Selection of individuals for prevention of fractures due to bone fragility.

Most patients with fractures go untreated because of the lack of awareness of osteoporosis. Treatment is indicated for women and men with osteoporosis and women and men with fractures with either osteoporosis or osteopenia because (a) fractures increase morbidity and mortality, (b) the burden of fractures is increasing because longevity is increasing, and (c) bone loss accelerates, rather than decelerates in old age. The indication for drug therapy is less clear in women or men with osteopenia because drugs have not been proved to reduce fracture risk in this group. There is no evidence that treating individuals with only risk factors reduces the fracture rate. Screening has not been shown to reduce the burden of fractures. Altering the bone mineral density by a few percent in the population is likely to reduce the number of fractures, but how this can be achieved is unknown. The rigorously investigated drugs reducing the spine fracture rate are alendronate, raloxifene and risedronate. Calcium and vitamin D reduce hip fractures in nursing home residents but not community-dwellers. In the community, only alendronate and risedronate have been reported to reduce hip fractures in randomized trials. The evidence for hormone replacement therapy is less satisfactory. It is likely to reduce the number of spinal fractures, but its role in hip fracture prevention is uncertain. Only alendronate has been reported to reduce spine fractures in men with osteoporosis. Evidence for the use of other drugs (calcitonin, fluoride, anabolic steroids and active vitamin D metabolites) in women or men is insufficient to justify their use.     

Steroid induced osteoporosis: prevention and treatment

PURPOSE: Corticosteroid induced osteoporosis (CIO) is the most frequent complication of long-term corticosteroid therapy, and the most frequent cause of secondary osteoporosis. New data from biological, epidemiological and therapeutic studies provide basis for optimal management of this bone disease. MAIN POINTS: Corticosteroids are responsible for both quantitative and qualitative deleterious effects on bone, through their effect on bone cells, mainly on osteoblasts (with both a decrease in osteoblast activity and an increase in apoptosis). Epidemiological studies have shown an increased risk of fractures related to CIO, even for low doses, and during the first 6 months of treatment. Relative risk is 1.3 and 2.6 for peripheral and vertebral fractures respectively. Bone mineral density, measured by dual-energy X-ray absorptiometry, is decreased at spine and hip; the risk of fracture is higher in CIO as compared to post-menopausal osteoporosis, for a similar bone density. Prevention of CIO needs the use of the minimal efficacious dose, and treatment of calcium, vitamin D and gonadal hormones insufficiencies. Patients at risk of fracture, as post-menopausal women with prevalent fractures, should receive a bisphosphonate. PERSPECTIVE: It may be possible to reduce the fracture risk in patients on long-term corticosteroid therapy.     

Basics and management of glucocorticoid-induced osteoporosis

Glucocorticoids interfere with bone metabolism at different levels. Therefore, glucocorticoid-induced osteoporosis (GIO) is the most frequent form of secondary osteoporosis and up to 50 percent of patients on chronic glucocorticoid therapy suffer fractures. This is also because GIO is still under-diagnosed and not adequately treated. Besides, the fracture risk is higher in GIO than in primary osteoporosis even in the presence of equal bone mass density. The risk of osteoporotic fractures increases with dose and duration of glucocorticoid therapy, although the loss of bone mass is more prominent within the first three to twelve months after initiation of treatment. Besides glucocorticoid treatment, other factors, such as e.g. the underlying disease, substantially influence the fracture risk. Therefore, a diagnostic screening is mandatory in each case and should include the patient's history, physical examination, laboratory studies, evaluation of the bone-mass density by dual X-ray absorptiometry and imaging of the spine. Education of the patients and pharmacological prevention are very important, antiresorptive therapy has to be started earlier than in primary osteoporosis and osteoanabolic agents have also been proven to be effective.     

Grundlagen und Management der glukokortikoidinduzierten Osteoporose

Glucocorticoids interfere with bone metabolism at different levels. Therefore, glucocorticoid-induced osteoporosis (GIO) is the most frequent form of secondary osteoporosis and up to 50 percent of patients on chronic glucocorticoid therapy suffer fractures. This is also because GIO is still under-diagnosed and not adequately treated. Besides, the fracture risk is higher in GIO than in primary osteoporosis even in the presence of equal bone mass density. The risk of osteoporotic fractures increases with dose and duration of glucocorticoid therapy, although the loss of bone mass is more prominent within the first three to twelve months after initiation of treatment. Besides glucocorticoid treatment, other factors, such as e.g. the underlying disease, substantially influence the fracture risk. Therefore, a diagnostic screening is mandatory in each case and should include the patient’s history, physical examination, laboratory studies, evaluation of the bone-mass density by dual X-ray absorptiometry and imaging of the spine. Education of the patients and pharmacological prevention are very important, antiresorptive therapy has to be started earlier than in primary osteoporosis and osteoanabolic agents have also been proven to be effective.     

Prevention and treatment strategies for glucocorticoid-induced osteoporotic fractures

Glucocorticoids are the most common cause of drug-related osteoporosis. We reviewed current evidence on risk factors for glucocorticoid-induced osteoporosis (GIOP) and prevention and treatment of GIOP-related fractures. Guidelines for GIOP management published since 2000 were also reviewed. Significant bone loss and increased fracture risk is seen with daily prednisone doses as low as 5 mg. Alternate-day glucocorticoid therapy can lead to similar bone loss. No conclusive evidence exists for a safe minimum dose or duration of glucocorticoid exposure. Physicians should consider risk factors for involutional osteoporosis such as older age, postmenopausal status, and baseline bone density measurements as they assess patients for prevention or treatment of GIOP. Bisphosphonates were reported to reduce GIOP-related vertebral fractures, but inconclusive data exist for hip fractures associated with glucocorticoid use. Hormone replacement therapy and parathyroid hormone analogs are effective in preserving bone density in GIOP. The risk of osteoporosis and fractures should be routinely assessed in patients receiving glucocorticoid therapy. Effective prevention and treatment options are available and can result in meaningful reduction of GIOP-related morbidity and mortality. Current guidelines for GIOP management recommend bisphosphonates, especially alendronate and risedronate, as first-line agents for GIOP, and these guidelines propose the preventive use of bisphosphonates early in the course of glucocorticoid therapy in high-risk patient subgroups.     

Osteoporosis and osteoporotic fractures in men: a clinical perspective.

The lifetime risk of any fracture of the hip, spine or distal forearm in men aged 50 years has been estimated to be 13%, compared with 40% in women. Although the overall incidence of osteoporosis is less in men than in women, the disease still represents an important public health problem. In particular, hip fractures are associated with substantial mortality and morbidity, even more so than in women. In male patients presenting with osteoporotic fractures, major causes of skeletal fragility, such as hypogonadism, glucocorticoid excess, primary hyperparathyroidism and alcohol abuse, can often be identified. In as many as 50% of osteoporotic men, however, no aetiology can be found: these men suffer from a syndrome commonly referred to as idiopathic osteoporosis, which is presumably related to some type of osteoblast dysfunction. Recent evidence indicates that the loss of skeletal integrity in ageing men may be partially related to endocrine deficiencies, including vitamin D, androgen and/or oestrogen deficiency. While the consequences of vitamin D or oestrogen deficiency in women have been well established, the skeletal impact of these (partial) age-related deficiencies in men remains to be clarified. Osteoporosis in elderly men is a multifactorial disease, as it is in women. The prevention of osteoporosis should therefore focus not only on increasing the bone strength, but also on decreasing the risk of falls. However, the prevention and therapy of osteoporotic disorders in men are virtually unexplored. To date, the use of specific osteoporotic drugs in osteoporotic men is still based on reasonable but untested assumptions.     

Pattern of bone mineral density in idiopathic male osteoporosis

The mechanisms of male idiopathic osteoporosis are little known. We evaluated bone mineral loss by dual-energy X-ray absorptiometry and determined its cortical or trabecular nature in a cohort of men with idiopathic osteoporosis with fractures. Thirty-nine men (mean age 60?±?13?years), with negative investigations for the cause of osteoporosis, were studied. All had fragility fractures: vertebral 51%, peripheral 25%, and both types 24%. Bone density was measured at the lumbar spine (L2-L4), total hip and whole body. The limb/axial skeleton (spine?+?hips) and hip/L2-L4 BMD ratios were calculated. Serum 25-hydroxy-vitamin D, PTH, bone alkaline phosphatase and CTX were measured. Bone mineral loss predominated at the lumbar spine (mean L2-L4 T-score -3?±?0.93, mean total hip T-score -1.87?±?0.75). Limb/axial skeleton and total hip/L2-L4 BMD were strongly correlated, but not hip and spine BMD. The ratio values were widely scattered, indicating markedly heterogeneous bone loss. Vitamin D, PTH, bone alkaline phosphatase and CTX levels did not differ between predominantly trabecular and cortical osteoporosis. Bone mineral density measurement in male idiopathic osteoporosis with fractures demonstrated that bone loss predominated in the spine and that it was very heterogeneous, principally affecting cortical or trabecular bone depending on the patient.     

Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis

Glucocorticoid-induced bone loss should be prevented, and if present, should be treated (Table 2). Supplementation with calcium and vitamin D at a dosage of 800 IU/day, or an activated form of vitamin D (e.g., alfacalcidiol at 1 microg/day or calcitriol at 0.5 microg/day), should be offered to all patients receiving glucocorticoids, to restore normal calcium balance. This combination has been shown to maintain bone mass in patients receiving long-term low-to-medium-dose glucocorticoid therapy who have normal levels of gonadal hormones. However, while supplementation with calcium and vitamin D alone generally will not prevent bone loss in patients in whom medium-to-high-dose glucocorticoid therapy is being initiated, supplementation with calcium and an activated form of vitamin D will prevent bone loss. There are no data available to support any conclusion about the antifracture efficacy of the combination of calcium supplementation plus an activated form of vitamin D. Antiresorptive agents are effective in the treatment of glucocorticoid-induced bone loss. All of these agents either prevent bone loss or modestly increase lumbar spine bone mass and maintain hip bone mass. While there are no randomized controlled trials of prevention of glucocorticoid-induced bone loss or radiographic vertebral fracture outcomes with HRT or testosterone, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered HRT. The bisphosphonates are effective for both the prevention and the treatment of glucocorticoid-induced bone loss. Large studies have demonstrated that bisphosphonates also reduce the incidence of radiographic vertebral fractures in postmenopausal women with glucocorticoid-induced osteoporosis. Treatment with a bisphosphonate is recommended to prevent bone loss in all men and postmenopausal women in whom long-term glucocorticoid treatment at > or =5 mg/day is being initiated, as well as in men and postmenopausal women receiving long-term glucocorticoids in whom the BMD T-score at either the lumbar spine or the hip is below normal. While there is little information on the prevention or treatment of bone loss in premenopausal women, these women, too, may lose bone mass if they are being treated with glucocorticoids, so prevention of bone loss with antiresorptive agents should be considered. If bisphosphonate therapy is being considered for a premenopausal woman, she must be counseled regarding use of appropriate contraception. The therapies to prevent or treat glucocorticoid-induced bone loss should be continued as long as the patient is receiving glucocorticoids. Data from large studies of anabolic agents (e.g., PTH) and further studies of combination therapy in patients receiving glucocorticoids are eagerly awaited so additional options will be available for the prevention of this serious complication of glucocorticoid treatment.     

Approach to the prostate cancer patient with bone disease

Prostate cancer is the most common visceral malignancy in men. Androgen deprivation therapy (ADT) is commonly used in patients with nonmetastatic prostate cancer and is associated with significant bone loss and fractures. The greatest bone loss occurs during initiation of ADT. Men should have assessment of skeletal integrity with bone mineral density examination by dual x-ray absorptiometry of the hip and spine. Men with fragility fractures or osteoporosis by bone density should be considered for bisphosphonate therapy. Men with low bone mass may need antiresorptive therapy, depending on other risk factors. Men with a normal bone mineral density should be followed up closely with bone densitometry while on ADT. All men should receive preventive measures with calcium (1200 mg daily in divided doses), vitamin D (800-1000 IU/d), and weight-bearing exercise. Men should be evaluated for additional secondary causes of bone loss including vitamin D insufficiency. Guidelines are needed for androgen-induced bone loss screening and treatment.     

Leitliniengerechte Diagnostik und Therapie der Osteoporose 2010

Osteoporotic fractures are a frequent cause of disability and loss of quality of life in old age. Maintaining muscle function and balance, a daily calcium intake of 1000 mg, sufficient vitamin D and prudent use of drugs associated with falls and osteoporosis are key components to fracture prevention. The German guideline recommends that a specific long-term osteoporosis medication be initiated in individuals with a 30% 10-year risk for hip fractures and vertebral fractures.     

Skeletal morbidity in inflammatory bowel disease

Patients with Crohn's disease are at increased risk of developing disturbances in bone and mineral metabolism because of several factors, including the cytokine-mediated nature of the inflammatory bowel disease, the intestinal malabsorption resulting from disease activity or from extensive intestinal resection and the use of glucucorticoids to control disease activity. Inability to achieve peak bone mass when the disease starts in childhood, malnutrition, immobilization, low BMI, smoking and hypogonadism may also play a contributing role in the pathogenesis of bone loss. The relationship between long-term use of glucocorticoids for any disease indication and increased risk for osteoporosis and fractures is well established. However, the relationship between Crohn's disease and ulcerative colitis and bone loss remains controversial. Depending on the population studied the prevalence of osteoporosis has thus been variably reported to range from 12 to 42% in patients with inflammatory bowel disease (IBD). In IBD most studies demonstrate a negative correlation between bone mineral density (BMD) and glucocorticoid use, but not all authors agree on the relationship between long-term glucocorticoid use and continuing bone loss. Whereas prospective studies do suggest sustained bone loss at both trabecular and cortical sites in long-term glucocorticoid users with inflammatory bowel disease, a decrease in bone mass is also observed in patients with active Crohn's disease not using glucocorticoids, and bone loss is not universally observed in patients with Crohn's disease using orally or rectally administered glucocorticoids. Data on vertebral fractures are scarce and there is no agreement about the risk of non-vertebral fractures in patients with Crohn's disease, although it has been suggested that non-vertebral fracture risk may be increased by up to 60% in patients with IBD. A recent publication reports an increased risk of hip fractures in Crohn's disease related to current and cumulative corticosteroid use and use of opiates, although these fractures could not be related to the severity of osteoporosis. The issue of the magnitude of the problem of osteoporosis has become particularly relevant in Crohn's disease, since the ability of therapeutic interventions to beneficially influence skeletal morbidity has been clearly established in patients with osteoporosis, whether post-menopausal women, men or glucocorticoid users. The main question that arises is whether all patients with Crohn's disease should be treated with bone protective agents on the assumption that they all have the potential to develop osteoporosis or whether the use of these agents should be restricted to patients clearly at risk of osteoporosis and fractures, providing these can be identified. We recommend, based on the available literature and our own experience, that all patients with Crohn's disease should be screened for osteoporosis by means of a bone mineral density measurement in addition to full correction of any potential calcium and vitamin D deficiency, to allow timely therapeutic intervention of the patient at risk while sparing the vast majority unnecessary medical treatment.     

Treatment-related osteoporosis in men with prostate cancer

Osteoporosis is an important complication of androgen-deprivation therapy (ADT) for prostate cancer. ADT by either bilateral orchiectomies or treatment with a gonadotropin-releasing hormone (GnRH) agonist decreases bone mineral density (BMD) and increases the risk of fracture. Prospective data about treatment or prevention of osteoporosis in men with prostate cancer are limited. Supplemental calcium and vitamin D are recommended. Additional therapy may be warranted for men with osteoporosis or fractures. Intravenous pamidronate prevents bone loss in the hip and spine during ADT. Intravenous zoledronic acid not only prevents bone loss but also increases BMD. Alendronate is approved to treatmen with osteoporosis although the efficacy of alendronate or other oral bisphosphonates has not been evaluated during ADT. Additional prospective studies are needed to evaluate the long-term effects of bisphosphonates and other the rapies on fracture risk and disease-related outcomes.     

Osteoporosis: prophylaxis, diagnostics and therapy according to the guidelines

Osteoporotic fractures are a frequent cause of functional disabilities and loss of quality of life. Preventive measurements need to focus on training of muscle function and coordination, and adequate daily calcium and vitamin D supplementation; furthermore a regular check up for drugs associated with falls and osteoporosis. The German guideline recommends that a specific osteoporosis medication should be initiated in individuals with a 10-year risk for hip and vertebral fractures of 30%. This article presents the current guideline for osteoporosis including the actual updates.     

Efficacy,effectiveness and side effects of medications used to prevent fractures

There is an increasing number of effective therapies for fracture prevention in adults at risk of osteoporosis. However, shortcomings in the evidence underpinning our management of osteoporosis still exist. Evidence of antifracture efficacy in the groups of patients who most commonly use calcium and vitamin D supplements is lacking, the safety of calcium supplements is in doubt, and the safety and efficacy of high doses of vitamin D give cause for concern. Alendronate, risedronate, zoledronate and denosumab have been shown to prevent spine, nonspine and hip fractures; in addition, teriparatide and strontium ranelate prevent both spine and nonspine fractures, and raloxifene and ibandronate prevent spine fractures. However, most trials provide little information regarding long‐term efficacy or safety. A particular concern at present is the possibility that oral bisphosphonates might cause atypical femoral fractures. Observational data suggest that the incidence of this type of fracture increases steeply with duration of bisphosphonate use, resulting in concern that the benefit–risk balance may become negative in the long term, particularly in patients in whom the osteoporotic fracture risk is not high. Therefore, reappraisal of ongoing use of bisphosphonates after about 5 years is endorsed by expert consensus, and ‘drug holidays’ should be considered at this time. Further studies are needed to guide clinical practice in this area.     

Osteoporose

Osteoporotic fractures are a frequent cause of functional disabilities and loss of quality of life. Preventive measurements need to focus on training of muscle function and coordination, and adequate daily calcium and vitamin?D supplementation; furthermore a regular check up for drugs associated with falls and osteoporosis. The German guideline recommends that a specific osteoporosis medication should be initiated in individuals with a 10-year risk for hip and vertebral fractures of 30%. This article presents the current guideline for osteoporosis including the actual updates.     

Treatment of postmenopausal osteoporosis

The aim of treatment of postmenopausal osteoporosis is to reduce the frequency of vertebral and non-vertebral fractures (especially at the hip), which are responsible for morbidity associated with the disease. Results of large placebo controlled trials have shown that alendronate, raloxifene, risedronate, the 1-34 fragment of parathyroid hormone, and nasal calcitonin, greatly reduce the risk of vertebral fractures. Furthermore, a large reduction of non-vertebral fractures has been shown for alendronate, risedronate, and the 1-34 fragment of parathyroid hormone. Calcium and vitamin D supplementation is not sufficient to treat individuals with osteoporosis but is useful, especially in elderly women in care homes. Hormone replacement therapy remains a valuable option for the prevention of osteoporosis in early postmenopausal women. Choice of treatment depends on age, the presence or absence of prevalent fractures, especially at the spine, and the degree of bone mineral density measured at the spine and hip. Non-pharmacological interventions include adequate calcium intake and diet, selected exercise programmes, reduction of other risk factors for osteoporotic fractures, and reduction of the risk of falls in elderly individuals.     

Recognizing and treating glucocorticoid-induced osteoporosis in patients with pulmonary diseases

Glucocorticoids are frequently used to treat patients with pulmonary diseases, but continuous long-term use of glucocorticoids may lead to significant bone loss and an increased risk of fragility fractures. Patients with certain lung diseases, regardless of pharmacotherapy-particularly COPD and cystic fibrosis-and patients waiting for lung transplantation are also at increased risk of osteoporosis. Fragility fractures, especially of the hip, will have substantial effects on the health and well-being of older patients. Vertebral collapse and kyphosis secondary to glucocorticoid-induced osteoporosis (GIO) may affect lung function. Identification of patients with osteopenia, osteoporosis, or fragility fractures related to osteoporosis is strongly recommended and should lead to appropriate treatment. Prevention of GIO in patients receiving continuous oral glucocorticoids is also recommended. In patients receiving either high-dose inhaled glucocorticoids or low- to medium-dose inhaled glucocorticoids with frequent courses of oral glucocorticoids, bone mineral density measurements should be performed to screen for osteopenia and osteoporosis. A bisphosphonate (risedronate or alendronate), calcium and vitamin D supplementation, and lifestyle modifications are recommended for the prevention and treatment of GIO.     

Bone metabolism alterations after kidney transplantation

Early after renal transplantation (RT) a rapid decrease in bone mineral density at the lumbar spine, femoral neck, and femoral shaft has been documented. In addition, an appreciable proportion of patients still remain losing bone late after RT. As a consequence, RT patients are at a high risk of bone fractures as compared to general population. Most fractures involve appendicular skeleton, particularly the feet and ankles, and the diabetic patient is at increased risk of fractures. Thus, early institution of preventive measures and treatment of established osteoporosis are central. The major cause of post-transplantation bone loss is corticosteroid treatment, and this should be used at the lower dose compatible with graft survival. Preexisting hyperparathyroidism also affects the early cancellous bone loss at the spine, and post-transplantation bone loss reflects variable individual susceptibility, resembling the polygenic determination of bone mineral density in general. Clinical trials have demonstrated that bisphosphonates or vitamin D plus calcium supplementation, prevent post-transplantation bone loss during the first 6-12 months. However, their role in preventing bone fractures has not been proven. Finally, recommendations for management, prevention and treatment, are summarized.     

An update on glucocorticoid-induced osteoporosis

In general, bone loss from glucocorticoid treatment occurs rapidly within the first 6 months of therapy. Glucocorticoids alter bone metabolism by multiple pathways; however, the bone loss is greatest in areas rich in trabecular bone. Preventive measures should be initiated early. It is the author's opinion that all subjects initiating treatment with prednisone at 7.5 mg or greater require calcium supplementation (diet plus supplement) at a dose of 1500 mg and vitamin D at a dose of 400 to 800 IU/d. If the patient is going to remain on this dose of glucocorticoid for more than 4 weeks, an antiresorptive agent should be started (e.g., estrogen, bisphosphonate, raloxifene). If a patient has established osteoporosis and is either initiating glucocorticoid therapy or is chronically treated with prednisone at 5 mg d or greater in addition to calcium and vitamin D supplementation, a potent antiresorptive agent (bisphosphonate) should be started. A bone mineral density measurement of either the lumbar spine or the hip may be helpful is assessing an individual's risk of osteoporosis, may improve compliance with treatment, and can be used to monitor the efficacy of the prescribed therapy. There is no reason to withhold treatment for glucocorticoid-induced bone loss until a bone mass measurement is taken, however. In motivated patients, a weight-bearing and resistance exercise program should be prescribed to help retain muscle strength and prevent depression. If hypercalciuria develops with glucocorticoid use, either thiazide diuretics or sodium restriction may be helpful. In patients who continue to lose bone or experience fracture's despite antiresorptive therapy while on glucocorticoids, bone-building anabolic agents (e.g., hPTH 1-34 or PTH 1-84) may be available someday soon.     

Osteoporosis in males

A shorter life expectancy, a higher peak bone mass and the absence of distinct menopause equivalent explain the lower incidence of osteoporotic fractures in men. In contrast to women, osteoporosis in younger men is in most cases secondary. Causes such as prolonged glucocorticoid therapy, ethanol abuse, hypogonadism and gastrointestinal disorders are now well recognized. The impact of cigarette smoking, low calcium intake, vitamin D deficiency, hypercalciuria and thyrotoxicosis is more controversial but seems to constitute real risk factors for bone loss. Furthermore increased propensity to fall also plays a major role in fracture risk, particularly in alcoholic patients and in elderly men with neurologic disorders.