; however, more research is needed regarding optimal doses and regimens (continuous versus intermittent, oral versus parenteral), comparisons with other agents, and their use in combination with other agents.